In Harm鈥檚 Way:
Toxic Threats
to Child
Development
A REPORT BY
Greater Boston Physicians
for Social Responsibility
Prepared for a Joint Project
with Clean Water Fund
In Harm鈥檚 Way:
Toxic Threats
to Child
Development
Principal Authors A REPORT BY
Greater Boston Physicians
Ted Schettler MD, MPH
for Social Responsibility
Jill Stein MD
Prepared for a Joint Project
Fay Reich PsyD
with Clean Water Fund
Maria Valenti
MAY, 2000
Contributing Author
David Wallinga MD
漏 2000 Greater Boston Physicians for Social Responsibility (GBPSR)
GBPSR grants permission to reprint properly credited excerpts from this book. Photography and
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Acknowledgements ORGANIZATIONS
Greater Boston Physicians for Social Responsibility
REVIEWERS (GBPSR) is an affiliate of Physicians for Social
Responsibility, a national organization of over 15,000
We gratefully acknowledge the following people who
reviewed draft sections or chapters of the report, and/or physicians, health care professionals and supporters who
are committed to the elimination of nuclear and other
the entire report, noting that their review does not
constitute an endorsement of the final findings or weapons of mass destruction, the preservation of a
sustainable environment, and the reduction of violence
conclusions of the report. Their insightful comments have
helped to strengthen its contents, and transform it into a and its causes. PSR is the national affiliate of International
Physicians for the Prevention of Nuclear War, recipient of
more accessible document.
the 1985 Nobel Peace Prize. GBPSR鈥檚 Human Health and
Mary Ampolla, Paul Burns, Jane Collins, Bobbie Gallagher,
the Environment Project (HHEP) was one of the first in the
Eric Hollander, Lee Ketelsen, Sharon Kreder, Philip Landrigan,
organization nationally to focus on the public health
Michael McCally, Edward F. MacNichol, Jr., Audrey McMahon,
consequences of environmental pollution. Since 1992 the
Betty Mekdeci, Elise Miller, Peggy Middaugh, Marybeth
HHEP has been active in educating the medical
Palmigiano, Deborah Rice, Sherry Sellors Vinson, Nancy
community on the linkages between environmental
Shapiro, Betsy Speicher, Joel Tickner, David Wallinga.
exposures and health, activating members to work to
protect public health, assisting grassroots groups with
CONTRIBUTORS
technical and scientific issues relating to human health
Special thanks to John Andrews for his editorial and
and environment issues, and participating in public policy
content contributions including numerous graphs and
debates. In addition to In Harm鈥檚 Way: Toxic Threats to
charts throughout the report. Also thanks to Elizabeth
Child Development, current projects include Generations
Guillette for allowing us to use her drawings from the
at Risk: Reproductive Health and the Environment; the
Yaqui Indian children鈥檚 study; to Liz Harriman for
Boston Sustainable Hospitals Project of Health Care
additional data from the Toxics Use Reduction Act
Without Harm, an organization that is working
Information Release; and to Paul Orum for additional
internationally to prevent pollution and the use of
data on issues related to the Toxics Release Inventory.
toxic products in the health care industry; and No
Room to Breathe, focusing on the health effects of
FUNDERS
air pollution. For information on other reports and
We sincerely thank the Trustees and Board members of materials available from GBPSR, please see our web site
the John Merck Fund, the Jessie B. Cox Charitable Trust, at http://www.igc.org/psr/
the W. Alton Jones Foundation, the Mitchell Kapor
Clean Water Fund (CWF) is a national nonprofit research
Foundation and the Alida R. Messinger Charitable Lead
and educational organization, with locally staffed
Trust for financial support for this work, which has made
environmental and health protection programs serving
this report and related educational materials possible. We
communities in over twenty states. CWF鈥檚 mission is to
are especially grateful to Ruth Hennig of the John Merck
develop strong grassroots environmental leadership and
Fund who has been an invaluable and tireless ally in
to bring together diverse constituencies to work
shepherding this work, and to Rachel Pohl of the Jessie
cooperatively for changes that improve their lives,
B. Cox Charitable Trust for her long-term support and
focused on health, consumer, environmental and
valuable advice.
community problems. Since 1978, CWF has helped people
AUTHORS campaign successfully for cleaner and safer water, cleaner
air, and protection from toxic pollution in our homes,
This report was prepared by Drs. Ted Schettler and Jill Stein serve
neighborhoods and workplaces. Organizations and
on the Steering Committee of GBPSR
Greater Boston Physicians for coalitions formed and assisted by CWF have worked
and co-chair GBPSR鈥檚 Human Health
Social Responsibility for a joint together to improve environmental conditions, prevent or
and Environment Project. Ted Schettler
clean up health-threatening pollution in hundreds of
educational project with Clean is Science Director of the Science and
communities and to strengthen policies locally and
Environmental Health Network. Maria
Water Fund. Primary goals of nationally. CWF鈥檚 programs build on and complement
Valenti is GBPSR鈥檚 Environmental
the project include the examination those of Clean Water Action, a 700,000-member national
Program Director. Dr. Fay Reich is a
organization which has helped develop, pass, strengthen
of environmental contributors consultant to GBPSR. Dr. David Wallinga
and defend the nation鈥檚 major water and toxics laws such as
is Senior Scientist, Public Health Program,
to learning, behavioral and the Clean Water Act, Safe Drinking Water Act, Superfund
Natural Resources Defense Council.
developmental disabilities, and and others, including their state-level counterparts.
PRODUCTION
education about the preventable Clean Water Fund
nature of these exposures. Graphic design and illustration by Stephen 4455 Connecticut Ave., NW, Suite A300
Burdick, photography by Robert Burdick.
Washington, DC 20008
Printing by Red Sun Press, Boston.
http://www.cleanwater.org
ii I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
Table of Contents
CHAPTER PAGE
Foreword by Philip Landrigan MD, MSc ................................................................................................... v
Executive Summary .............................................................................................................................. 1
Chapter I: Nature of the Problem ............................................................................................................. 9
Illustrations: Framework for Understanding
Bioaccumulation
Charts/Graphs: Population Effects of Small I.Q. Shift
Declining Threshold of Harm 鈥? Mercury
Spotlights: Missing: National Registry for Developmental Disabilities
Citizen Database Fills Government Void
Chapter 2: Normal Brain Development and Developmental Toxicology ............................................. 23
Illustrations: Neuronal Migration
Synapse
Chapter 3: The Spectrum of Developmental Disorders and Their Public Health Impact .................... 29
Graphics/Charts: Developmental Disorders: Conventional Classifications Chart
Spectrum of Disorders
Chapter 4: The Long Road from Research to Real Life ......................................................................... 43
Chapter 5: The Multiple Causes of Disabilities ...................................................................................... 49
Illustration: Environmental Influences on Development
Graphics/Charts: Spectrum of Vulnerability
Chapter 6: Known and Suspected Developmental Neurotoxicants .................................................... 59
Illustrations: Factory to Fetus鈥? Dioxins and PCBs
Yaqui Children Drawings
Graphics/Charts: Mercury鈥? Inadequate Margin of Safety
Dioxin Exposures
Dioxin - Inadequate Margin of Safety
PCBs- Inadequate Margin of Safety
Toxicant and Health Effects Chart
Spotlight: How Much Mercury in My Tuna Sandwich?
Glossary: Tests of Behavior and Learning in Animals
Chapter 7: Chemicals, Regulations and the Environment .................................................................. 103
Graphics/Charts: Toxics Release Inventory (TRI) Neurotoxicants
Toxics Use Reduction Act (TURA) Neurotoxicants
Increase in Lead Use - TURA
Spotlight: Autism Cluster Sparks Study of Environment
Chapter 8: Conclusions .......................................................................................................................... 117
Illustration: Tip of the Iceberg
Graphics/Charts: Proving Harm
Appendix: Clinical Spectrum of Developmental Disorders ................................................................ 123
Greater Boston Physicians for Social Responsibility iii
iv I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
FOREWORD
Foreword
T he intersection between environmental that subtle changes in the concentrations
chemicals and child development is of normally occurring chemicals such as
a new area of public health science. It hormones鈥攁s well as the presence of
is only in the past few years that we toxic agents like lead, mercury or PCBs鈥?
have begun to grasp the potential health can produce profound and permanent
effects of even slight disturbances in changes in the developing nervous system.
child development. So much hinges These changes can lead to decrements in
on understanding the effects of mental performance and alterations of
environmental chemicals on these the reproductive system.
processes: developmental disabilities, A picture is unfolding supported
including attention deficit/hyperactivity by a variety of laboratory, clinical and
disorder, autism, and related neurodevel- epidemiological research that suggests
opmental diseases, affect millions of that neurotoxic chemicals in the environ-
American children. The consequences of ment may play a role in developmental
these disorders are often tragic. The familial,
disabilities. The implications of this notion
societal and economic costs are immense, are profound. If we can understand the
and the disabilities can be life-long. role of environmental chemicals in neuro-
In the last two decades there has developmental disorders, we can take
been an explosion of neurobiological concrete steps toward the prevention of
research into attention, memory and these disorders. By reducing and eliminat-
other cognitive functions. In addition, ing exposures to specific environmental
the patterns and stages of normal brain chemicals through the use of regulatory
development are now well understood. bans, development and promotion of
This new knowledge has given us a better alternative agents and exposure minimi-
understanding of the special vulnerability zation, we may, in time, be able to reduce
of the developing nervous system to the the occurrence of neurodevelopmental
internal chemical environment. It is now disability. We may even be able to prevent
clear from studies of animals and children some disabilities from ever again limiting
a child鈥檚 potential, an extraordinary prospect.
Greater Boston Physicians for Social Responsibility v
FOREWORD
Yet such potential is often obscured learning disability? When does inatten-
by a voluminous and at times confusing tion qualify as attention deficit hyper-
scientific literature. In Harm鈥檚 Way is an activity disorder? While clinicians have
analysis of that literature. Ted Schettler devised ways of answering these and
and his co-authors have prepared a text other similar questions, the labeling
on neurodevelopmental disorders and problem remains at the heart of efforts to
environmental chemicals that makes a understand patterns of neurobehavioral
complex body of scientific information disabilities. The most basic of public
accessible to health professionals and the health research efforts鈥攁 simple count
scientifically literate general public. of the number of cases鈥攑ersists as a
stumbling block, fraught with contested
The authors elucidate the evidence
assumptions and rival criteria.
for specific scientific claims and help
readers understand what is known and As one example of its eminently
what is conjectured. They begin with trenchant analysis, In Harm鈥檚 Way
two linked observations: (1) that develop- carefully reviews the labeling problem
mental disabilities are common in such that clinicians, basic scientists, policy
American children; and (2) that the makers, advocates, and parents can forge
causes of these disabilities are largely shared understanding. Such is the useful-
unknown. In Harm鈥檚 Way presents an ness of In Harm鈥檚 Way. Throughout, it
elegant discussion of normal brain identifies some of the areas of greatest
development and explores why these confusion in this new field, and delineates
developmental processes are so vulner- the underlying logic and lines of evidence.
able to environmental insult. It goes on As a result, this book is sure to inform
to highlight a series of case studies describ- discussions among representatives of
ing chemicals in the environment that widely varying disciplines.
are known to disrupt brain development We stand at the brink of an era that
in laboratory animals and in children. will almost certainly see the identifi-
One of the difficulties in talking cation of the causes of a wide range of
about neurodevelopmental disabilities neurobehavioral disorders. It will also
is that these disorders are not easily enable preventive measures to be taken.
defined. They do not lend themselves to In Harm鈥檚 Way has clarified a starting point
simple diagnostic tests like blood sugar for this next era of environmental health.
in diabetes or the EEG in epilepsy. They Not-for-profit health advocacy
are defined in loose clinical or behavioral organizations are now major players in
terms and often present as a range or health and environmental policy making.
spectrum of behaviors. At what point is The successful passage of the Clean Air
difficulty learning diagnosed as a Act Reauthorization in 1996 was
vi I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
FOREWORD
achieved by the efforts of advocacy
groups supporting the EPA. The
same organizations, known in the
United Nations as non-governmental
organization (NGOs), are now
participants in international treaty
negotiations. Previously excluded from
environmental health discussions in the
UN and the World Health Organization,
NGOs in the last 10 years have
achieved a place at the negotiating
table. To accomplish this, the not-for-
profit advocacy organizations have
become more effective politically edited by Eric Chivian, which gave
a broad overview of the connection
and more professional scientifically.
between health and global environ-
The best of these organizations are
mental change. In 1999, Ted Schettler
able to provide scientifically credible
and Maria Valenti, along with Gina
information as an alternative point of
Solomon and Annette Huddle, authored
view to government and industry. They
Generations at Risk: Reproductive
can synthesize and review data in what
Health and the Environment, in which
are often emerging fields with contra-
they analyzed the science of reproductive
dictory signposts. Nowhere are the
health damage by chemical pollution. In
benefits of this capability more evident
other professional capacities physicians
than in the field of environmental health.
associated with PSR have participated in
Experts from advocacy organizations
scientific analysis of the health effects of
now sit as scientific peers with represen-
global warming and reemerging infectious
tatives of government, academia and
disease as well as of biodiversity and
industry, as, for example, on the EPA鈥檚
species loss. With In Harm鈥檚 Way, PSR
recently concluded Endocrine Disruptor
lends its characteristic clarity to the field
Screening and Testing Advisory Committee.
of children鈥檚 environmental health. PSR鈥?
Physicians for Social Responsibility
both the Greater Boston Chapter and its
(PSR) is an NGO at the forefront of
National Office鈥攊s to be commended
efforts to establish for both the public
for commissioning this important work.
and for policy makers the present state
The present situation of
of the science in environmental health.
environmental health argues for
In 1994, PSR released Critical Condition:
precaution. We have apparently
Human Health and the Environment,
increasing incidence of significant
Greater Boston Physicians for Social Responsibility vii
FOREWARDR D
FOREWO
developmental disabilities. We have we must increase our understanding of
plausible biological mechanisms the neurotoxicity of chemical agents now
connecting environmental toxicants in the environment, and we must adopt
with health effects, as demonstrated in public health policies that limit the
laboratory animals. We have accumulat- exposure of fetuses and children to
ing evidence of neurotoxic damage to environmental chemicals.
children by environmental agents, such as Philip Landrigan MD, MSc
lead and PCBs. The authors of In Harm鈥檚 Director
The Center for Children鈥檚 Health and the Environment
Way provide compelling, scientifically
Mount Sinai School of Medicine
documented arguments laying out the New York, NY
next steps we as a society must take: April, 2000
viii I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
EXECUTIVE SUMMARY
Executive Summary
T his report examines the contribution since 1971 to reach its current
of toxic chemicals to neurodevelop- estimate of about 1.5 million.
mental, learning, and behavioral disabilities 鈥? Learning disabilities alone may
in children. These disabilities are clearly Toxic exposures
affect approximately 5-10% of
the result of complex interactions among deserve special
children in public schools.
genetic, environmental and social factors scrutiny because
鈥? The number of children in special
that impact children during vulnerable they are preventable
education programs classified with
periods of development. Toxic exposures causes of harm.
learning disabilities increased 191%
deserve special scrutiny because they are
from 1977-1994.
preventable causes of harm.
鈥? Approximately 1% of all children
1. An epidemic of developmental, are mentally retarded.
learning, and behavioral disabilities
鈥? The incidence of autism may be as
has become evident among children.
high as 2 per 1000 children. One
鈥? It is estimated that nearly 12 million study of autism prevalence between
children (17%) in the United States 1966 and 1997 showed a doubling
under age 18 suffer from one or of rates over that time frame. Within
more learning, developmental, the state of California, the number
or behavioral disabilities. of children entered into the autism
registry increased by 210% between
鈥? Attention deficit hyperactivity
1987 and 1998.
disorder (ADHD), according to
conservative estimates, affects 3 to These trends may reflect true
6% of all school children, though increases, improved detection, reporting
recent evidence suggests the or record keeping, or some combination
prevalence may be as high as 17%. of these factors. Whether new or newly
The number of children taking the recognized, these statistics suggest a
drug Ritalin for this disorder has problem of epidemic proportion.
roughly doubled every 4-7 years
Greater Boston Physicians for Social Responsibility 1
EXECUTIVE SUMMARY
2. Animal and human studies
demonstrate that a variety of
chemicals commonly encountered in
industry and the home can contribute
to developmental, learning, and
behavioral disabilities.
Developmental neurotoxicants are
chemicals that are toxic to the developing Manganese
brain. They include the metals lead, mercury, 鈥? Unlike many other metals, some
cadmium, and manganese; nicotine; manganese is essential as a catalyst
pesticides such as organophosphates and in several critically important
others that are widely used in homes and enzymatic processes. However,
schools; dioxin and PCBs that bioaccumu- several studies report a relationship
late in the food chain; and solvents, including between excessive childhood levels
ethanol and others used in paints, glues of manganese exposure and
and cleaning solutions. These chemicals hyperactivity or learning disabilities.
may be directly toxic to cells or interfere
Nicotine
with hormones (endocrine disruptors),
鈥? Children born to women who
neurotransmitters, or other growth factors.
smoke during pregnancy are at
Lead
risk for IQ deficits, learning
鈥? Increases in blood lead levels during disorders, and attention deficits.
infancy and childhood are associated
鈥? Children born to women who are
with attention deficits, increased
passively exposed to cigarette smoke
impulsiveness, reduced school
are also at risk for impaired speech,
performance, aggression, and
language skills, and intelligence.
delinquent behavior.
Dioxins and PCBs
鈥? Effects on learning are seen at
鈥? Monkeys exposed to dioxin
blood lead levels below those
as fetuses show evidence of
currently considered 鈥渟afe.鈥?
learning disabilities.
Mercury
鈥? Humans and animals exposed to
鈥? Large fetal exposures to methylmercury
low levels of PCBs as fetuses have
cause mental retardation, gait and
learning disabilities.
visual disturbances.
鈥? Children exposed to PCBs
鈥? Smaller fetal exposures, such as
during fetal life show IQ deficits,
those resulting from regular
hyperactivity, and attention deficits
maternal fish consumption, have
when tested years later.
been implicated in language,
attention, and memory impairments
that appear to be permanent.
2 I N H A R M 鈥? S W AY : To x i c T h re a t s t o C h i l d D e v e l o p m e n t
EXECUTIVE SUMMARY
鈥? Animal and limited human studies
Pesticides
show that exposures to common
鈥? Animal tests of pesticides
chemicals like toluene,
belonging to the commonly-used
trichloroethylene, xylene, and styrene
organophosphate class of chemicals
during pregnancy can also cause
show that small single doses on a
learning deficiencies and altered
critical day of development can cause
behavior in offspring, particularly
hyperactivity and permanent changes
after fairly large exposures.
in neurotransmitter receptor levels in
the brain. 3. A deluge of highly technical
information has created
鈥? One of the most commonly used
communication gaps within the
organophosphates, chlorpyrifos
(Dursban), decreases DNA synthesis field of child development.
in the developing brain, resulting in 鈥? The recent explosion of research in
deficits in cell numbers. the many sciences related to child
development has produced a glut
鈥? Some pyrethroids, another commonly
of highly technical
used class of pesticides, also cause
Some pyrethroids cause
information not readily
permanent hyperactivity in animals
permanent hyperactivity
understood by those
exposed to small doses on a single
in animals exposed to small
outside the field in
critical day of development.
doses on a single critical
which the research
鈥? Children exposed to a variety of day of development.
was performed.
pesticides in an agricultural
community in Mexico show impaired 鈥? A communication gap
has resulted, dividing fields of
stamina, coordination, memory, and
research and separating the domains
capacity to represent familiar subjects
of research, clinical practice, and
in drawings.
the public.
Solvents
鈥? Behavior and cognition can be
鈥? Exposure to organic solvents during
described using clinical disorders,
development may cause a spectrum
such as ADHD or Asper ger鈥檚
of disorders including structural birth
syndrome, which are categorical and
defects, hyperactivity, attention
qualitative. Alternatively, behavior
deficits, reduced IQ, learning and
and cognition can be described using
memory deficiencies.
abilities/traits, such as attention and
鈥? As little as one alcoholic drink a day memory, which are continuous and
by a mother during pregnancy may quantitative. Abilities/traits cluster
cause her offspring to exhibit into disorders in various ways and
impulsive behavior and lasting are emerging as an important bridge
deficits in memory, IQ, school among the scientific disciplines
performance, and social adaptability. focusing on child development.
Greater Boston Physicians for Social Responsibility 3
EXECUTIVE SUMMARY
streptococcal antibodies that cross
4. Although genetic factors are
react with critical brain structures in
important, they should not be
genetically susceptible children.
viewed in isolation.
Certain genes may be susceptible to 5. Neurotoxicants are not merely a
or cause individuals to be more potential threat to children. In some
susceptible to environmental 鈥渢riggers.鈥? instances, adverse impacts are seen
Particular vulnerability to a chemical at current exposure levels.
exposure may be the result of a single or 鈥? According to EPA estimates, about
multiple interacting genes. For example: 1.16 million women in the U.S. of
Breast-fed infants 鈥? Gene-coding for certain enzymes can childbearing years eat sufficient
are exposed to influence how chemicals are amounts of mercury-contaminated
levels of dioxin metabolized or stored in the body, or fish to risk damaging brain
that exceed adult increase a person鈥檚 susceptibility to a development of their children.
exposures by as chemical. For example, a gene 鈥? Breast-fed infants are exposed to
much as a factor coding for the enzyme, delta levels of dioxin that exceed adult
of 50. aminolevulinic acid dehydratase exposures by as much as a factor
(ALA-D), can influence lead of 50. Dioxin exposures of this
metabolism, bone storage of lead, magnitude have been shown to cause
and blood lead levels. abnormal social behavior in monkeys
鈥? Two genes increase susceptibility to exposed before birth through the
organophosphate pesticides. One, maternal diet. (While breast milk
carried by 4% of the population, contaminants may compromise
results in lower levels of some of the cognitive benefits of
acetylcholinesterase, the target breast feeding, breast milk remains
enzyme of organophosphates. The strongly preferred over infant formula
other, carried by 30-40% of the due to numerous important benefits
population, results in reductions in to infant health.)
paroxonase, an enzyme that plays an 鈥? Prenatal exposure to PCBs at
important role in breaking down ambient environmental levels
organophosphate pesticides. adversely affects brain development,
鈥? Antibody reactions to infections is causing attention and IQ deficits,
another important gene-environment which remain detectable years later
interaction. For example, studies and may be permanent.
suggest that 鈥淧ANDAS鈥? (pediatric 鈥? Neurotoxicants that appear to have
autoimmune neuropsychiatric trivial effects on an individual have
disorders associated with profound impacts when applied
streptococcal infection), that may across populations. For example, a
affect patients with obsessive loss of 5 points in IQ is of minimal
compulsive disorder, Tourette鈥檚 significance in a person with an
syndrome and tics, result from average IQ. However a shift of 5 IQ
4 I N H A R M 鈥? S W AY : To x i c T h re a t s t o C h i l d D e v e l o p m e n t
EXECUTIVE SUMMARY
points in the average IQ of a
population of 260 million increases
the number of functionally disabled
by over 50% (from 6 to 9.4 million),
and decreases the number of gifted
by over 50% (from 6 to 2.6 million).
6. Vast quantities of neurotoxic
chemicals are released into the
environment each year.
鈥? Of the top 20 chemicals reported by
the Toxics Release Inventory as
released in the largest quantities into
the environment in 1997, nearly 鈥? An additional 1.2 billion pounds of
three-quarters are known or registered pesticide products are
suspected neurotoxicants. They intentionally and legally released
include methanol, ammonia, each year in the United States.
manganese compounds, toluene, 鈥? Mercury contamination of our
phosphoric acid, xylene, n-hexane, waterways is so widespread that 40
chlorine, methyl ethyl ketone, carbon states have issued one or more health
disulfide, dichloromethane, styrene, advisories warning pregnant women
lead compounds, and glycol ethers. or women of reproductive age to
Over a billion pounds of these avoid or limit fish consumption. Ten
neurotoxic chemicals were released states have issued advisories for every
directly on-site by large, industrial lake and river within the state鈥檚
facilities into the air, water, and land. borders.
鈥? Vast quantities of neurotoxic 7. Environmental releases often lead
chemicals are also used in industrial to human exposures with potential
processes and incorporated into for harm.
products. For example, according to
1997 data from the Massachusetts Dispersion of these chemicals is global.
Toxics Use Reduction Act, over half
鈥? One million children in the US
of the top twenty chemicals in use
exceed the currently accepted
(over 500 million pounds), and half
threshold for blood lead level
of those incorporated into products
exposure that affects behavior and
in Massachusetts, are known or
cognition (10 micrograms/dl).
suspected neurotoxicants.
Updating the toxic threshold in
鈥? Use of lead in manufacturing keeping with the results of the most
increased 77% in Massachusetts
between 1990-1997.
Greater Boston Physicians for Social Responsibility 5
EXECUTIVE SUMMARY
recent studies would further lower Such results raise serious
this threshold, resulting in the questions about the adequacy of the
addition of millions children to the current regulatory regime, which, by
roles of those impaired by lead design, permits children to be exposed
exposure. up to 鈥渢oxic thresholds鈥? that rapidly
become obsolete.
鈥? A metabolite of the pesticide
chlorpyrifos is present in the urine of b. Most chemicals are not tested for their
over 80% of adults and 90% of general toxicity in animals or humans, not
children from representative to mention toxicity to a child鈥檚 developing
population samples. brain specifically.
鈥? Inuit mothers in the Arctic, far from Nearly 75% of the top high
sources of industrial pollution, have production and volume chemicals have
some of the highest levels of PCBs in undergone little or no toxicity testing.
their breast milk as a result of a diet However, the EPA estimates that up to
rich in marine mammal fat. 28% of all chemicals in the current
inventory of about 80,000 have
8. The historical record clearly reveals
neurotoxic potential. In addition:
that our scientific understanding of
鈥? Complete tests for developmental
the effects of toxic exposures is not
neurotoxicity have been submitted
sufficiently developed to accurately
to EPA for only 12 chemicals - nine
predict the impact of toxicants, and
pesticides and three solvents 鈥? as of
that our regulatory regime has failed
December 1998.
to protect children.
鈥? Testing for developmental
a. As testing procedures advance, we learn
neurotoxicity is not required even in
that lower and lower doses are harmful.
the registration or re-registration of
The historical record shows
pesticides, one of the strictest areas
that 鈥渟afe thresholds鈥? for known
of chemical regulation
neurotoxicants have been continuously
revised downward as scientific c. Even when regulated, the risks from
knowledge advances. For example, the chemical exposure are estimated for one
initial 鈥渟afe鈥? blood lead level was set at chemical at a time, while children are exposed
60 micrograms/deciliter (ug/dl) in 1960. to many toxicants in complex mixtures
This was revised down to 10 ug/dl in throughout development. Multiple chemical
1990. Current studies suggest that lead exposures often interact to magnify
may have no identifiable exposure level damaging effects or cause new types of harm.
that is 鈥渟afe.鈥? The estimated 鈥渢oxic With the exception of pesticides
threshold鈥? for mercury has also used on the food supply, current regimes
relentlessly fallen, and like lead, any regulate only one chemical at a time and
level of exposure may be harmful. do not take into account the potential
for interactions. Since real world
6 I N H A R M 鈥? S W AY : To x i c T h re a t s t o C h i l d D e v e l o p m e n t
EXECUTIVE SUMMARY
d. Animal studies generally underestimate
human vulnerability to neurotoxicants.
鈥? Animal studies of lead, mercury and
PCBs each underestimated the levels
of exposures that cause effects in
humans by 100-10,000-fold.
鈥? Regulatory decisions that rely largely
on toxicity testing in genetically
similar animals under controlled
laboratory conditions will continue
to fail to reflect threats to the
capacities and complexity of the
human brain as well as important
gene-environment interactions.
9. Protecting our children from
exposures are to multiple chemicals,
preventable and potentially harmful
current regulatory standards, based on
exposures requires a precautionary
single chemical exposures, are inherently
policy that can only occur with basic
incapable of providing adequate margins
changes in the regulatory process.
of safety.
鈥? The inability of the current
鈥? New studies in humans and in the
regulatory system to protect public
laboratory show that PCBs and
health is not surprising, considering
mercury interact to cause harm at
the disproportionate influence of
lower thresholds than either
special interests in the regulatory
substance acting alone.
process. When there is evidence for
鈥? A recent 5-year pesticide study
serious, widespread and irreversible
suggests that combinations of
harm, as described in this report,
commonly used agricultural
residual scientific uncertainties
chemicals, in levels typically found in
should not be used to delay
groundwater, can significantly
precautionary actions. Actions
influence immune and endocrine
should include reduction and or
systems, as well as neurological
elimination of exposures as well as
function, in laboratory animals.
further scientific investigation of
developmental neurotoxicity.
Greater Boston Physicians for Social Responsibility 7
EXECUTIVE SUMMARY
Framework for Understanding
Learning, behavior, and developmental disorder, autism or learning disability. Such labels
disabilities in children are clearly the result of are useful for the purpose of providing clinical
complex interactions among chemical, genetic and interventions. However, traits are generally better
social-environmental factors that influence children suited to research since they can be readily defined,
during vulnerable periods of development. This quantitatively measured, and are more amenable to
report focuses on the role of toxic exposures since animal models. As a result, a large body of scientific
they are a preventable cause of harm. data has begun to describe the effects of chemicals
The cognitive and behavioral characteristics or other influences on neurodevelopment in terms
that result from these interacting influences can be of effects on traits, rather than on clinical syndromes
described as traits or abilities, such as attention or associated with diagnostic labels. In addition, traits
memory, which can be measured quantitatively using provide a common denominator between different
a variety of neuropsychological tests. fields of research, and allow us to acknowledge
Aggregates of these traits are often described influences on the neurocognitive function of
using diagnostic labels that identify clinical 鈥渘ormal鈥? populations, as well as on those with
syndromes, such as attention deficit/hyperactivity diagnostic labels.
8 I N H A R M 鈥? S W AY : To x i c T h re a t s t o C h i l d D e v e l o p m e n t
CHAPTER I 鈥? Nature of the Problem
Chapter 1
Nature of the Problem
C hildren today face extraordinary Lead, mercury, alcohol, other
challenges in the effort to succeed in solvents, some commonly used
an increasingly complex and demanding pesticides, dioxins, and PCBs interfere
world. Parents, teachers, psychologists, with normal brain development, with
and social workers know all too well long term consequences for brain
that in the context of a high-tech, fast- function. Some of these
Unlike an adult, the
paced world, many children are failing to chemicals are used
developing child exposed to
meet fundamental challenges of daily life. extensively in manufacturing
neurotoxic chemicals during
In particular, the expectation to learn, and are emitted annually
critical developmental
exercise self-control, and participate in the millions of pounds
windows of vulnerability
respectfully in social groups has become into the environment. Some
may suffer from lifelong
for many a daunting challenge. These bioaccumulate in the food
impacts on brain function.
children are sometimes labeled as having chain and end up in our
learning disabilities, attention deficits, bones, blood, fat, urine,
hyperactivity, autism spectrum disorders, breast milk, ovaries, and sperm. They
or any one of a range of other develop- may then be passed to the developing
mental problems, depending on the mix child across the placenta, through breast
and severity of their symptoms. milk, or in food. Many are so widely
dispersed globally that Inuits in the
This report begins to examine the
Arctic, far from sources of industrial
contribution of toxic chemicals to the
pollution, carry a large body burden
origins of these disorders. We focus
specifically on how neurotoxic chemicals of some of these chemicals. We believe
that we can no longer ignore the
contribute to developmental delays,
mounting evidence that chemical
hyperactivity, memory loss, attention
deficit, learning disabilities, and aggres- exposures contribute to the epidemic
of developmental disabilities.
sive behavior. Unlike an adult, the
developing child exposed to neurotoxic It is equally important that we
chemicals during critical developmental understand why, with few exceptions,
windows of vulnerability may suffer from this connection has not been widely and
lifelong impacts on brain function. openly discussed鈥攁 serious failure, since
environmental exposures are eminently
preventable. The reasons are complex,
Greater Boston Physicians for Social Responsibility 9
CHAPTER I 鈥? Nature of the Problem
The Magnitude of the Problem
varying from the differing
Bioconcentration historical interests of The impact of children鈥檚
professional disciplines to developmental disorders on children and
the corporate influence on families is immense. Parents, teachers,
regulation of toxic materials. school administrators, and communities
For decades various scientific spend increasing amounts of time, money,
disciplines have carved out and energy trying to help children acquire
their sovereign territories skills that once came more naturally.
within which they work. Afflicted children risk early school drop-
Geneticists, toxicologists, out, teen parenting, drug abuse, crime,
sociologists, educators, and institutionalization and suicide. A
healthcare providers do not constant, consuming struggle at the verge
seem to communicate easily of failure is known all too well by the
or frequently enough with one children, their families, and providers.
another. A broader perspective The struggle to pull these kids out of the
looks across professional river, or keep them from falling in, is so
boundaries and recognizes that consuming that we have little time to consider
interactions among genetic the disturbing question of what put them
inheritance and social and in this precarious state in the first place.
physical environmental factors
The number of children known to be
challenge a more simplistic
affected by developmental disabilities is
understanding of each alone.
staggering and appears to be increasing.
Meanwhile, the chemical
鈥? It is estimated that nearly 12 million
manufacturing industry
children (17%) in the United States
continues to wield enormous
under age 18 suffer from one or
influence in Congress and the
more developmental disabilities,
regulatory system. Requests
(defined as deafness, blindness,
for neurodevelopmental toxicity testing
At one point, it was
epilepsy, stuttering or other speech
thought that 鈥渢he of marketed pesticides are ignored and data
solution to pollution
defects, cerebral palsy, delay in
are virtually absent for all but a few of
is dilution鈥?. But we
growth and development, emotional
the industrial chemicals in widespread use.
have found that certain
persistent toxins do or behavioral problems, learning
In this brief report, we review evidence
not stay dispersed.
disabilities).1 2
Through the process of for chemical contributions to some neuro-
bioconcentration they
logical developmental disabilities and explore 鈥? Learning disabilities alone may affect
are reconcentrated in
approximately 5-10% of children in
reasons for the relative silence that surrounds
the food chain. They are
appearing in dangerous public schools.3 4
this issue. Some readers may find the
concentrations in food,
material too technical, others too simplistic. 鈥? The number of children in special
especially in meat, fish,
and dairy products. Our goal, however, is simply to help advance education programs classified with
and inform the discussion so that we might learning disabilities increased 191%
begin to remove our children out of harm鈥檚 way. from 1977-1994.5
10 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER I 鈥? Nature of the Problem
鈥? Attention deficit hyperactivity better detection and record keeping,
disorder (ADHD), according to increased reporting, or a result of rising
conservative estimates, affects 3 to demands of an increasingly technologic
6% of all school children, though society that places a high premium on the
recent evidence suggests the ability to perform more complex tasks at
prevalence may be as high as 17%. 6 younger ages. While these explanations
7
The number of children taking the may be partially correct, they are not
drug Ritalin for this disorder has convincing for teachers, providers, and
roughly doubled every 4-7 years parents of affected children. Many who
since 1971 to reach its current are closest to these children doubt that
estimate of about 1.5 million.8 disabilities of the observed magnitude and
incidence can be fully explained by rising
鈥? The incidence of autism may be as
expectations, and they can not imagine that
high as 2 per 1000 children. 9 One
such disabilities escaped notice in the past.
study of autism prevalence between
1966 and 1977 showed a doubling Although there is little doubt that
of rates over that time frame.10 many aspects of learning and develop-
Within the state of California, the ment are genetically influenced, for the
number of children entered into the vast majority of these disorders there is
autism registry increased by 210% no evidence that genetic factors are the
between 1987 and 1998.11 predominant cause. In fact, the few
syndromes that appear to be exclusively
鈥? Approximately one percent of all
genetic (i.e. Lesh Nyhan, Tay-Sachs,
children are mentally retarded.12
Fragile X etc.) are fleetingly rare. Studies
These statistics suggest problems of
of adopted children and twins shed light
epidemic proportions. The proliferation
on the degree to which genetic and
of agencies, organizations, networks,
environmental factors contribute to
and special education programs
neurodevelopmental outcomes. Although
dedicated to assisting children and
our understanding is incomplete, we are
families affected by developmental
now certain that complex interactions
disabilities underscores the magnitude
among genetic and environmental factors
of concern. The cost of remedial
play extremely important roles. It is no
programs, though not fully known,
longer in keeping with the state of
clearly places a heavy burden upon the
scientific understanding to attribute the
limited resources of educational and
bulk of these developmental disabilities
social service organizations.
to genetic inheritance. Rather, we now
The Origin of the Problem understand that the outcomes are the
A variety of explanations have been result of interacting factors, among
offered in response to these trends. One which are exposures to environmental
line of thought holds that the epidemic is contaminants that are preventable.
more apparent than real - a product of
Greater Boston Physicians for Social Responsibility 11
CHAPTER I 鈥? Nature of the Problem
In this report we review important environment in the evolutionary time
findings from developmental neuro- frame. Documented and potential
toxicology, a science dedicated to the exposures are substantial, as indicated by
study of the impact of chemicals on the presence of chemicals in humans
the developing human brain. It is well (biomonitoring), environmental
beyond the scope of this report to monitoring, and chemical use and release
address this topic exhaustively. Rather, information. From the moment of
we provide a brief overview of the conception until reaching adulthood,
process of brain development, how it children are regularly exposed to large
may be disrupted by chemical exposures numbers of metals, solvents, pesticides
during periods of vulnerability, and and other industrial substances, alone
Information concentrate on several common and in complex mixtures.
about the exposures or contaminants. We The degree to which these exposures
potential emphasize that information about the disrupt development of humans and
neurotoxicity neurotoxic potential of many other wildlife is a question of considerable
or developmental chemicals and pollutants is woefully importance and concern. Yet, of the
neurotoxicity inadequate. We embed this discussion in chemicals on the EPA鈥檚 inventory, even
of most of these a larger framework that acknowledges basic toxicity information is missing
chemicals is the interactions among chemical, from publicly available sources for
virtually absent. genetic, and socioeconomic factors in nearly 75% of the top 3000 high
the origins of developmental disorders. production volume substances.14
While the disciplines of biology, Information about the potential
environmental sciences, psychology, and neurotoxicity or developmental
sociology are typically separated by neurotoxicity of most of these
distinct methods, concepts, and chemicals is virtually absent. For the
traditions, an integrated perspective of relatively few chemicals that have
child development is likely to be much undergone developmental neurotoxicity
more valid and informative. The child, testing, animal tests are used to predict
at the center of this disciplinary risks of human exposure. Yet, considered
fragmentation, will particularly benefit in the absence of human data, our
from an integrated perspective that takes experience with lead, mercury, and
advantage of advances in each field. polychlorinated biphenyls (PCBs) shows
that animal tests often grossly under-
Chemical Proliferation, Exposures,
estimate risks to human neurological
and Inadequate Toxicity Testing
development. For most chemicals, even
About 80,000 chemicals are in animal data are totally missing, and no
commercial use in the United States.13 systematic effort is in place to examine
The great majority of these compounds the neurodevelopmental consequences of
have been synthesized since World War exposure to mixtures of compounds that
II and are, therefore, new to the human characterize the real world.
12 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER I 鈥? Nature of the Problem
Cautions
In summary, large numbers of
chemicals are widely used in consumer As is almost always the case when
products and regularly discharged to the considering conditions with multiple,
environment, resulting in widespread interacting causative factors, under-
exposures. Our limited understanding standing the cause(s) of a particular
of their full neurotoxic potential, has child鈥檚 neurological developmental
one particularly unsettling implication: disability is extraordinarily difficult. This
What we already know about neuro- is particularly true when much of the
developmental toxic threats to children is research that identifies risk factors like,
likely to be only the tip of an iceberg. for example, elevated lead levels, is based
on epidemiological rather than individual
How This Report is Organized studies. Although we can conclude with
certainty that, across a population,
In the following chapters we review
elevated lead levels during child
the intersection of several disciplines. We
development will impair cognition and
discuss the tightly orchestrated, intricate
alter behavior, we can never say with any
cascade of processes that unfold during
certainty the degree to which those
brain development, many of which are
vulnerable to disruption by environmental functions are impaired in a particular
child because of lead exposure. This is
factors. We discuss the spectrum of
because cognition and behavior are the
developmental disabilities, their public
health impacts, and what is known about result of complex interactions among
genetic, social, and physical environ-
their multifactorial origins, including
genetics and gene-environment interactions. mental factors. Those interactions are
virtually never understood in detail in a
We review documented links between
single individual, and although it is tempt-
exposure to a selection of neurotoxic
ing to attribute a particular outcome in a
chemicals and traits that appear during
child development or in animal testing. In particular person to one or another factor,
such a conclusion is rarely possible. Rather,
addition, we present evidence of wide-
we must learn what we can from available
spread exposure to some neurotoxic
population-based information, prevent
chemicals and note the failure of the
potentially harmful exposures whenever
regulators to require adequate testing for
possible, and accept the limits of our
health effects in order to protect vulner-
ability to assign causes in individuals.
able populations. We also present
evidence that developmental neurotoxic Our understanding of the benefits of
effects are not merely a potential threat, treatment after a disability is detected is
but that, for some chemicals, they occur limited. For example, even though we
at commonly encountered exposure levels. know that low-level lead exposures will
Finally, an appendix provides a summary impact brain development, it is difficult to
of the clinical syndromes addressed predict the degree to which an individual
throughout the report. child will benefit from lowering elevated
Greater Boston Physicians for Social Responsibility 13
CHAPTER I 鈥? Nature of the Problem
lead levels by chelation therapy. currently recognized. Similarly, over the
However, environmental remediation past 30 years, the recognized threshold
designed to eliminate ongoing exposures for harm from mercury exposure has
is obviously a sensible first step. also relentlessly fallen. Recent studies
suggest that, like lead, mercury may
This report is intended to summarize
have no threshold below which adverse
and interpret important research, much
effects do not occur.
of which is largely unknown to the
public. The benefits of prudently These observations raise serious
avoiding exposure to known, suspected, questions about the adequacy of the
or potential neurotoxicants are clearly current regulatory regime, which permits
implied. The implications of these exposures up to 鈥渢oxic thresholds鈥? that
findings for therapeutic medicine, eventually become obsolete only after
however, are separate, complex issues more and more children are injured.
that we do not address. What more do we really need to know
before concluding that we must take the
Historical Lessons steps necessary to avoid contaminating
food with mercury if we want to protect
Placing our current understanding of
the developing brain?
these matters in an historical context is,
as usual, a worthwhile exercise. The It is also important to recognize that
historical record clearly reveals that what the implications of a small shift in some
are considered 鈥渟afe thresholds鈥? for measure of neurological function differ
known neurotoxicants have been for individuals and populations. For
continuously revised downward as example, lead-related shifts in IQ or
scientific knowledge advances. For other neurobehavioral endpoints may be
example, the initial 鈥渟afe鈥? level of blood relatively small on an individual basis,
lead levels was set at 60 microgm/dl in but impacts at a population level are
1960. This was revised to 10 microgm/dl highly significant with broad
in 1990 when neurodevelopmental ramifications. A 5- point decrease in
effects became clear at lower levels of the average IQ in a population of 260
exposure during critical windows of million will increase the number of
vulnerability. Now we know that functionally disabled individuals by
neurodevelopmental effects occur at even over 50 percent (those with IQ鈥檚 of 70
lower levels of exposure, and many or less), from 6 to 9.4 million, and
neurotoxicologists believe that there is no simultaneously decrease the number of
exposure, no matter how small, that is gifted individuals by over 50 percent (those
without impact on the developing brain. with IQ鈥檚 of 130 or greater), from 6 to
Updating the toxic threshold for lead 2.4 million. This shift translates into
with this new information would result increased needs for special education
in the addition of millions of children to and services as well as a significantly
the roles of those impacted by lead diminished intellectual capacity within
exposure 鈥? in addition to the one million the population as a whole.
14 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER I 鈥? Nature of the Problem
Declining Threshold of Harm for Mercury
level associated with
100 harmful effect
severe retardation regulatory standard
(newborns, Iraq,NOEL) (maximum safe exposure or high
delayed development
[1&2] end exposure from allowed fish
(2 yr olds,Iraq) [4]
contamination)
10
delayed walking - delayed walking delayed walking
(2 yr olds,Iraq) [5]
(2 yr olds,Iraq) [3] (2 yr olds, Iraq) [8] decreased
DAILY INTAKE
(micrograms/kg/day Hg)
attention,
decreased IQ
memory,
(7 yr olds,
learning
FDA New Zealand) [9]
(7 yr olds,
Faroe I.) [11]
1
abnormal reflexes
(2 yr old boys,Quebec) [6]
WHO ATSDR
developmental delays
(4 yr olds, New Zealand)
0.1 [7] decreased activity increased
EPA
(2 yr old males, blood
Seychelles I.)[10] pressure
(Faroe I.)
[12]
0.01
1970 1980 1990 2000
YEAR
The proven threshold of harm tends to for mercury effects by using increasingly represent World Health Organization
decrease as knowledge is accumulated. sensitive measures of neurological (WHO), EPA, and Agency for Toxic
function, and better statistical methods.4
This figure shows the trend for one Substances and Disease Registry (ATSDR)
5 6 7 8 9 10 11 12
neurotoxicant: mercury. Scientific recommended limits for human mercury
understanding of mercury鈥檚 develop- A large, recent study has identified exposure. The standard issued by the FDA,
mental neurotoxicity began with studies deficits in language, memory and it should be noted, regulates the level of
of the 1972 epidemic of mercury attention that occur at prenatal mercury mercury in fish, rather than in people. As
poisoning in Iraq. At that time case exposures under 0.85 ug/kg/d. This level a result, a wide variety of exposures may
reports of infants severely retarded at is less than 3% of the toxic threshold occur within the FDA regulatory limit,
birth identified an apparent toxic identified in the initial observations depending on how much and how often
threshold for mercury exposure of greater from the Iraqi epidemic. The presence one eats fish, and the mercury level of the
than 34 ug/kg/d.1 2 (This appeared to be a of a 鈥渄iscernible insidious effect鈥? on fish consumed. The indicated exposure is
鈥渘o effect level鈥?, or NOEL, for severe language, memory and attention was that of a 60 kg woman eating at the high
retardation at birth.) Within a few years, noted, however, below even this low end of fish consumption (100gm/d, the 95-
level13 of 0.85 ug/kg/d, suggesting that 97th percentile),14 eating fish which are
however, it became apparent that many
children exposed prenatally to lower the recognized threshold for neuro- contaminated at the FDA permitted limit.
levels of mercury were delayed in logical toxicity will continue declining In this worst case scenario, the woman is
learning to walk and talk, in spite of as research methods improve. exposed to 1.65 ugm/kg/d, or about 16.5
apparently 鈥渘ormal鈥? development in The black squares on the graph times EPA鈥檚 recommended safe limit.
infancy.3 Subsequently, a variety of represent prenatal mercury exposures
studies on diverse populations have associated with adverse neurodevelop-
established progressively lower thresholds mental outcomes. The grey triangles
Notes- 1.) Studies of the neurodevelopmental effects of mercury generally use hair or blood levels as markers
of exposure, since these are more accurate indicators of exposure than dietary surveys. Health-based guidelines,
however, are expressed as recommended limits of dietary exposure. For the purpose of comparing data
between studies, and for comparing effects levels with regulatory guidelines, exposures as indicated by hair and
blood levels of mercury have been converted to approximate equivalent dietary exposures. The quantitative
relationships between food intake, hair and blood levels of mercury are described in the ATSDR Toxicological
Profile for Mercury.15 2.) Study results that identified a range of exposures within which an effect was
observed have been shown at the mid point of that range. Due to differences in study methodology, results are
not strictly comparable between studies, and shown here mainly to indicate general trends over time.
Greater Boston Physicians for Social Responsibility 15
CHAPTER I 鈥? Nature of the Problem
Original IQ Distribution
mean 100
POPULATION EFFECTS OF A SMALL
SHIFT IN AVERAGE IQ
鈥? The upper chart shows the distribution of
IQ scores in a population where the
average IQ is 100, and the standard
6.0 million 6.0 million deviation is 15. The grey area under the
"mentally retarded" "gifted" left 鈥渢ail鈥? of the curve represents the
2.3% of the population with an IQ <70,
the score used to define mental retard-
ation. In a population of 260 million,
about 6 million people would fall below
40 60 80 100 120 140 160 this line.
I.Q.
70 130
鈥? The lower chart depicts an IQ distribution
that results from lowering the average IQ
by 5 points from 100 to 95. Now, 3.2% of
Effect of a 5 Point Shift in Average IQ the population, or 9.4 million people
have an IQ below 70. This represents
mean 95
more than a 50% increase in the
numbers of mentally retarded. The
numbers of gifted, defined as those with
57% INCREASE
IQ鈥檚 greater than 130, have declined by
IN
more than 50% from 6 million to 2.4
"MENTALLY
million. Thus a small shift in average IQ
RETARDED"
results in greatly increased need for
POPULATION
special education and services, as well as
diminished intellectual capacity within
the population as a whole.16
9.4 million 2.4 million
"mentally retarded" "gifted"
40 80 100 120 140 160
60
70 130
16 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER I 鈥? Nature of the Problem
Missing: National Registry for Developmental Disabilities
P ublic health surveillance systems, such as birth defect registries and programs
to monitor exposures to toxic substances, provide opportunities to follow trends,
identify clusters, study causes, and plan preventive and service programs. Historically,
federal and state government surveillance systems have focused on structural birth
defects rather than developmental disabilities. As we have
noted, however, some developmental disabilities may be
DEVELOPMENTAL DISABILITY AS
thought of as functional birth defects, though they are
A FUNCTIONAL BIRTH DEFECT
often not accompanied by more easily detected structural
P
abnormalities. Although this report is concerned with hysical abnormalities evident at or soon after
neurological developmental disabilities, the immune, birth are readily recognized as birth defects,
endocrine, reproductive, and other systems may also and chemical exposures are among several
function abnormally as a result of interactions of known causes of these abnormalities. Familiar
environmental and genetic factors during development. examples include the severe arm and leg
deformities resulting from prenatal exposure to
Public health agencies often consider developmental
the therapeutic drug, thalidomide.
disabilities quite separate from birth defects, though
there is considerable overlap between the two. For Just as chemical exposures can cause defects in
example, the Centers for Disease Control the physical structure of a limb or an organ
and Prevention (CDC) assigns birth defect system, early-life exposures can also impair
and developmental disability surveillance function, often for a lifetime. Although structural
to two separate departments, which birth defects resulting from maternal exposure to
organize their programs in different some teratogens have been recognized for
ways. Yet, according to the CDC, nineteen centuries, functional defects have only relatively
percent of those with developmental recently been recognized as part of a continuum
disabilities also have birth defects, and 6.6 percent of of injuries that can result from prenatal toxic
those with birth defects have developmental deficits. chemical exposures. For example, lifelong
Definitions of developmental disabilities vary from changes in endocrine, immune, or neurological
federal to state and state to state agencies, particularly for function may result from chemical exposures
cognitive disorders, and learning disabilities. This variability before birth. Functional defects are often less
makes it difficult to monitor incidence, prevalence, and immediately obvious than structural
trends on a regional or national scale. abnormalities, but are no less important since they
continued
constitute permanent impairments in the ability
of an organ system to perform its function.
Greater Boston Physicians for Social Responsibility 17
CHAPTER I 鈥? Nature of the Problem
Public Interest Concerns
Public health and public interest groups have expressed three major concerns
about ongoing surveillance activities:
1. Exposure data lacking
Monitoring or estimating exposures to environmental contaminants, as well as
health outcomes, is essential to identifying environmental factors that may be
Environmental responsible for unexplained birth defects and developmental disabilities. Even a
monitoring well-designed and implemented birth defect registry will have limited value if
databases may be exposure data are lacking. Exposure monitoring may be accomplished by biological
the only information sampling (biomonitoring) or less accurately, by maternal questionnaires.
available and are Biomonitoring may include testing umbilical cord or infant blood, maternal blood,
sometimes used, or maternal hair samples for metals, and other chemicals. DNA sampling can be
though those data used not only to examine for genetic causes of abnormalities but also, in some
are even less instances, to examine for exposures, since some toxicants leave a chemical specific
accurate surrogates 鈥淒NA fingerprint.鈥? Environmental monitoring databases may be the only
of exposure levels. information available and are sometimes used, though those data are even less
accurate surrogates of exposure levels.
2. Developmental disabilities not included
Although major structural birth defects certainly deserve attention, many
functional defects or developmental disabilities, including cognitive and behavioral
abnormalites, remain uninvestigated. Surveillance for developmental disabilities,
other than mental retardation, cerebral palsy, hearing and visual impairment, and
epilepsy, is largely non-existent on a meaningful scale. In part this reflects the difficulty
and expense encountered in establishing a large surveillance system for other
disorders, but may also signal a reluctance to pursue incidence and trend data too
aggressively because of the economic implications of diagnoses with attached
mandated services.
3. Privacy concerns
Programs that include banking DNA or other biological specimens raise concerns
about privacy and confidentiality. Some analytic data are predictive of future health
or disease and have profound implications for insurability or employability. Because
of concerns about unauthorized disclosure of information, individuals are often
reluctant to participate in public health research projects that include the collection
of personally identifiable data. Study participants usually lack ultimate ownership
and control of data, and efforts to protect the privacy of individuals do not
necessarily overcome underlying fears of inappropriate disclosure. The need for
limited access to medical information by insurance companies, potential employers,
health maintenance organizations, and others is recognized, but what the limits
should be and how they are to be enforced is widely debated.
18 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER I 鈥? Nature of the Problem
Mohawk Women鈥檚 Breast Milk Study: Community Based Research Model
T he Mohawk women鈥檚 breast milk study was a research project designed to
address concerns about privacy and data ownership. Investigators wanted to
study the relationship between fish consumption and PCB breast milk contamination
among nursing Mohawk women at Akwesasne, along the St. Lawrence River.
Previously, PCBs from a nearby General Electric facility had been dumped or spilled
onto Native American lands or into the river, contaminating soils, sediments, and the
food chain. Mohawk women were reluctant to agree to participate in a study of their
breast milk, without fundamentally restructuring their relationship with investigators
from the New York State Department of Health. Rather than allowing outside experts
to conduct a study in which community members would be passive participants,
Mohawk women insisted on a more co-equal relationship in which they would assist
in study design as well as own and control the analytic data. The study and results
have been published in peer-reviewed journals.1 Community members are among the
authors. Breast milk PCB levels declined in the last three years of the six-year study,
perhaps as a result of more consistent attention to advisories recommending against
consumption of local fish by pregnant and nursing Mohawk women. This experience
may serve as a useful starting point for dealing with concerns about privacy,
confidentiality, and control of data in other circumstances.
1 Fitzgerald E, Hwang S, Bush B, Cook K, Worswick P. Fish consumption and breast milk PCB concentrations among Mohawk women at
Akwesasne. Am J Epidemiol 148(2):164-172, 1998.
Greater Boston Physicians for Social Responsibility 19
CHAPTER I 鈥? Nature of the Problem
Citizen Database Fills Government Void
(With information taken from a piece written by Betty Mekdeci, Executive Director of the Association of Birth Defect Children, for Birth
Gazette, Fall, 1997, with additional information added from a presentation by Ms. Mekdeci in October 1999)
T he modern study of teratology (the study of birth defects) was born out of a
world tragedy that occurred in 1962鈥攐ver 10,000 babies born deformed as a
consequence of their mothers taking the drug thalidomide. The National Birth Defects
Registry (NBDR) was born out of the frustration of mothers, educators and
other concerned citizens that critical information about birth defects and
developmental disabilities was not being collected in the United States. It
was created and is sponsored by the Association of Birth Defect Children
with Betty Mekdeci at the helm. For twenty years Mekdeci has led a
crusade to unravel the mysteries of why birth defects occur. Her efforts
have brought her into the halls of Congress and into the lives of thousands of parents.
Like a sleuth collecting clues, the NBDR compiles information directly from the parents
of infants and older children with birth defects, including functional defects that may go
unrecognized at birth. Over 10,000 questionnaires have been distributed to try to piece
together the puzzle of what has caused abnormalities ranging from limb deformities to
learning disabilities.
The database
The database has recently been utilized to analyze disabilities in the children of
has recently been
Vietnam veterans, with some disturbing results. The registry has revealed a pattern of
utilized to analyze
functional problems in Vietnam vets鈥? children that includes significant increases in learning
disabilities in the
and attention problems, chronic skin disorders, benign tumors and cysts, allergic disorders,
children of Vietnam
growth hormone deficiency, chronic infections, emotional/behavioral problems, prolapsed
veterans, with some
heart valves, and a range of conditions that may be consistent with a malfunctioning
disturbing results.
immune system. This pattern of disabilities is consistent with other research suggesting
prenatal effects of dioxin on the developing immune system. The Vietnam veterans data has
been presented to Congress, and cited in the report 鈥淰eterans and Agent Orange鈥? (dioxin is
a constituent of Agent Orange, the defoliant used in Vietnam).
This is no amateur operation. The questionnaire used to compile these findings has
been evaluated and endorsed by a seven-member advisory board of national experts in
reproductive biology, epidemiology, endocrinology, biochemistry and environmental
biology. It is designed to act as an alert practitioner on a grand scale by searching for the
鈥渇ingerprints鈥? of teratogens. The reporting parent is also asked about the pre-conceptual
exposures of the mother, and the father and mother鈥檚 exposure history during pregnancy.
Data from questionnaires are entered into a customized computer format, and
automatically entered into more than 20 separate tables that can be connected in The Association of Birth Defect
Children, Betty Mekdeci,
multiple ways for data analysis. Executive Director, can be
contacted at 930 Woodcock
A recent report by the Pew Environmental Health Commission entitled 鈥淗ealthy From Road, Suite 225, Orlando, FL
32803. 407-245-7035.
the Start: Why America Needs a Better System to Track and Understand Birth Defects and www.birthdefects.org
the Environment,鈥? outlines the deficiencies of the state and national data collection
systems for these disabilities. This is not news to Betty Mekdeci and her colleagues in
Florida, who have been listening to the cries of the disabled children for decades.
20 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER I 鈥? Nature of the Problem
Footnotes to diagrams Footnotes to text
1 Amin-Zaki L, Elhassani S, Majeed MA, et al. Perinatal 1 Boyle CA, Decoufle P, Yeargin-Allsopp M. Prevalence and health
Methylmercury Poisoning in Iraq. Am J Dis Child 130, Oct 1976, impact of developmental disabilities in US children.- Pediatrics
1070-8. March 93(3):399-403, 1994.
2 Amin-Zaki L, Elhassani S, Majeed MA, et al. Intra-uterine 2 U.S. Census Bureau Population Estimates Program, Washington
Methylmercury Poisoning in Iraq. Pediatrics 54(5) p.587-95, 1974. DC. www.census.gov/population/estimate/nation/inttfile2-1.txt
3 Marsh D. Fetal methylmercury poisoning: new data on clinical 3 American Psychiatric Association. Diagnostic and Statistical
and toxicologic aspects. Trans Am Neurol Assoc 102:69-71, 1977. Manual of Mental Disorders, Fourth Edition. 1994.
4 Marsh DO, Myers GJ, Clarkson TW et al. Fetal methylmercury 4 Parrill M. Research implications for health and human services.
poisoning: clinical and toxicological data on 29 cases. Ann Neurol In Learning Disabilities, Lifelong Issues. Cramer and Ellis, Eds.
7:348-353, 1980. 1996. Pgs. 227-295.
5 Marsh DO, GJ Myers, Clarkson TW et al. Dose-Response 5 Kavale KA, Forness RR. Co-variants in learning disability and
Relationship for Human Fetal Exposure to Methylmercury. Clinical behavior disorders:an examination of classification and placement
Toxicology, 18(11): 1311-1318, 1981. issues. Advances in Learning and Behavioral Disabilities, 12:1-42,
1992.
6 McKeown-Eyssen GE, Ruedy J Neims A. Methyl mercury
exposure in Northern Quebec II. Neurologic findings in children. 6 Goldman L, Genel M, et al. Diagnosis and treatment of
American J of Epidemiology 118(4): 470-479, 1983. attention deficit hyperactivity disorder in children and
adolescents. JAMA 279(14):1100-1107, 1998.
7 Marsh DO, Clarkson TW, Cox C et al. Fetal Methylmercury
Poisoning. Arch Neurol 1987;44:1017-1022. 7 Rowland, A. Prevalence and Risk Factors for ADHD in a North
Carolina County:Study Design and Preliminary Results.
8 Marsh DO, Turner MD, Smith JC et al. Fetal methyl mercury Environmental Influences on Children conference, New York
study in a Peruvian fish-eating population. Neurotoxicology Academy of Medicine, May 1999.
16(4):717-726, 1995.
8 Safer D, Zito J, Fine E. Increased methylphenidate usage for
9 Cox C, Clarkson TW, Marsh DO et al. Dose-response analysis of attention deficit disorder in 1990s. Pediatrics 98(6):1084-1088,
infants prenatally exposed to methylmercury: dan application of 1996.
a single compartment model to single-strand hair analysis.
Environmental research 49: 318-332, 1989. 9 Centers for Disease Control and Prevention, National Center for
Environmental Health, Division of Birth Defects and Disability and
10 Davidson PW, Myers GH, Cox C. Longitudinal Health, Developmental Disabilities Branch. http://www.cdc.gov/
neurodevelopmental study of Seychellois children following in nceh/programs/CDDH/dd/ddautism.htm
utero exposure to methylmercury from maternal fish ingestion:
outcomes at 19 and 29 months. Neurotoxicology 16(4):677-688, 10 Gillberg C, Wing L, Autism: not an extremely rare disorder.
1995. Acta Psychiatr Scand 99(6):339-406, 1999.
11 WHO task group on environmental health criteria for 11 California Health and Human Services, Department of
methylmercury. Methylmercury, Environmental Health Criteria Development Services. Changes In the Population of persons with
101. World Health Organization, 1990. Autism and Pervasive Developmental Disorders in California鈥檚
Developmental Services System:1987 through 1998. A Report to
12 Sorensen N, Murata K, Budtz-Jorgensen et al. Prenatal the Legislature, Mar 1999. http://www.autism.com/ari/dds/
methylmercury exposure as a cardiovascular risk factor at seven dds.html
years of age. Epidemiology 10(4):370-5,1999.
12 American Psychiatric Association. Diagnostic and Statistical
13 Grandjean P, Weihe P, White R. Cognitive Deficit in 7-year-old Manual of Mental Disorders, Fourth Edition. 1994.
children with prenatal exposure to methylmercury.
Neurotoxicology and Teratology 19(6):417-428. 13 U.S. EPA. Office of Prevention, Pesticides and Toxic Substances.
Endocrine Disruptor Screening and Testing Advisory Committee.
14 EPA. Mercury Study Report to Congress. Volume I, p.3-39. EPA- Final Report. Washington DC. 1998.
452/R-97-003. 12/97.
14 Roe D, Pease W, Florini K, Silbergeld E. Toxic Ignorance: The
15 ATSDR. Toxicologic Profile for Mercury. US Department of Continuing Absence of Basic Health Testing for Top-Selling
Health and Human Services. 1998. Chemicals in The United States. Environmental Defense Fund.
1997.
16 Adapted from Weiss, B. Endrocrine dispruptors and sexually
dimorphic behaviors; a question of heads and tails. Neurotox
18:581-6, 1997.
Greater Boston Physicians for Social Responsibility 21
CHAPTER I 鈥? Nature of the Problem
22 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
C H A P T E R 2 : N o r m a l B r a i n D e v e l o p m e n t a n d D e v e l o p m e n t a l To x i c o l o g y
Chapter 2
Normal Brain Development
and Developmental Toxicology
Normal Brain Development neurites, develop into long axons
or shorter dendrites, each of which
B rain development begins early in the makes contact with neighboring
child鈥檚 first envir onment of the neurons. Connections
uterus and continues well beyond birth Normal brain development requires the
between neurons,
into adolescence. Normal brain intricate unfolding of a cascade of processes
called synapses,
development requires the intricate that do not occur during any other life
enable complex
unfolding of a cascade of processes that stage. Consequently, developing fetuses and
circuits to be
do not occur during any other life stage. infants are uniquely vulnerable to disruption
established in the
Consequently , developing fetuses and of these processes by environmental factors,
brain. Other cells,
infants are uniquely vulnerable to including chemical contaminants and
called glia, are
disruption of these processes by nutritional deficiencies.
responsible for the
environmental factors, including synthesis and
chemical contaminants and nutritional maintenance of myelin, a coating around
deficiencies. Cell proliferation, larger axons, which facilitates nerve
migration, differentiation, and synapse transmission. Myelin consists largely
formation normally progress in a tightly of lipids (fats) with smaller amounts of
programmed and orderly fashion. protein. Some glial cells also provide
Subsequently , neural cir cuits ar e refined scaffolding for the migration of neurons
and consolidated through programmed during development and help to maintain
cell death (apoptosis), a process that a normal biochemical environment.
continues into childhood and
The timeline of normal brain
adolescence. Interference with any stage
development has been studied in detail
of this cascade of events may alter
in animals and to some degree in
normal progression of subsequent stages
humans. Embryonic and early fetal
so that even short-term disruptions may
development are characterized first by
have long-term effects later in life.
neuronal proliferation and migration.
Neurons are the nerve cells in brain
Later, cellular dif fer entiation and
or peripheral nerves responsible for
synapse formation dominate. During
transmitting nerve impulses. Outgrowths
normal development, neurons migrate
from these cells, collectively called
to their final positions in a specific
Greater Boston Physicians for Social Responsibility 23
C H A P T E R 2 : N o r m a l B r a i n D e v e l o p m e n t a n d D e v e l o p m e n t a l To x i c o l o g y
NEURONAL MIGRATION
structur es. Consequently , at any one
time, some areas are undergoing cellular
proliferation while others are undergoing
primarily dif fer entiation. T iming is,
therefore, important when considering
CP
the potential effects of exposure to an
environmental agent that disrupts specific
developmental processes.
CC
Neurotransmitters, hormones, neuro-
RG
trophins, and growth factors orchestrate
the intricate process of brain development.
Neurotrophins are proteins that help
TR
regulate differentiation and survival of
VZ
neurons. In the adult, neurotransmitters
serve primarily to transmit nerve im-
pulses fr om one neur on to another . In
sequence with those migrating to the the developing brain, however , neur o-
During brain
development neurons cortex early forming the deepest layers transmitters serve an additional and very
originate near the
while later arriving cells are more important role, helping to orchestrate the
center of the brain
(ventricular zone, VZ) superficial. Proper positioning of the cascade of events necessary for normal
and migrate along
neurons is essential for establishing brain development. Major neurotransmitters
radial glial guides (RG)
normal neural circuitry and brain include acetylcholine (ACh), norepineph-
to their final location
closer to the surface of function. Cell proliferation continues in rine, dopamine, serotonin, gamma-amino
the brain (cortical plate,
the rat brain up to about 3 weeks after butyric acid (GABA), glutamate, and
CP). As the neurons
migrate they intercept birth. In humans, neuron formation is aspartate. Growth, thyroid, steroid, and
nerve fibers from other
largely complete at birth, and almost all sex hormones also play important roles
portions of the brain
neurons of the cerebral cortex have in brain development. Neurotransmitters,
(thalamus, TR; the
opposite side of the reached their final positions. Glia, neurotrophins, and hormones exert their
brain, CC). Later-
however , continue to develop thr oughout effects by attaching to specific cellular
developing neurons
migrate to final life. Many synapses formed during the receptors, initiating a biological response.
positions closer to the
first two years of life are later eliminated Receptor location and density are also
brain surface, remaining
as circuits ar e pr uned. However , new determined during early brain development.
in columns (outlined
by cylinders) that synapses form throughout life, During prenatal life, neurotransmitters
correspond to columns
explaining how we can continue to learn
from which they and their cellular receptors also develop
originated. (adapted and r emember . Myelination continues on a specific timeline. For example,
from Rakic, 1988)
well into the teenage years. 1 receptors for the neurotransmitter,
Rakic P. Specification of
Development does not, however , acetylcholine, develop slowly from 16-20
cerebral cortical areas. Science
241(4862):170-176, 1988.
progress uniformly in every area of the weeks, followed by a lag time of about 4
brain. For example, the cerebellum weeks, and then rapid receptor formation
during the last trimester of pregnancy.2
develops later than many other brain
24 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
C H A P T E R 2 : N o r m a l B r a i n D e v e l o p m e n t a n d D e v e l o p m e n t a l To x i c o l o g y
The class of neurotransmitters that differentiation of nerve cells into those
includes dopamine and norepinephrine with more specialized functions.
matures later. In general, cholinergic neurons
The cholinergic neurotransmitter frequently make contact with non-
The brain
system, which utilizes acetylcholine as its cholinergic structures, leading
undergoes
chemical messenger, includes two types investigators to conclude that an
rapid structural
of receptors 鈥? muscarinic and nicotinic, important role is to modulate the activity
and functional
so named because of their selective of other types of neurons. For example,
changes during
stimulation by muscarine (a chemical ACh released from one neuron, acting
late pregnancy
that can be extracted from certain on the receptors of other neurons,
and in the
mushrooms) and nicotine. Both types modulates their release of norepineph-
neonatal
rine, dopamine, GABA,
period.
serotonin, glutamate, and
SYNAPSE
acetylcholine. 5
TRANSMISSION AT SYNAPSE
(ARROW INDICATES DIRECTION OF IMPULSE)
The brain undergoes rapid
structural and functional
VESICLES OF NEUROTRANSMITTER
changes during late pregnancy
AXON OF PRESYNAPTIC NEURON DENDRITE OF
and in the neonatal period.
POSTSYNAPTIC
NEURON
Cognitive functions and
behavior arise from multiple
sources and depend on more
than one neurotransmitter and
more than one portion of the
brain. Attention, memor y,
language skills, learning
NEUROTRANSMITTER
(ACETYLCHOLINE)
capacity , and behavior r esult
RECEPTOR INACTIVATOR
SITE (CHOLINESTERASE)
from integration of multiple
structural and functional
factors with cultural and
of receptors are found in the central social for ces. These complex inter -
nervous system and their respective roles actions make it exceedingly difficult to
in brain development are gradually study the contribution of each factor
coming into focus, though considerable independently . These complexities also
information is still missing. Normal make it dif ficult to study and under -
development of muscarinic ACh stand when, if, or to what degree
receptors is important for later learning environmental factors play a role.
and cognition.3 Initially, neurotransmitters Differing professional interests also
promote DNA synthesis and cell help to explain the varying approaches
proliferation.4 Later, with increases in of investigators from separate disciplines
synaptic proliferation and nerve activity, as they attempt to understand human
the same transmitters promote behavior and cognitive abilities.
Greater Boston Physicians for Social Responsibility 25
C H A P T E R 2 : N o r m a l B r a i n D e v e l o p m e n t a n d D e v e l o p m e n t a l To x i c o l o g y
Developmental Neur
otoxicology between direct and indirect toxicity is of
no practical importance, since the child
Developmental neurotoxicants,
is still impaired. It is also critically
including lead, mer cury, pesticides, and
important to keep in mind that
others, may directly interfere with any of
neurotoxicants may interfere with brain
the processes required for normal brain
development and subsequent function at
development. Cell division, migration,
exposure levels that have minimal,
differentiation, synapse formation, and
transient, or no effect on the adult brain.
apoptosis may be accelerated or delayed.
Myelin formation may also be altered by The Role of Thyroid Hormone
toxic exposures or nutritional
Among the various growth factors
deficiencies. 6 Some neurotoxicants, like
and hormones necessary for normal
lead and alcohol, interfere with normal
brain development, thyroid hormone
neurite development through a variety of
(thyroxine), which is essential for
mechanisms. Unique developmental
neuronal proliferation and
processes, including myelination,
differentiation, plays a particularly
synapse formation, and apoptosis
important role. 8 It appears that any
continue under genetic and
toxicant that lowers thyroxine levels, or
environmental control at least through
otherwise interferes with thyroid
puber ty.7 The timing, patter n, and level
hormone action, even to a small degree,
of toxic exposure largely determine
is likely to have an adverse impact on IQ
which parts of the brain will be affected
and potentially other brain functions.
and to what degr ee. Various stages of
Even transient decreases in thyroxine in
development provide critical windows of
the CNS during critical developmental
vulnerability during which exposure to a
periods may produce alteration in
chemical substance may have lasting
neuronal branching and cellular
adverse effects on brain function.
architecture in the brain.
Different learning or behavioral effects
It has long been known that
may result from exposure to the same
maternal and fetal hypothyroidism, as
agent at different times in brain
determined by distinctly subnormal
development, depending on the location
thyroxine levels, produce cognitive
in the brain where susceptible
impair ment in childr en. However , a
neurodevelopmental events are taking
recent study reports that even minor
place at the time of the exposure.
reductions in maternal thyroxine levels
Some toxicants act indir ectly by ,
result in reduced performance on IQ
for example, interfering with normal
tests in childr en. 9 In this study , elevated
placental function, altering umbilical
levels of thyrotropin, the pituitary
circulation, causing general growth
hormone responsible for stimulating
retardation, or altering function or
the thyroid to release thyroxine even
metabolism of hormones (endocrine
when slightly decreased, predicted
disruptors). However , the distinction
reduced per formance on the W echsler
26 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
C H A P T E R 2 : N o r m a l B r a i n D e v e l o p m e n t a n d D e v e l o p m e n t a l To x i c o l o g y
Intelligence Scale for Children. IQ scores
were 4 points lower in children of
women with elevated thyrotropin levels
compared to matched controls. Fifteen
percent of the children had IQ scores of
85 or less compared to 5% of control
children. Only some of the women with
elevated thyrotropin also had low
thyroxine levels.
Challenges to Identifying
Neurotoxic Effects
One of the main problems
encountered in studying the effect of
chemical exposures on subsequent brain
function is the possibility of a long
latent period between the exposure and
recognition of a functional deficit. For differentiation of the brain. Lack of
example, impaired language or reading specificity of symptoms, multiple
skills may not become apparent until potential causes, and long latent
school age. Indeed, some investigators periods between exposures and
report that some chemicals administered recognition of symptoms combine
during development have effects on to ensure that establishing causal
brain function in subsequent connections between symptoms and
generations. 10 Delays of this sort make chemical exposures will be difficult.
it extremely difficult to attribute a
Neurodevelopmental
functional brain abnormality to an
Toxicity Testing
earlier chemical exposure.
Laboratory and epidemiological
In addition, the symptoms of
research over several decades has led to
impaired brain function are not
considerable insight into the capacity of
specific for each potential cause. That
a few neurodevelopmental toxicants to
is, cognitive and behavioral disorders,
interfere with normal brain
or even mental retardation, may have
development, often with severe and
multiple causes, including genetic and
lasting consequences. Unfor tunately ,
envir onmental factors. Mor eover , even
extensive information is available for
a known neurodevelopmental toxicant,
only a few chemicals, though more
like alcohol, may cause a range of
neurodevelopmental data on many
adverse ef fects including pr ematurity ,
others are urgently needed. As new
cognitive disorders, mental retarda-
research is contemplated, an important
tion, and disturbances of sexual
question focuses on the degree to which
Greater Boston Physicians for Social Responsibility 27
C H A P T E R 2 : N o r m a l B r a i n D e v e l o p m e n t a n d D e v e l o p m e n t a l To x i c o l o g y
animal testing data predict neurological underestimate the sensitivity of the
consequences of exposure in humans. developing human brain. For example,
A retrospective look at the evolution based on comparisons of animal and
human data, animal studies of lead,
of understanding of the neurodevelop-
mercury, and PCBs predict a 鈥渟afe鈥?
mental toxicity of lead, mercury, and
exposure level in humans that is 2-4
PCBs is instructive. In an historical
review of this question, Rice et al. conclude orders of magnitude (100-10,000 fold)
higher than levels that actually cause
that animal studies, particularly rodent
studies, are disappointing in their ability effects in humans. These sobering limitations
to predict 鈥渟afe鈥? exposure levels, below must be kept in mind as we use the results
which no human health effects are likely of animal testing to estimate 鈥渟afe鈥?
human exposure levels. (see Chapter 7)
to occur.11 Rodent studies often vastly
1 Paus T, Zijdenbos A, Worsley K, et al. Structural maturation of 7 Paus T, Zijdenbos A, Worsley K, et al. Structural maturation of
neural pathways in children and adolescents: in vivo study. neural pathways in children and adolescents: in vivo study. Science
Science 283:1908-1911, 1999. 283:1908-1911, 1999.
2 Ravikumar BV, Sastry PS. Muscarinic cholinergic receptors in 8 Porterfield SP. Vulnerability of the developing brain to thyroid
human fetal brain: characterization and ontogeny of 3H- abnormalities: environmental insults to the thyroid system. Environ
quinuclidinylbenzilate binding sites in frontal cortex. J Health Perspect 102(suppl 2):125-130, 1994.
Neurochem 44:240-246, 1985.
9 Haddow JE, Palomaki GE, Allan WC, Williams JR, et al. Maternal
3 Ahlbom, J, Fredriksson A, Erikson P. Neonatal exposure to a thyroid deficiency during pregnancy and subsequent
type-1 pyrethroid (bioallethrin) induces dose-response changes neuropsychological development of the child. N Engl J Med
in brain muscarinic receptors and behavior in neonatal and adult 341(8):549-555, 1999.
mice. Brain Res 645:318-324, 1994.
10 Campbell JH, Perkins P. Transgenerational effects of drug and
4 Lauder JM, Schambra UB. Morphogenetic roles of hormonal treatments in mammals: a review of observations and
acetylcholine. Environ Health Perspect 109(suppl 1):65-69, 1999. ideas. Prog Brain Res 73:chapter 33, 1988.
5 McGehee DS, Heath MJS, Gelber S, et al. Nicotine enhancement 11 Rice D, Evangelista de Duffard A, Duffard R, et al. Lessons for
of fast excitatory synaptic transmission in CNS by presynaptic neurotoxicology from selected model compounds: SGOMSEC joint
receptors. Science 269:1692-1696, 1995. report. Environ Health Perspect 104(suppl 2):205-215, 1996.
6 Wiggins RC. Myelination: a critical stage in development.
Neurotoxicol 7:103-120, 1986.
28 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 3 : The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
Chapter 3
The Clinical Spectrum of
Developmental, Learning and
Behavioral Disorders in Children
What鈥? In a Label? - W
s orking neural circuitry, cellular and subcellular
Definitions in Evolution structure and function.3 4 5 6 Since most
of these details lie beyond the current
T he disorders of learning, behavior
limits of science, the
and development cover a wide
Distinguishing among the
biological basis of these
spectr um of disability , ranging fr om
various syndromes, and the
disorders remains poorly
subtle to devastating. Distinguishing
understood. Consequently, 鈥渘ormal鈥? from the 鈥渁bnormal鈥?
among the various syndromes, and the
is a subject of considerable
the developmental
鈥渘ormal鈥? from the 鈥渁bnormal鈥? is a
discussion and uncertainty...
syndromes are defined by
subject of considerable discussion and
these disorders may be best
clinical symptoms, such as
uncer tainty .1 The lack of consensus on
characterized as works in
how children appear or
these issues is reflected in the large
progress, rather than rigid
behave. Since these
number of alternate approaches to
diagnostic entities.
defining symptoms are
diagnosis and classification, and in the
nonspecific, each symptom
frequency with which old syndromes are
may occur as a part of many
redefined 2 and new ones appear . As a
developmental, medical and psychiatric
result, these disorders may be best
conditions, as well as in normal children.7 8
characterized as works in progress,
rather than rigid diagnostic entities. Developmental disorders are most
often diagnosed according to a system of
The difficulties in diagnosis are not
classification known as the DSM-IV ,
surprising, since learning, behavior, and
(The Diagnostic and Statistical Manual
developmental disorders lack specific
of Mental Disorders, Edition IV). As a
markers - such as unique symptoms,
categorical system of classification, the
blood tests or physical attributes. The
DSM-IV uses 鈥渃linically derived
limits of current scientific knowledge also
categories of classification based mostly
prevent an understanding of biological
on subjective consensus.鈥? 9 The DSM-IV
underpinnings of these disorders. While
enumerates criteria for diagnosing
gross brain structure usually appears
generally recognized mental health
normal, it is widely assumed that
disorders. These criteria typically include
underlying problems exist at the level of
Greater Boston Physicians for Social Responsibility 29
CHAPTER 3: The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
symptoms, their durations, and
exclusions. For a partial list of
DIAGNOSTIC
diagnostic criteria for development,
DILEMMAS
learning and behavioral disorders,
C
onsider the question
see the chart on page 35.
of whether a fidgety,
Observers have identified a number
forgetful child has ADHD.
of drawbacks with this system of
According to the most recent, widely used
diagnosis, problems which are often
definition, set by DSM IV in 1994, a child has
associated with categorical
ADHD if she/he exhibits at least six maladap-
classification. They include 10 :
tive, age-inappropriate symptoms in the areas
1. Lack of empirical foundations;
of inattention or hyperactivity/impulsivity,
with the added condition that these symptoms
2. Reliance on subjective-
have been present for at least six months.
impressionistic criteria to
The criteria symptoms, however, lack both
derive individual categories;
specific definitions and thresholds for determin-
3. Unsubstantiated assumptions
ing when a symptomatic behavior is occurring.
regarding etiology;
Consider one of the DSM IV criteria symptoms:
4. Lack of objective, validated criteria
鈥渇ails to give close attention to details.鈥? How
for assigning diagnostic labels;
close is close, and at what level of detail? A
10 year old might fail to notice the name of 5. Failure to integrate the influence
the 5th president from the complete list of US of context into diagnostic criteria;
presidents, the color of the teacher鈥檚 shoes, or
6. Lack of demonstrated relevance
today鈥檚 homework assignment written on the
to treatment;
blackboard. And how often should the child
The lack of a unifying, empirically-
have failed to pay close attention, 1%, 5%, or
derived classification framework has
50% of the time? Is a child failing to pay close
several important consequences. The
attention to detail if s/he neglects to bring in
considerable impact on clinical practice
his homework one, two, three or eight times
was summarized by one observer as
a month? Clearly the conclusion that a child is
follows: 鈥淟ooked at realistically, what
鈥渋nattentive鈥? is subjective and depends on the
this means is that after the elaborate
expectations and judgment of the observer.
procedures used in most clinics are
completed, the child is placed in a
category, which says exactly what we
Empirical: knew about him in the first place, that
DEF I NI TI O N -
he has a problem.鈥?11 In addition, as a
Derived from experience,
result of the reliance on subjective
observation or experiment.
diagnostic criteria, up to 30% of parents
report their children have been labeled
with three or more different diagnoses.12
30 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 3 : The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
settings. 17 In some cases labels also
The lack of a unifying framework
also makes communication difficult provide access to supportive services.
In spite of the limits
These syndromes are described in detail
among professionals, who may call
to the current system
similar disabilities by different names, or in the appendix. As an introduction for
of classification, the
different disabilities by the same name. readers not already familiar with them,
clinical syndromes
we present here an abbreviated,
Research is also impaired when terms are
commonly used to
ambiguous, since data from diverse admittedly oversimplified account of
label children with
sources cannot be readily compared. these disor ders as cur rently defined. T o
developmental
organize this discussion, we use a
These concerns were summarized by two
disabilities provide a
noted researchers, Achenbach and pragmatic framework representing a
set of management
Edelbrock, in their observation that 鈥渢he composite of W olraich, author of a
strategies.
18
widely used text in child development,
study of psychopathology in children has
long lacked a coherent taxonomic and the DSM-IV. While this framework
framework within which training, differs slightly from the traditional
DSM-IV this appr oach is suited to the
,
treatment, epidemiology, and research
could be integrated.鈥?13 brief discussion offered here.
Fortunately , much of the cur rent
research in learning and developmental
OVERLAPPING SYNDROMES:
disorders focuses on improving With thousands
diagnosis and classification of childhood Percentpotentially ADHD that also have
of of kids with
disabilities. 14 This will establish a more other developmental and social/psychiatric
neurotoxic
meaningful use of diagnostic labels. In disorders24
chemicals in
addition, there is increasing recognition widespread use,
鈥? 10-30% have learning disabilities.
of the importance of integrating our snail鈥檚 pace
methods, vocabular y, concepts and 鈥? 30-50% have language disability (a core symptom of autism
approach to
knowledge across disciplines. 15 16 This when expressed in its extreme form.)
regulation clearly
will ultimately improve research on sets children in a
鈥? 30-80% have oppositional disorder or conduct disorder.
underlying mechanisms, causes, minefield of
鈥? Frequently associated with other neurodevelopmental disorders:
treatments and prevention. uncertainty and
Asperger鈥檚, obsessive compulsive disorder, tic disorders, and
potential harm
A Brief Overview of the Disor
ders mental retardation.
of Learning, Behavior and 鈥? May accompany social and psychiatric disorders: anxiety, depres-
Development sion, schizophrenia. (In the presence of a mental disorder, the
In spite of the limits to the current diagnosis of ADHD cannot be made if the symptoms can be better
system of classification, the clinical accounted for by the accompanying social/psychiatric condition.)
syndromes commonly used to label
children with developmental disabilities
provide a set of management strategies.
These strategies address the practical
concerns of managing dysfunctional or
inappropriate behavior in various
Greater Boston Physicians for Social Responsibility 31
CHAPTER 3: The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
1.Academic Disorders 2. Pervasive Developmental Disorders
Disorders predomin- As the scope of disability increases,
antly expressed in the problems tend to extend beyond the
learning environment can classroom setting. If several functions are
be classified as 鈥渁cademic impaired, a child is considered to have
disorders.鈥? These include a 鈥減er vasive developmental disor der,鈥?
learning disabilities, such or PDD. The mildest pervasive
as the disorders of developmental disor der, Asper ger 鈥檚
reading, math, and syndrome, is characterized by impaired
written expression. social interactions and restricted behavior
Attention deficit and interests. Social impairment is
hyperactivity disor der, characterized by lack of emotional
or ADHD, can also be recipr ocity, impair ed nonverbal
considered an 鈥渁cademic exchanges such as eye-to-eye gaze and
disor der.鈥? Although pr oblems must facial expressions, and disinterest in
occur in more than one setting in order shared experience. Restricted, repetitive
to meet diagnostic criteria, for most behaviors and interests are characterized
children the strongest expression of by encompassing preoccupations,
ADHD occurs in the school setting. adherence to nonfunctional routines or
As the scope of ADHD consists of a mix of attentional rituals, or repetitive motor mannerisms
disability increases, problems, which are considered such as hand flapping or finger twisting.
problems tend to cognitive disabilities, and impaired When language deficits compound
extend beyond the impulse control. Impulse control is social impairments and restricted/
classroom setting. thought to be an expression of the repetitive behaviors, a child is considered
If several functions ability to self-regulate, a trait technically to have a more serious pervasive
are impaired, a referred to as 鈥渆xecutive function.鈥? 19 developmental disor der. Autism is the
child is considered Impairment in the ability to self-regulate prototype of these serious PDDs, which
to have a 鈥減ervasive is increasingly recognized as a unifying in most cases are marked by loss of the
developmental feature of ADHD. In the domain of capacity for self care as well. The serious
disorder,鈥? or PDD. motor activity , this is expr essed as PDD鈥? may be characterized by mor e
s
hyperactivity , for example by fr equent extreme restricted/repetitive behaviors,
fidgeting or the inability to sit still. In such as spinning, hand flapping, or head
the domain of social behavior , impair ed or body rocking. Interests are severely
self-regulation is expressed in intrusive restricted in autism, as exemplified by the
actions such as the inability to await relative absence of pr etend play . This is
one鈥? s tur n, or recur rently intr uding into illustrated, for example, in the
conversations and games. observation that autistic children,
compared to control children, are more
32 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 3 : The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
likely to arrange objects into patterns surprising considering the fine line
or lines, or to shake or twirl toys rather between impaired impulse control and
than play imaginatively with them. 20 disruptive or aggr essive behavior . The
close relationship of these disorders is
Mental r etar dation and PDD鈥? s
Behavioral disorders
reflected in the fact that 30-80% of
are both characterized by severe
are also prominently
children diagnosed with ADHD are also
functional impairment, and many
expressed well
children with PDD鈥? s will also meet test
beyond the
criteria for mental r etar dation. PDD鈥檚
EXAMPLE OF SYMPTOM OVERLAP classroom setting.
are distinguished from mental retardation
(OR NONSPECIFICITY): 鈥淪TEREOTYPIES鈥?: Children are labeled
by the presence of repetitive, restricted
with these disorders
R
behaviors, and social and communication estricted, repetitive patterns of behavior
when their behavior
impairments that are disproportionately and interests, which characterize
is marked by the
impaired for a given IQ level. 21 pervasive developmental disorders, are
predominance of
referred to as 鈥渟tereotypies.鈥? Although
3. Behavioral Disorders disruptive or
stereotypies are a
Behavioral disorders are also aggressive features.
necessary condition
prominently expressed well beyond the
for making the diag-
classroom setting. Children are labeled
`nosis of a pervasive
with these disorders when their behavior
developmental disorder,
is marked by the predominance of
they are not unique to pervasive develop-
disruptive or aggressive features. When
mental disorders. They are also present in
this behavior is directed mainly towards
mental retardation, schizophrenia, Parkinson鈥檚
authority figures, the disorder is
Disease and obsessive-compulsive disorder.25
typically labeled as Oppositional
Defiant Disorder (ODD). When
felt to have ODD or CD 23 . The
disruptive/aggressive bevavior is more
similarities of ADHD, ODD and CD are
broadly directed, and of sufficient
further reflected in the fact that ADHD
intensity to violate social norms and the
is commonly classified not as an
rights of others, the problem is likely to
academic disor der, but rather as the
be labeled Conduct Disorder (CD). 22
mildest of the behavioral disorders.
These disorders are distinguished from
PDD鈥? by the pr ominence of disr uptive/
s For the sake of discussion in this
aggr essive behavior , by relatively nor mal report, learning and developmental
verbal and nonverbal communication disabilities can be organized in an
skills, and by the absence of repetitive/ admittedly over -simplified framework
restricted behaviors and interests. using three intersecting arrays of related
disorders. Each array can be thought of
The clinical descriptions of
behavioral disorders notably overlap
with that of ADHD. This is not
Greater Boston Physicians for Social Responsibility 33
CHAPTER 3: The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
as a different dimension of function,
Spectrum of Developmental Disorders
along which the syndromes represent
various degr ees of disability . From this
perspective, Asper ger 鈥檚 and autism
Conduct
Disorder
represent increasing impairment along
BEHAVIOR
a developmental axis including social
Oppositional
Defiant
dysfunction, restricted behaviors, and
Behavior
r's
impaired communication. On a second
ge m
er tt's tis
D
p
CD Au
Re
As
ADHD
axis, ADHD, ODD and CD can be
DEVELOPMENT seen as progressive expressions of
VE
disruptive/aggr essive behavior . On a
TI
AD
NI
HD
Le
G
third axis, ADHD, LD, and MR can
Di ar
O
sa nin
/C
bil g
be considered progressive expressions
M itie
Re ent
IC
s
ta al
EM
of cognitive dysfunction.
rd
ar
AD
ion
AC
Figure: A
File: IHW
For the purpose of discussion,
developmental disorders can be
organized using a framework of inter-
secting arrays. Each array represents a
different dimension of function, along
which the syndromes represent varying
degrees of disability. Each dimension can
be seen as a spectrum of disability, in
which there is considerable overlap
between the various disorders.
Cognitive:
DEF I NI TI O N -
Pertaining to the process of the
mind, such as perceiving, thinking,
or remembering.
34 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 3 : The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
Developmental Syndromes: Conventional Clinical Classifications
POSSIBLE COGNITIVE/
BEHAVIORAL
SYNDROME DEFINITION EXPRESSIONS
鈥淎cademic鈥? Disorders
Disorder in one or more of basic
Learning Disorders - Including Cognitive processing
processes involved in understanding
Disorders of Reading, deficits
or using language including reading,
Mathematics, Written Communication deficits
writing and mathematical skills.
Expression; and also
Achievement on standardized tests
Communication Disorders,
significantly lower than expected for
including Disorders of Expressive
age, schooling and level of intelligence
Language, Mixed-Receptive
(2 standard deviations). Interfere with
Expressive Language,
academic achievement or activities of
Phonological, Stuttering
daily life that require those skills.
鈥淎cademic鈥? and Behavioral Disorders
Attention Deficit Persistent pattern of at least Hyperactivity
Hyperactivity Disorder 6 symptoms of inattention and/or Impulsivity
(ADHD) hyperactivity-impulsivity for at least 6 Inattention
months that were present prior to age
Types:
7, that impair normal functioning, and
鈥? Combined that appear in 2 or more settings.
Impairment in social, academic or
鈥? Predominately Hyperactive
occupational functioning.
鈥? Predominately Inattentive
Behavioral Disorders
A repetitive and persistent pattern of
Conduct Disorders including Aggression
behavior in which the basic rights of
those that are Mild, Moderate Fighting
others or major age-appropriate
and Severe Stealing
societal norms or rules are violated. Vandalism
At least three (or more) of following Blaming others
criteria (in past 12 months with one Low self-esteem
criterion in last 6 months): Poor tolerance
irritability, temper
Aggression to people and animals,
tantrums
destruction of property, deceitfulness,
Lying
theft, serious violation of rules. Little
Truancy
empathy/concern for well being of
Substance abuse
others. Childhood Onset Type and
Adolescent Onset Type.
Greater Boston Physicians for Social Responsibility 35
CHAPTER 3: The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
Developmental Syndromes: Conventional Clinical Classifications continued
POSSIBLE COGNITIVE/
BEHAVIORAL
SYNDROME DEFINITION EXPRESSIONS
Behavioral Disorders
Oppositional Defiant Disorder Pattern of negativistic, defiant, Hostility
disobedient and hostile behavior toward Verbal aggression
authority figures for at least 6 months. Anger
Onset usually prior to age 8, not later
than early adolescence, with symptoms
increasing with age. Must exhibit at least
4 of the following behaviors 鈥搇oses
temper, argues with adults, defies rules,
deliberately annoys, blames others,
angry, resentful, spiteful, overreactive.
Developmental Delays
Significantly sub-average intellectual
Mental Retardation 鈥? Including Mental retardation
functioning (I.Q. 70 or below鈥攁t least
Mild, Moderate, Severe, Deficits in a range of
2 standard deviations below the mean)
Profound, Unspecified cognitive/behavior traits
WITH significant limitation in adaptive
functioning. Onset prior to age 18.
Pervasive Developmental Disorders
Severe and sustained impairment Motor delays,
Asperger鈥檚 Syndrome
motor clumsiness
in social interaction with restricted,
Idiosyncratic or
repetitive patterns of behavior, interest
circumscribed interests
and activities.
Problems with empathy
and modulation of
social interaction
Abnormal
Impaired social interaction, impaired
Autism
non-verbal gestures
communications skills, restricted and
Delay in or lack of
stereotyped repertoire of activity and
spoken language
interests. Must have total of six with no other form
characteristics in above 3 categories. of compensation
Hyperactivity
Onset prior to age 3.
Attention deficit
Aggression
Violence to self
Repetitive motor
mannerisms
36 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 3 : The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
Developmental Syndromes: Conventional Clinical Classifications continued
POSSIBLE COGNITIVE/
BEHAVIORAL
SYNDROME DEFINITION EXPRESSIONS
Pervasive Developmental Disorders
Regressive development physically and Deceleration of head
Rett鈥檚 Disorder
mentally after normal development in growth
first-second year of life. Usually Severe psychomotor
associated with severe or profound retardation
mental retardation. Onset usually prior Cognitive deficits
to age 4. Reported only in females.
Motor dysfunction
Impaired social
interaction
Stereotyped hand
movements
Regression in multiple areas of
Childhood Disintegrative Delay or lack of speech
functioning after at least 2 years of
Disorder Repetitive and
apparently normal development. Loss stereotyped behavior
of previously acquired skills in
Cognitive deficits
expressive or receptive language, social
Motor dysfunction
skills or adaptive behavior, bowel or
Impaired social
bladder control, play, or motor skills.
interaction
Usually associated with severe mental
retardation. Onset between ages 3-4.
More common in males.
Notes:
1. Definitions are those from the Diagnostic and Statistical
Manual of Mental Disorders IV (DSM IV), although definitions of
learning disabilities as a general category may change from state
to state and also as classified for funding for treatment purposes.
See Appendix for references.
2. Many of the syndromes have overlapping traits with others.
These have not been detailed.
Greater Boston Physicians for Social Responsibility 37
CHAPTER 3: The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
Public Health Impact Nearly 40% of adults with
learning disabilities have
Behavioral problems, learning
significant difficulties with
disabilities and developmental delays
employment or social
have important public health effects in
adjustment.
the United States, as demonstrated by
the following statistics:
unemployed one year after
鈥? It is estimated that 5% - 10% of the
graduating high school. 6
school age population have learning
disabilities. 1 2 52% of all students in 鈥? 35% of all students identified as
special education in public schools learning disabled drop out of high
have learning disabilities. This equals school. This is twice the rate of their
about 2.25 million children. 3 peers without disabilities. 7
鈥? 50% of females with learning
disabilities will be mothers (many of
READING DISABILITY MAY HAVE CONSEQUENCES
them single) within 3-5 years after
BEYOND SCHOOL17
leaving high school. 8
T
鈥? he eager third graders experiencing reading
鈥? Up to 60% of adolescents in
difficulties become, in turn, the frustrated
treatment for substance abuse have
ninth graders who drop out of school, the barely
undetected learning disabilities. 9
literate 25-year-olds who read at a fourth or fifth
鈥? Learning disabilities and substance
grade level, the thirty-something generation who
abuse are the most common
are unemployed, and the defeated adults now
impediments to the employment of
raising families and needing public assistance.鈥?
welfare clients. 10
鈥? 31% of adolescents with learning
鈥? Nearly 40% of adults with disabilities will be arrested 3-5 years
after leaving high school. 11 The only
learning disabilities have
significant difficulties with adolescents with a higher arrest rate
4
employment or social adjustment. were those with emotional
disturbance (57.6%). 12
鈥? Individuals with ADHD obtain less
schooling and have poorer 鈥? Adolescents with learning disabilities
vocational achievement than their are disproportionately involved with
peers. 5 62% of students with the juvenile justice system. 50% of
learning disabilities were juvenile delinquents tested were
found to have undetected learning
disabilities. The cost of juvenile
incarceration is between $35,000 to
$60,000 per year per person. 13
38 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 3 : The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
LEARNING DISABILITIES WERE RECOGNIZED
AS A FEDERALLY DESIGNATED HANDICAPPING
CONDITION IN 1968
Public Law 94-142, the Education for all Handicapped
Children Act of 1975, was reauthorized and amended
several times and reenacted as the Individuals with
Disabilities Education Act of 1990 (IDEA) (PL-476) and the
Americans with Disabilities Act of 1990 (ADA) (PL101-336).18
E ver since the first effort to define learning disabilities in 1962
there has been controversy surrounding the diagnosis,
鈥? Learning disabled individuals
interventions, and educational policies regarding learning disabilities.
are more likely to be found
Some of the controversy can be attributed to the fact that definitions
delinquent in juvenile court, to
used by educators are not always the same as those used by mental
be taken into custody by the police,
health (psychological) professionals and/or those engaged in
and to receive more severe penalties
neurological research. Establishing a definition for a learning disability
because of their inability to
is important because governmental research, policy and funding, such
effectively communicate or
as the number of children eligible for special education services and
understand their situation. 14 15
what these services will be, are based on the individual meeting the
鈥? It is estimated that 42% of adults
appropriate criteria. For example, it is not unusual for a learning
in correctional institutions were
disability condition or diagnosis to change when an individual moves
eligible for special education. 16
from one state to another. Definitions of Learning Disabilities are
Significant public funds and described in further detail in the Appendix.
resources are spent each year on
diagnosis, treatment and the study of
these disorders. Implementation, design for failure in the classroom or the
and adequate funding of appropriate workplace.19 For many, these difficulties
treatment and prevention programs to are lifelong and continue to cause
best serve the children and public will hardships in adulthood. For example,
require coordinated efforts on the part according to employers, individuals with
of parents, teachers, policy makers, learning disabilities have a harder time
researchers, and the government. keeping a job, learning new occupational
skills, and getting along with co-
Social Impact workers.20
Children with learning disabilities, Children with these disorders may
developmental delays, and behavioral encounter a number of social, inter -
disorders encounter a wide range of personal, and emotional difficulties that
difficulties in learning, speaking, reading, are associated with their disability/
writing, mathematics, attention, and disabilities. For example, students with
behavior that put them at substantial risk learning disabilities are often alienated,
Greater Boston Physicians for Social Responsibility 39
CHAPTER 3: The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
isolated, and misunderstood, which can additional costs of adequately caring for
lead to difficulties with social adjustment such a child can be staggering for the
and life goal attainment. 21 They also are family . Depending on the level of
more likely to engage in substance abuse, disability , the child may need additional
become delinquent, commit crimes as psychological, medical, and/or
adults, and have higher rates of suicide educational services, which may not be
and mental illness than are other completely covered by medical insurance
students. 22 The risk of these difficulties is and/or other funding sources. In
enhanced if the individual is from a addition, parents or caretakers of
lower social economic status. Many of developmentally delayed children may
these same difficulties are associated encounter difficulties such as a lack of
with those children diagnosed with programs to sustain their children in
ADHD, as they are more likely to obtain appropriate educational environments
less schooling, have poorer vocational and/or supported living situations. Other
achievement, and have a higher difficulties, including lack of respite care
prevalence of mood disorders and and other support services, may occur in
anxiety disorders. 23 terms of funding and/or finding adequate
living and work situations when their
There is also likely to be additional
children become adults. Many quality of
stress placed on the family of a child
life issues are raised for children with the
diagnosed with a learning,
aforementioned disorders. Adequate
developmental, and/or behavioral
funding of appropriate services is a
disor der. Even if a developmentally
public health concern that needs to be
delayed child lives at home, the
addressed.
40 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 3 : The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
Footnotes, Part 1 20 Stone WL, Ousley OY. Pervasive developmental disorders:
autism. In: Disorders of Development and Learning. Second
1 Mash EJ, Terdal LG. Assessment of child and family
Edition. Ed. Wolraich ML. St. Louis: Mosby, 1996, p.389.
disturbance:a behavioral-system approach. In: Assessment of
Childhood Disorders.Third Edition. Eds. Mash EM, Terdal LG. New 21 American Psychiatric Association. Diagnostic and Statistical
York: Guilford Press, 1997, p.3. Manual of Mental Disorders. Fourth Edition. Washington:
American Psychiatric Association. 1994.
2 Mann CC. Behavioral genetics in transition. Science 264:1686-
1689, 1994. 22 McMahon RJ, Estes AM. Conduct problems. In: Assessment of
Childhood Disorders.Third Edition. Eds. Mash EM, Terdal LG. New
3 Stone WL, Ousley OY. Pervasive developmental disorders:
York: Guilford Press, 1997.
autism. In: Disorders of Development and Learning. Second
Edition. Ed. Wolraich ML. St. Louis: Mosby, 1996, p.381. 23 Baumgaertel A, Copeland L, Wolraich ML. Attention deficit
hyperactivity disorder. In: Disorders of Development and
4 Baumgaertel A, Copeland L, Wolraich ML. Attention deficit
Learning. Second Edition. Ed. Wolraich ML. St. Louis: Mosby,
hyperactivity disorder. In: Disorders of Development and
1996,p.428.
Learning. Second Edition. Ed. Wolraich ML. St. Louis: Mosby,
1996, p.432. 24 Baumgaertel A, Copeland L, Wolraich ML.ibid.
5 Coyle J. Foreward. Handbook of Developmental 25 Ridley RM. The psychology of perseverative and stereotyped
Neurotoxicology. Eds. Slikker W, Chang LW. San Diego: Academic behavior. Prog Neurobiol Oct:44(2):221-31, 1994.
Press, 1998, p. xv.
6 Taylor HG. Critical issues and future directions in the Footnotes, Part 2
development of theories, models, and measurements for
1 American Psychiatric Association. Diagnostic and Statistical
attention, memory, and executive function. In:Attention,
Manual, Fourth Edition. Washington, DC. 1994.
Memory and Executive Function. Eds. Lyon GR, Krasnegor NA.
2 Parrill M. Research Implications for health and human services.
Baltimore: Paul H. Brookes Publishing Co, 1996, p.405.
In Cramer SC, Ellis E. Learning disabilities: Lifelong issues. Paul H.
7 Stone WL, Ousley OY. Pervasive developmental disorders:
Brookes Publishing Company, Inc, Baltimore, 1996. Pgs. 277-293.
autism. In: Disorders of Development and Learning. Second
3 U.S. Department of Education. In Cramer SC, Ellis E (eds).
Edition. Ed. Wolraich ML. St. Louis: Mosby, 1996.
Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
8 Baumgaertel A, Copeland L, Wolraich ML. Attention deficit
Company, Inc., Baltimore; 1996. P.xxx (introduction).
hyperactivity disorder. In: Disorders of Development and
4 American Psychiatric Association. Diagnostic and Statistical
Learning. Second Edition. Ed. Wolraich ML. St. Louis: Mosby,
Manual, Fourth Edition. Washington, DC. 1994.
1996.
5 American Psychiatric Association, Diagnostic and Statistical
9 Mash EJ, Terdal LG. Assessment of child and family
Manual. Fourth Edition. Washington, DC. 1994.
disturbance:a behavioral-system approach. In: Assessment of
Childhood Disorders.Third Edition. Eds. Mash EM, Terdal LG. New 6 Wagner M, Newman L et al. In Cramer SC, Ellis E (eds).
York: Guilford Press, 1997, p.17. Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
Company, Inc., Baltimore; 1996.
10 Mash EJ, Terdal LG ibid, p.16.
7 Wagner M, Newman L et al. In Cramer SC, Ellis E (eds).
11 Dreger RM, Lewis PM, Rich TA et al. Behavioral classification
Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
project. Journal of Consulting Psychology 28:1-13, 1968. Cited in
Company, Inc, Baltimore; 1996. p.xxx (introduction).
Assessment of Childhood Disorders.Third Edition. Eds. Mash EM,
Terdal LG. New York: Guilford Press, 1997,p.16. 8 Wagner M, Newman L et al. In Cramer SC, Ellis E (eds).
Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
12 Gorham KA, DesJardins C, Page R. et al. Effect on parents. In:
Company, Inc., Baltimore; 1996. p.xxx (introduction).
Issues in the Classification of Children, Ed. Hobbs N, Vol. 2, p. 154-
188. San Francisco:Jossey-Bass, 1974. Cited in Assessment of 9 Wagner M, Newman L et al. In Cramer SC, Ellis E (eds).
Childhood Disorders.Third Edition. Eds. Mash EM, Terdal LG. New Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
York: Guilford Press, 1997,p.16. Company, Inc., Baltimore; 1996. p.xxx (introduction).
13 Achenbach TM, Edelbrock CS. The classification of child 10 Office of the Inspector General. In Cramer SC, Ellis E (eds).
psychology: A review and analysis of empirical efforts. Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
Psychological Bulletin 85:1275-1301. 1978. Cited in Mash ibid, Company, Inc., Baltimore; 1996. p.xxx (introduction).
p.16. 11 Wagner M, Newman L et al. In Cramer SC, Ellis E (eds).
14 Mash EJ, Terdal LG. Assessment of child and family Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
disturbance:a behavioral-system approach. In: Assessment of Company, Inc., Baltimore; 1996. p.xxx (introduction).
Childhood Disorders.Third Edition. Eds. Mash EM, Terdal LG. New 12 Parrill M. Research Implications for health and human
York: Guilford Press, 1997. services. In Cramer SC, Ellis E (eds). Learning disabilities: Lifelong
15 Lyon GR. Preface. Attention, Memory and Executive Function. issues. Paul H. Brookes Publishing Company, Inc., Baltimore;
Eds. Lyon GR, Krasnegor NA. Baltimore: Paul H. Brookes 1996. Pgs. 277- 293.
Publishing Co, 1996 13 McGee TP. Reducing school behavior and preventing criminal
16 Taylor HG. Critical issues and future directions in the behavior. In Cramer SC, Ellis E (eds). Learning disabilities:
development of theories, models, and measurements for Lifelong issues. Paul H. Brookes Publishing Company, Inc.,
attention, memory, and executive function. In:Attention, Baltimore; 1996. Pgs. 229-233.
Memory and Executive Function. Eds. Lyon GR, Krasnegor NA. 14 Eggleston CR. The justice system. In Cramer SC, Ellis E (eds).
Baltimore: Paul H. Brookes Publishing Co, 1996. Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
17 Wolraich ML. Ed. Disorders of Development and Learning. Company, Inc., Baltimore; 1996. Pgs. 197-201.
Second Edition. Ed.. St. Louis: Mosby, 1996. 15 Dickman GE. The link between learning disabilities and
18 Wolraich ML. Ibid. behavior. In Cramer SC, Ellis E (eds). Learning disabilities:
Lifelong issues. Paul H. Brookes Publishing Company, Inc.,
19 Barkley RA. Attention-deficit/hyperactivity disorder. In:
Baltimore; 1996. Pgs. 215-228.
Assessment of Childhood Disorders.Third Edition. Eds. Mash EM,
Terdal LG. New York: Guilford Press, 1997, p.77. 16 Eggleston CR. The justice system. In Cramer SC, Ellis E (eds).
Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
Company, Inc., Baltimore; 1996. Pgs. 197-201.
Greater Boston Physicians for Social Responsibility 41
CHAPTER 3: The Clinical Spectrum of Developmental, Learning and Behavioral Disorders in Children
17 Shaywitz SA, Shaywitz B. Unlocking learning disabilities: The 21 Eggleston CR. The justice system. In Cramer SC, Ellis E (eds).
neurological basis. In Cramer SC, Ellis E (eds). Learning disabilities: Learning disabilities: Lifelong issues. Paul H. Brookes Publishing
Lifelong issues. Paul H. Brookes Publishing Company, Inc., Company, Inc., Baltimore; 1996. Pgs. 197-201.
Baltimore; 1996. Pgs. 255-260. 22 Dickman GE. The link between learning disabilities and
18 Lyon GR. The state of research. In Cramer SC, Ellis E (eds). behavior. In Cramer SC, Ellis E (eds). Learning disabilities: Lifelong
Learning disabilities: Lifelong issues. Paul H. Brookes Publishing issues. Paul H. Brookes Publishing Company, Inc., Baltimore; 1996.
Company, Inc., Baltimore; 1996. Pgs. 3-61. Pgs. 215-228.
19 Alexander D. Learning disabilities as a public health concern. In 23 American Psychiatric Association. Diagnostic and Statistical
Cramer SC, Ellis E (eds). Learning disabilities: Lifelong issues. Paul Manual, Fourth Edition. Washington, DC. 1994.
H. Brookes Publishing Company, Inc., Baltimore; 1996. Pgs.249-253.
20 Alexander D. Learning disabilities as a public health concern. In
Cramer SC, Ellis E (eds). Learning disabilities: Lifelong issues. Paul
H. Brookes Publishing Company, Inc., Baltimore; 1996. Pgs.249-253.
42 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 4: The Long Road From Research to Real Life
Chapter 4
The Long Road From
Research to Real Life
The Widening Gap This explosion of information in
child development results from a variety
I n the past two decades, several of new technologies and methods. For
disciplines have emerged that open example, developments in molecular
exciting new perspectives in child biology revolutionized molecular
development and learning. As genetics and molecular neur ochemistr y,
summarized by G. Reid L yon, a noted permitting us to explore a variety of
researcher in child development, domains within the cell, including the
鈥淎n explosion of research activity in human genome, and the processes of
attention, memor y, and executive gene expression, neurotransmitter
function has occurred since the mid- production, and cellular communication.
1980s. Unfor tunately , the literatur e Powerful new neuroimaging technologies,
relevant to these domains is so including magnetic resonance imaging
voluminous that the important and positron emission tomography
converging trends in the data are (PET scans), vastly improved the D E F I N I T I O N - Genome:
sometimes difficult to identify and understanding of brain structure.
The complete set of genetic
to apply to development and learning Because these technologies can information contained in the
in children. This difficulty is exacerbated selectively highlight regions of the brain chromosomes..
by the application of divergent theories, that are mentally active at the time of
methodologies, and vocabularies that testing, neuroimaging studies can now be
are used to identify and describe normal used to explore the link between brain
and atypical development鈥︹?? 1 structure and function in real time.
While these comments were made Other critical improvements
in reference to particular areas of occurred in spectrometry and gas
research, the problems they describe chromatography . These developments
pervade the field of learning and enabled scientists to measure
development in general. W ith so much unprecedented tiny concentrations of
new information on so many fronts, chemicals, permitting the identification
clinicians and the public are hard and testing of previously unrecognized
pressed to absorb new developments. toxicants. In addition, the application of
Greater Boston Physicians for Social Responsibility 43
CHAPTER 4: The Long Road From Research to Real Life
new computer technologies to the study 3. Research is often constrained by
of cognition generated entirely new technical and methodologic concerns.
models for understanding how the brain 4. Funding sources may preferentially
processes information. favor research with marketable
With the application of these technical applications rather than
new technologies, a variety of new , research relevant to less lucrative
increasingly specialized fields have clinical concerns.
5. Busy clinicians may have limited
interest in new academic topics
lacking clear clinical applications.
By taking an interdisciplinary
approach, this report attempts to narrow
a part of the gap between research,
clinical practice and public understanding.
An interdisciplinary discussion on child
development also supports the evolution
of an over -arching bio-behavioral
framework needed to integrate divergent
2
perspectives on child development.
We focus on r ecent findings in
developmental neurotoxicology because
this research readily translates into
emer ged. W ith incr easing specialization,
simple preventive measures to help
it is no surprise to see widening gaps
protect children at risk. In addition to
between the disciplines of child
having practical applications, the research
development, and between the domains
findings of developmental neurotoxic-
of research and clinical practice. Several
ology are also of considerable academic
factors may contribute to this
interest. Since this research dovetails with
unfortunate rift.
research in other domains, particularly
1. Much of the new information is so
neuroscience and behavioral genetics, it
highly technical it is understood only
furthers our understanding of the biologi-
by experts within the field from
cal basis of development in general. In
which the information originates.
promoting a wider dialogue, we also
2. Researchers and clinicians often hope to make research findings from the
have little contact. Consequently several 鈥渂iological鈥? domains more
research agendas may not accessible to parents and clinicians.
adequately reflect the concerns
of clinicians or parents.
44 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 4: The Long Road From Research to Real Life
Traits: A Bridge Between measures. 10 While the relationship
Divergent Disciplines of traits and clinical syndromes is
(Neurotoxicology, Genetics and being explored, concurrent research
the Clinical Disorders) is attempting to better define and
understand the traits . 11
Child development, like other
behavioral sciences often uses categories Because traits are the subject of
to describe learning, behavior and research in a variety of fields, they
development. 3 Categories focus on provide a basis for
Because traits are the subject of
disease entities such as ADHD, autism, interdisciplinary
research in a variety of fields, they
and other specific disorders. Categories dialogue. This was
provide a basis for interdisciplinary
are inherently dichotomous, meaning illustrated in the
dialogue. Aside from linking the
they imply only two possibilities: the focus of a recent
divergent disciplines of child develop-
child either has or does not have a particu- National Institute of
ment, traits/abilities are well suited to
lar disor der. Alter natively , behavior can Child Health and
Human Development research because they can be tested
be described using the concepts of abilities
and quantified as specific functions.
or traits, which vary as gradations along conference on
a continuum. 4 5 Shor t ter m memor y, attention, memory
impulsivity , and attentional ability ar e and executive function, three traits of
examples of traits relevant to learning, central importance to development and
behavior and development. There is learning. Focusing on traits permitted
growing consensus that a better under - researchers and clinicians from a variety
standing of these traits is critical to of domains, including psychology,
understanding the clinical disorders. 6 neurology, pediatrics and special
education, to exchange information on
Deficits in traits/abilities appear to
methods, concepts, and findings. Since a
correspond to clinical syndromes, but
large body of genetic research has also
relationships have not been clearly
focused on cognitive and behavioral
established. 7 For example, deficits in the
traits, behavioral genetics can also be
trait attention appear to correspond to
integrated into the larger discussion
the clinical syndrome ADHD, however
utilizing traits as a common denominator.
the relationship is not straightforward.
For example, studies show that boys Traits As Useful Outcome
with ADHD perform poorly on Measures in Research
measures of sustained attention, but are Aside from linking the divergent
not impaired in the ability to selectively disciplines of child development,
focus their attention. 8 9 Other studies traits/abilities are well suited to
show that attention deficits in ADHD research because they can be tested
depend on the setting, and that the mere and quantified as specific functions.
presence of an adult in the room at the In toxicology , resear chers incr easingly
time of testing improves attention
Greater Boston Physicians for Social Responsibility 45
CHAPTER 4: The Long Road From Research to Real Life
鈥渆xamine specific functions and superior in detecting subtle
14
processes rather than milestones, neurobehavioral dysfunction.鈥?
accumulated knowledge or general Clinical syndromes like ADHD
abilities.鈥?12 For example, the effects of or Asper ger 鈥檚 syndr ome, may be
in-utero cocaine exposure have been problematic in research because
detected at various stages of infancy and they are categorical rather than
childhood using tests of specific function quantitative, and because their
such as visual definitions continue to change over
recognition time. 15 In addition, clinical syndromes
memory or translate poorly into animal models
attentional which are often used to study the
ability. In effects of toxicants on neurodevelop-
contrast, ment. This is illustrated by the difficulties
standardized developing animal models for autism
THE CONTINUOUS PERFORMANCE
tests of general research. As summarized by Patricia
TEST: AN EXAMPLE OF A TEST FOR
cognitive ability , Rodier, a leading r esear cher in the field,
ATTENTIONAL ABILITY (from Grandjean ) 17
(such as the 鈥?..the behavioral criteria by which
I n the Continuous Performance Test, children Bayley Scales autism and related disorders are
watch a series of animal silhouettes flashed of Infant diagnosed鈥o not invite animal
on a screen. The child鈥檚 task is to press a button Development, experiments鈥uch of our most specific
every time a cat appears over a 4-minute or the Stanford- behavioral information鈥? relates to
interval. The test is scored by the number of Binet Intelligence behaviors that probably are exclusive to
missed responses and the average reaction Scale) have shown humans, such as language, associative
time during the last three minutes. This test little differences pointing, and imitation.鈥? 16
is considered to be a measure of vigilance, between exposed
For all these reasons, the effects of
a particular kind of attention. and unexposed
various factors on neurodevelopment are
children. 13
often measured on specific behavioral
Likewise,
and cognitive abilities rather than on
specific tests of attention, such as the
clinical syndromes or global measures of
Continuous Per formance Test, ar e mor e
development or intelligence. Focusing on
sensitive than global assessments or
traits generally provides a common
neurological exam to low levels of
denominator between different fields of
prenatal mercury exposure. As a
research, produces more reliable and
computer -assisted neur opsychological
sensitive measures, and allows us to
test, the Continuous Per formance Test
study the effects of toxicants and genetics
is sensitive to 鈥渕inute differences in
on the 鈥渘ormal鈥? population as well as
responses鈥? [and] therefore statistically
on those with diagnostic labels.
46 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 4: The Long Road From Research to Real Life
1 Lyon GR. Preface. Attention, Memory and Executive Function. 9 Barkley RA. ADHD and the Nature of Self-Control. New York:
Eds. Lyon GR, Baltimore: Paul H. Brookes Publishing Co., 1996, p.xv. Guildord Press, 1997, p. 10.
2 Taylor HG. Critical issues and future directions in the 10 Barkley RA. Ibid, p.12.
development of theories, models, and measurements for
11 Taylor HG. Ibid. p.401-405.
attention, memory, and executive function. In:Attention, Memory
and Executive Function. Eds. Lyon GR, Krasnegor NA, Baltimore:
12 Fried PA. Behavioral evaluation of the older infant and child.
Paul H. Brookes Publishing Co., 1996, p.400-401.
In: Handbook of Developmental Neurotoxicology. Eds. Slikker W,
Chang LW. San Diego: Academic Press, 1998, p.474-476.
3 Mash EJ, Terdal LG. Assessment of child and family disturbance:a
behavioral-system approach. In: Assessment of Childhood
13 Fried PA. Ibid, p. 476.
Disorders.Third Edition. Eds. Mash EM, Terdal LG. New York:
Guilford Press, 1997, p.16-19. 14 Grandjean P, Weihe P, White RF, et al. Cognitive deficit in 7-
year-old children with prenatal exposure to methylmercury.
4 Plomin R, DeFries JC. The genetics of cognitive abilities and
Neurotoxicology and Teratology 19(6):417-428, 1997.
disabilities. Scientific American, May, 1998:62-69.
15 Mann CC. Behavioral genetics in transition. Science 264:1686-
5 McClearn GE, Volgler GP, Plomin R. Genetics and behavioral
1689, 1994.
medicine. Behavioral Medicine, 22:93-101, 1996.
16 Rodier PM. Neuroteratology of autism. In: Handbook of
6 Taylor HG. Critical issues and future directions in the
Developmental Neurotoxicology. Eds. Slikker W, Chang LW. San
development of theories, models, and measurements for
Diego: Academic Press, 1998, p.662.
attention, memory, and executive function. In:Attention, Memory
and Executive Function. Eds. Lyon GR, Krasnegor NA. Baltimore: 17 Grandjean P, Weihe P, White RF, et al. Cognitive deficit in 7-
Paul H. Brookes Publishing Co., 1996, p.401-405. year-old children with prenatal exposure to methylmercury.
Neurotoxicology and Teratology 19(6):417-428, 1997.
7 Taylor HG. Ibid. p.407.
8 Taylor HG. Ibid. p. 406.
Greater Boston Physicians for Social Responsibility 47
CHAPTER 4: The Long Road From Research to Real Life
48 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
Chapter 5
Multiple Causes of
Developmental, Learning and
Behavioral Disability
Introduction Genes or the Environment:
An Outdated Dichotomy
D iverse influences contribute to
developmental, learning and Over the past 20
behavioral disability . These influences years, studies of twins and
are generally divided into two broad adopted children have
groups: genetic factors, determined Genetic and
clarified important genetic
by hereditary information contained environmental
contributions to a variety
in human chromosomes, and influences seem to be
of cognitive, behavioral
environmental factors, which include all roughly equal in
and personality traits.
non-genetic influences. Environmental determining many
Altogether these studies
influences can be further subdivided into neurocognitive
suggest that for many of
several categories, including physical, characteristics.
these traits, heredity
chemical, infectious and social. accounts for about 50%
Chemical factors, which are the focus of of the observed
D E F I N I T I O N - Genotype:
this report, are broadly defined as differences among individuals. 4 5 Some
synthetic and naturally occurring mistakenly take this as evidence that The genetic makeup of
substances to which an individual is these traits are genetically determined. an individual.
exposed. Social-environmental factors According to Robert Plomin, director
are defined as encompassing family , of the Center for Developmental and
cultural and socioeconomic variables. Health Genetics at Pennsylvania State
University , 鈥渞esear ch into heritability
It is widely recognized that
is the best demonstration鈥f the
influences from various domains
importance of the environment.鈥?
interact in very complex ways, 1 2 3
If heredity accounts for 50% of the
though research has generally focused
variability in a trait, the other 50% of
on one domain at a time. As a result,
variability must be due to environmental
a truly over -arching framework and
influences. 6 7 In other words, genetic
methodology have yet to be developed
and environmental influences seem to
to examine the real-world interactions
be roughly equal in determining many
of these influences.
neurocognitive characteristics. 8
Greater Boston Physicians for Social Responsibility 49
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
PHENOTYPIC PLASTICITY
Genotype is a term that refers to the specific
genetic makeup of an individual, whereas
phenotype refers to the traits or characteristics
of that individual as they actually appear.
For many traits, phenotype is only partially a
result of the genotype. Environmental factors
encountered during fetal development, or even
after birth, also affect the phenotype. The
variability of phenotypes for a given genotype both the environmental cues that trigger the
or within populations of genetically similar variable phenotypes and the individual鈥檚 capacity
individuals is called phenotypic plasticity. to respond to those cues, based largely in the
Among the most genotype. In other words, phenotypic plasticity
dramatic examples of is a result of gene-environment interactions.
phenotypic plasticity are Phenotypic plasticity is of two types.1 One
the marked differences is the spectrum of phenotypes that may be
in genetically similar expressed by a given genotype in a range of
individuals in different different but relatively stable environments. To
environments. For study this, one would look for the appearance of
example, in the different traits in genetically similar populations
illustration, the tall located in different environments. The other
thin tree actually grew type of plasticity refers to the response of
in a dense forest, where individual organisms to variations in a single
rapid vertical growth environment. In this case, either the ability
was essential in order to to adapt, or conversely, the susceptibility to
compete successfully for adverse effects from even minor environmental
light. The genetically fluctuations, particularly during development,
similar, short, branched reflects the plasticity of the individuals.
tree grew on a south- In this report, we are largely concerned with
facing open slope where the second type of plasticity when we note that,
there was no competition at most, genotype accounts for about 40-60%
for light, allowing the of the variance in neurodevelopmental traits
tree to grow in a very or disorders, while the remainder is more
different manner. In persuasively explained by environmental
general, phenotypic factors and gene-environment interactions.
plasticity is a result of 1 Via S. The evolution of phenotypic plasticity: what do
we really know? In: Ecological Genetics, Ed: Real L.
Princeton University Press, Princeton NJ, 1994
50 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
Observers also point out that The medical model for approaching
inferences from these studies are based atherosclerotic heart disease entails
on the simplistic assumption that genes addressing all of the risk factors that are
and the environment have simple amenable to inter vention: obesity ,
additive effects. 9 10 In fact, current smoking, elevated blood pressure and
research shows that gene-environment cholesterol, diabetes, diet and sedentary
interactions can be extremely complex. lifestyle. Identifying a genetic marker for
As summed up by Plomin and his risk of heart disease, (such as the
Phenotype:
colleague Gerald McClearn, also from apolipoprotein E4), does not as of yet DEFINITION -
the Center for Developmental and trigger specific therapy , but it does The traits or characteristics of an
Health Genetics, in a recent review indicate the need for more vigorous individual as they actually appear.
Phenotype results from the
article: 鈥渟imple approaches to complex control of other risk factors. Applying interaction of genotype and the
phenotypes may lead to misleading or such a model to learning and environment.
erroneous conclusions. Particularly developmental disorders would argue for
inappropriate are questions couched in eliminating toxicant exposures, since
either -or ter ms: Is such and such a trait they are readily preventable, and for
the result of genes or of environment? improving the social environment of
Unfor tunately , this type of thinking children at risk. While genes themselves
was promoted for decades by the cannot be altered, the environmental
natur e-versus-nur ture contr oversy , triggers for some genetic diseases can be
which convinced many academicians reduced or eliminated. Clarifying
that they had to choose sides. W e genetic risks factors can also identify the
hope that this brief overview has made children most in need of additional
apparent the intellectual bankruptcy protection from toxicants and other
Gene:
of this either -or for mulation.鈥? 11 adverse environmental factors, including D E F I N I T I ON -
social factors.
Our approach to developmental The basic unit of heredity,
consisting of a segment of
disabilities can be informed by medical Rare Diseases Governed by Powerful
DNA that codes for a particular
models for addressing other complex 鈥淥GOD鈥? Genes: the PKU Prototype product, such as an enzyme.
Each gene occupies a certain
problems with multiple contributing In 1984, for the first time, a gene location on a chromosome.
factors. Athersclerotic heart disease, the associated with developmental disability
cause of heart attacks, is one example of was identified and localized within
a multifactorial problem in which human chromosomes: the gene that
modern medicine has had relatively causes phenylketonuria, (PKU), a rare
good success, markedly reducing the disorder that occurs in 1 in 10,000
incidence of the disease over the past births. PKU is a prototype 鈥渟ingle gene
several decades. 12 13 14 15 Like disor der.鈥? Such genes ar e also called
developmental disability , ather oscler otic OGOD genes, a term which stands for
heart disease is influenced by a variety 鈥渙ne gene, one disor der.鈥?16 The genetic
of factors, most of which have both component of a disease caused by an
genetic and environmental components. OGOD gene is controlled by one gene
only, unlike the common developmental
Greater Boston Physicians for Social Responsibility 51
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
disorders that screening program for PKU, in fact, was
PHENYLKETONURIA (PKU)
are genetically in place in Massachusetts more than 20
I n the past PKU was responsible for about influenced by the years before the discovery of the PKU
1% of cases of institutionalized mental combined tiny gene. Currently Massachusetts is piloting
retardation.17 When a child inherits the PKU contributions a newborn screening program that tests
gene from each parent, the child cannot of a myriad of for 20 rare, metabolic diseases associated
produce the enzyme phenylalanine hydroxylase, genes. Diseases with developmental disability . Dietar y
which is required to break down the amino that arise from interventions for these disorders also
acid phenylalanine.18 This leads to the build single gene defects predated the identification of their
up of phenylalanine in the blood, and, since are in theor y, at respective OGOD genes.
high levels of phenylalanine are harmful to least, particularly
While molecular genetics has allowed
the developing brain, severe brain damage amenable to
us to identify specific genes and to
results. As another consequence of high intervention
understand their chemical structure, it
blood phenylalanine levels, a related since they are
has not yet resulted in specific treatments
compound for which the disease is named, associated with a
for neur odevelopmental disability . Once
phenylketone, appears in the urine. single etiology .
a gene is identified, however , molecular
Simply by reducing phenylalanine in the
Many genetics studies can begin to clarify how
diet, the build up of toxic metabolites is
rare disorders the gene causes disease. While no 鈥渜uick
prevented, and neurologic development
affecting neuro- fixes鈥? have yet resulted from such
proceeds normally. Since phenylalanine, like
development have investigations, it is believed the identifi-
other amino acids, is a building block of
been identified as cation of genes will eventually lead to the
protein, it is found in all protein foods,
OGOD disorders development of specific preventions and
particularly those high in protein such as
by a characteristic treatments including environmental and
fish, eggs, meat, cheese, and peanuts. By
inheritance pattern. pharmaceutical interventions.
lowering the amount of protein in the diet,
These rare dis- Common Diseases Influenced by
the trigger for the disease is removed, and
orders include Multiple 鈥淧uny鈥? Genes
the defective gene becomes harmless.
other syndromes
In contrast to the powerful OGOD
which, like PKU,
gene of PKU, genetic influence over the
are caused by the inability to metabolize
common disorders of learning and
various nutrients, including other amino
D EFINITION -
development appears to be controlled by
Amino acids: acids and fatty acids. Like PKU, many
the cumulative impact of innumerable
of these disorders, as well as their
Organic compounds, genes. Such genes, which 鈥渁ct together
(marked by the presence developmental effects, are preventable
in a probablistic fashion to influence a
of both an amino and if the problematic nutrient is reduced in
a carboxyl group), which common trait鈥? are referred to as
the diet, beginning in early life. Specific
are the building blocks
鈥渜uantitative trait loci鈥? (QTLs). The
of proteins. 20 amino genes responsible for many of these
implication of this finding is that traits
acids are used by the
disorders have been identified. Dietary
body for growth and relevant to learning and development are
interventions to prevent these disorders,
metabolism. Some of
influenced not by single genes, but by
these can be produced however , wer e developed on the basis of
by the liver. The rest many genes, each of which makes a very
clinical studies long before the defective
must be supplied in
small contribution towards the trait. In
the diet. genes were identified. A newborn
52 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
the words of a prominent behavioral function of acetylcholinesterase, an
geneticist, each of these genes has a enzyme critical to the proper functioning
鈥減uny effect on phenotype,鈥? that is, the of the nervous system. Acetylcholines-
trait as it鈥? s actually expr essed. 19 terase, which is found throughout the
nervous system and the body in general,27
Gene-Environment Interactions: is responsible for breaking down the
A Spectrum of Complexity neurotransmitter acetylcholine.
Organophosphate pesticides (OPs),
The complexities of gene-environ-
however , inhibit the enzyme and pr event
ment interactions in neurodevelopment
it from performing this critical function.
are just beginning to be unraveled.
However , it is alr eady clear that there are
Enzymes:
D E F I N I T I ON -
an astounding variety of ways that genes
and the environment can interact. PKU Protein molecules, coded
for by genes, that facilitate
illustrates a straight forward 鈥渟imple
chemical reactions.
trigger鈥? interaction involving one gene
and one environmental factor. The three
examples that follow illustrate more ACUTE HIGH DOSE ORGANOPHOSPHATE
complex interactions. POISONING, AN EXPRESSION OF
MAJOR CHOLINESTERASE INHIBITION
Example 1: Complex Gene-
Environment Interactions Mediate
A cetylcholinesterase inhibition has long
Some Effects of Organophosphate been recognized in acute pesticide
Pesticides poisoning that follows high dose exposures
to pesticides. This syndrome consists of over-
The gene-environment interactions
that mediate the effects of organo- activation and dysfunction of the considerable
phosphate pesticides are extremely portion of the nervous system that uses
the neurotransmitter acetylcholine. The
complex, and not yet completely
understood. Some of the effects of consequences of this over-activation/
organophosphate pesticides are dysfunction are comparable to the clinical
effects of 鈥渘erve gas鈥? agents designed for
mediated by at least five different
enzymes, 20 some of which have been chemical warfare, chemicals from which some
shown to be influenced by their own modern pesticides are derived. The grim
picture of acute OP poisoning includes
set of environmental and/or genetic
factors. 21 22 23 24 25 26 T illustrate the
o excessive secretions (salivation, tears
complexity of this interaction, we will and bronchial secretions), slowing of the
respiratory rate, wheezing and respiratory
focus on the two enzymes that have
been most extensively researched to distress, unstable pulse and blood pressure,
date: paraoxonase and acetylcholinesterase. muscle twitches followed by weakness or
paralysis, vomiting and diarrhea, urinary
Since their development in the
and fecal incontinence, drowsiness, confusion
1930s, organophosphate chemicals
and ultimately coma and death.65
have been known to interfere with the
Greater Boston Physicians for Social Responsibility 53
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
As a result, acetylcholine builds up at the of functioning enzyme is more easily
junctions between nerve cells, first overwhelmed by OPs. Cholinesterase
causing over -stimulation, and then levels are also affected by a variety of
complete dysfunction of the involved other factors including age, body weight,
ner ve pathway . At high exposur es, this height, gender , pregnancy and liver
disease. 32 Thus a host of antecedent
results in the characteristic symptoms of
OP poisoning, which are identical to factors, both environmental and genetic,
those caused by organophosphate interact to determine acetylcholinesterase
chemical warfare agents. levels, which in turn help determine the
vulnerability of the fetal brain to environ-
While large exposures to OPs have
mental toxicants, in this case OPs.
long been recognized as causing the
nerve gas syndrome, more recent animal Another genetically determined
While large studies have suggested that low dose enzyme further modifies an individual鈥檚
exposures to OPs exposures can cause more insidious susceptibility to OP toxicity. This
have long been injury to the developing fetus, and can enzyme, paraoxonase, which is found in
recognized as do so at exposure levels that do not the blood, plays an important role in
causing the nerve cause clinical symptoms in the mother . detoxifying several organophosphate
gas syndrome, more Concern about fetal toxicity arises from pesticides.33 34 For example, individuals
recent animal studies the fact that very small alterations in vary 11-fold in the ability to deactivate
have suggested that acetylcholinesterase function alter levels the pesticide parathion depending on
low dose exposures of acetylcholine in the developing brain. which gene they carry for this enzyme.
can cause more Because the multiplication and Studies in mice show that low levels of
insidious injury differentiation of brain cells are guided paraoxonase increase susceptibility to
to the developing chlorpyrifos (Dursban) ,35 36 a pesticide
by local neurotransmitters, small changes
fetus, and can do so in the concentration of acetylcholine to which the US population is widely
at exposure levels caused by OP exposure may alter the exposed. High paraoxonase activity thus
that do not cause developing architecture of the exposed acts as a first line of defense against
clinical symptoms brain, and impair a variety of behaviors organophosphate effects. However, those
in the mother. later in life. (OPs also cause other forms with the relatively inactive form of
of fetal neurotoxicity that are indepen- paroxonase, an estimated 30%-38% of
the population,37 38 will be slower to
dent of the acetylcholinesterase mechanisms
break down these OPs and consequently
discussed here. See Chapter 6 for details.)
more vulnerable to acetylcholinesterase
Genetic factors markedly modify
inhibition. If in addition the individual
these OP effects that are mediated
has low levels of acetylcholinesterase, due
through acetylcholinesterase. About
to either genetic or environmental factors,
4% of the population carries a gene
the individual will have further increased
that produces a poorly functioning
susceptibility to acetylcholinesterase
form of acetylcholinesterase. 28 29 30 31
inhibition by organophosphate pesticides.
This greatly incr eases an individual鈥? s
vulnerability to cholinesterase inhibition Thus, as demonstrated in animal
by OPs, since the diminished reservoir studies, levels of OP exposure that are
54 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
Spectrum of Vulnerability
PERMITTED
NUMBER OF PEOPLE FOR WHOM INDICATED
AVERAGE THRESHOLD
EXPOSURE
EXPOSURE IS THE THRESHOLD OF HARM
OF HARM
There is wide variation
in individual sensitivity to
MARGIN
toxicant exposure. This means
OF SAFETY FOR
that in a large population with
AVERAGE
INDIVIDUAL
widespread exposures, even
individuals when the dosage is acceptable
harmed by on average, many people
the permitted will still be hurt. A significant
exposure margin of safety is required
to prevent such injuries.
more sensitive less sensitive
INCREASING EXPOSURE TO TOXICANT
individuals individuals
well tolerated by some individuals may practice. Unfortunately such 鈥渁fter the
cause permanent alterations in brain fact鈥? regulation allows generations to be
development and behavior in those harmed in the time required to clarify
who are more vulnerable due to a the complex interactions that create
complex mix of genetic, age-related vulnerability .
and environmental factors. Example 2: Gene-Environment
Individual differences in vulnerability Interactions in 鈥淧ANDAS,鈥? Pediatric
are widely recognized by scientists, but Autoimmune Neuropsychiatric
may be vastly under -estimated by r egula- Disorders Associated with
tory agencies. In chemical regulation, for Streptococcal Infection
example, EP A has typically used a stan- Another important area of gene-
dard tenfold uncertainty factor to account environment interactions
for all known and unknown human involve antibody
variability in susceptibility to that reactions to infection.
chemical, including differences between One example of this
adults and childr en. Yet as pr eviously interaction has recently
discussed, paraoxonase activity alone been recognized in
varies by a factor of 11. Since there are subsets of patients with
four other enzymes that mediate OP several neuropsychiatric
toxicity whose variability has not yet disorders. These
been characterized, individual differences patients, whose
in vulnerability to OPs may be several symptoms markedly
orders of magnitude greater than the worsen following
10-fold variation currently recognized infections with Group A
by regulatory agencies. streptococcus, (the cause of 鈥渟trep
Only after specific research on a throat鈥?) are considered to have
particular chemical has been conducted PANDAS. Post-str eptococcal
to demonstrate greater differences in exacerbations have been shown to occur
vulnerability will regulatory agencies in several disorders in which repetitive
consider implementing policies that are behaviors are a prominent feature.
more protective than the standard These include the neuropsychiatric
Greater Boston Physicians for Social Responsibility 55
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
syndrome obsessive-compulsive that showed therapies that reduce immune
disorder (OCD), and two involuntary reactions (plasma exchange and intra-
movement disor ders, tics and T ourette鈥? s venous immunoglobulin) are effective in
syndrome. 39 40 While post-streptococcal reducing symptom severity in children
exacerbations have not been documented with post-str eptococcal OCD, Tourette鈥? s
syndrome and tic disorders. 46
in autistic children, limited immunologic
D EFI NITI ON - Obsessive
data suggest that many autistic children
compulsive disorder: An autoimmune mechanism has been
have the same genetic susceptibility to proposed that suggests P ANDAS result
A disorder characterized by 41
recurrent and persistent thoughts post-streptococcal immune reactions. from streptococcal antibodies that cross
or impulses that are experienced
The clinical significance of PANDAS react with critical brain structures (basal
as intrusive and cause marked
anxiety. May be accompanied by has not yet been clarified. However, ganglia) in genetically susceptible
repetitive behaviors (such as hand several lines of evidence support an children. 47 48 49 50 51 This proposed
washing, ordering, counting) the
emerging consensus that PANDAS mechanism as well as the clinical
person feels compelled to do
represents a valid diagnostic construct42 significance of the P ANDAS syndrome
according to rigid rules.
and that PANDAS results from a unique will need to be fur ther clarified by lar ger ,
gene-enviroment interaction. One line of more comprehensive prospective studies
D EFI NITI ON - Tics:
evidence involves a series of immunologic that track infectious, immunologic and
Sudden, rapid, recurrent,
studies. In these investigations, patients neuropsychiatric events and outcomes.
stereotyped, involuntary motor
movements or vocalizations. with PANDAS have been shown to carry Example 3: Gene-Environment
May include actions such as eye
an immune marker in the blood (B Interactions Affecting Lead
blinking, neck jerking, facial
lymphocytes with D8/17 antigen), which
grimacing, stamping, and Metabolism
repeating words out of context. has been previously identified as a
They are typically exacerbated Gene-environment interactions have
marker of susceptibility to rheumatic
by stress, and stop during
also been identified that affect the way
absorbing activities and sleep. fever, a serious inflammatory disease
the body handles lead. These interactions
that occasionally follows streptococcal
involve a gene coding for the delta ALA
infection. A high incidence of OCD and
D EFI NITI ON -
enzyme (delta aminolevulinic acid
involuntary movement disorders in
Tourette鈥檚 Disorder:
dehydratase), which has been shown to
A syndrome consisting of multiple rheumatic fever provides a second, affect lead metabolism, bone storage and
clinical line of evidence supporting a
motor and vocal tics causing
blood lead levels. While studies
significant impairment in social link between streptococcal infection
or occupational functioning. have begun to understand how the gene
and neuropsychiatric disease.43 44
influences the way the body handles
There is also limited neuroimaging lead, the influence of the gene on the
Antigen:
D EFI NITI ON -
suppor t for the P ANDAS construct. This neurotoxicity of lead has not yet
A protein or carbohydrate is provided by a case report in which been clarified. 52 53 54 55 56 57 58 59 60
marker on the surface of a cell
serial magnetic resonance imaging
that identifies the cell as 鈥渟elf鈥?
or 鈥渘on self鈥?. (MRI) studies revealed acute enlargement The Role of the Social Environment
in a particular area of the brain (basal
Toxicants and genetics have emerged
ganglia) concurrent with post-strepto-
as important influences in learning and
coccal exacerbations of OCD. 45 And
development over the past two to three
finally , the constr uct is suppor ted by a
decades. The important role of the social
recent National Institute of Health study
environment in human development,
56 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
however, has been recognized for most The psychologists and educators who
of the 20th century.61 A large body of deal with the bulk of learning and
research documents the associations developmentally disabled children are
An autoimmune
between social environmental factors and generally trained in behavioral traditions
mechanism has
developmental outcomes.62 For instance, that focus on the social environment.
been proposed that
good parental mental health, social In contrast, toxicology and genetics have
suggests PANDAS
supports, education and parenting style not yet been routinely translated into the
result from strepto-
characterized by reciprocity have clinical domain, with the notable exception
coccal antibodies that
all been associated with improved of medical screening programs that test
cross react with critical
developmental outcomes. A large scale infants for lead, PKU, hypothyroidism
brain structures (basal
intervention study has also shown that and a variety of rare metabolic diseases
ganglia) in genetically
social supports, parenting skills training caused by gene defects.
susceptible children.
and high quality early childhood education The importance of the social
improve developmental outcomes in high environment is extensively addressed
risk children.63 64 in other literatur e. We will ther efor e not
As a practical matter , the impor tance discuss the social environment further
of the social environment is underscored in this report except to acknowledge its
by the fact that both the assessment importance as both a causal factor and
of developmental disability as well as as a therapeutic modality in learning
management interventions occur mainly and developmental disabilities.
in the domain of the social environment.
1 Mash EJ, Terdal LG. Assessment of child and family disturbance:a 13 Goldberg RJ, Yarzebski J, Lessard D et al. A two-decades (1975-
behavioral-system approach. In: Assessment of Childhood 1995) long experience in the incidence, in-hospital and long-term
Disorders.Third Edition. Eds. Mash EM, Terdal LG. New York: case-fatality rates of acute myocardial infaction: a community-
Guilford Press, 1997, p. 21-22. wide perspective. Journal American College of Cardiology
33(6):1533-9, 1999.
2 Plomin R, Craig I. Human behavioral genetics of cognitive
abilities and disabilities. BioEssays 19(12):1117-1124, 1997. 14 Wilhelmsen L. ESC population studies lecture 1996.
Cardiovascular monitoring of a city over 30 years. European Heart
3 Taylor HG. Critical issues and future directions in the
Journal 18(8):1220-30, 1997.
development of theories, models, and measurements for
attention, memory, and executive function. In:Attention, Memory 15 Pell S. Trends in the incidence of myocardial infaction and in
and Executive Function. Eds. Lyon GR, Krasnegor NA. Baltimore: associated mortality and morbidity in a large employed
Paul H. Brookes Publishing Co., 1996,p.401. population, 1957-1983. New England Journal of Medicine
312(16):1005-11, 1985.
4 Bouchard TJ. Genes, environment, and personality. Science Vol.
264: 1700-1701, 1994. 16 Plomin R, Owen MJ, McGuffin P. The genetic basis of complex
human behaviors. Science Vol. 264: 1733-1739, 1994.
5 Plomin R, Owen MJ, McGuffin P. The genetic basis of complex
human behaviors. Science Vol. 264: 1733-1739, 1994. 17 Plomin R, Owen MJ, McGuffin P. 1994. Ibid.
6 Mann CC. Behavioral genetics in transition. Science 264:1686- 18 Plomin R, EdFries JC, McClearn GE et al. Behavioral Genetics,
1689, 1994. Third Edition. New York: WH Freeman and Company, 1997, p. 111.
7 Plomin R, DeFries JC. The genetics of cognitive abilities and 19 McClearn GE, Vogler GP, Plomin R. Genetics and behavioral
disabilities. Scientific American, May, 1998:62-69. medicine. Behavioral Medicine 22:93-102, fall, 1996.
8 Plomin R, Owen MJ, McGuffin P. The genetic basis of complex 20 Mutch E, Blain PG, Williams FM. Interindividual variations in
human behaviors. Science Vol. 264: 1733-1739, 1994. enzymes controlling organophosphate toxicity in man. Human
and Experimental Toxicology 11(2):109-116, 1992.
9 Bailey RC. Hereditarian scientific fallacies. Genetica 99(2-1):125-
133, 1997. 21 Costa LG, Li WF, Richter RJ, Shih DM et al. The role of
paraoxonase (PON1) in the detoxification of organophosphates
10 Mann CC. Ibid.
and its human polymorphism. Chemico-Biological Interactions
11 McClearn GE, Vogler GP, Plomin R. Genetics and behavioral 119-120:429-38, 1999.
medicine. Behavioral Medicine 22:93-102, fall, 1996.
22 Clendenning JB, Humbert R, Green ED, et al. Structural
12 Lilly, LS. Ischemic heart disease in Textbook of Primary Care organization of the human PON1 gene. Genomics 35(3):586-9,
Medicine, Second Edition, Ed. Noble J. St. Louis: Mosby, 1996, 1996.
p.218.
Greater Boston Physicians for Social Responsibility 57
CHAPTER 5: Multiple Causes of Developmental, Learning and Behavioral Disability
46 Perlmutter SJ, Leitman SF, Garvey MA, et al. Therapeutic
23 Shih DM, Gu L, Xia YR, et al. Mice lacking serum paraoxonase
plasma exchange and intravenous immunoglobulin for obsessive-
are susceptible to organophosphate toxicity and atherosclerosis.
compulsive disorder and tic disorders in childhood. Lancet
Nature 394(6690):284-7, 1998.
354(9185):1153-8, 1999.
24 Genc S, Gurdol F, Guvene S, Kargi Y. Variations in serum
47 Hollander E, DelGiudice-Asch G, Simon L, et al, 1999. Ibid.
cholinesterase activity in different age and sex groups. European
Journal of Clinical Chemistry and Clinical Biochemistry 35(3):239- 48 Swedo SE, Leonard HL, Mittleman BB, et al. Identification of
40, 1997. children with pediatric autoimmune neuropsychiatric disorders
associated with streptococcal infections by a marker associated
25 Trundle D, Marcial G. Detection of chilinesterase inhibition.
with rheumatic fever. American Journal of Psychiatry 154(1):110-2,
The significance of cholinesterase measurements. Annals of
1997.
Clinical and Laboratory Science 18(5):345-2, 1988.
49 Garvey MA, Giedd J, Swedo SE. Journal of Child Neurology
26 Brock A, Brock V. Plasma cholinesterase activity in a healthy
13(9):413-23, 1998.
population group with no occupational exposure to known
cholinesterase inhibitors: relative influence of some factors 50 Asbahr FR, Negrao AB, Gentil V et al, 1998. Ibid.
related to normal inter-and intra-individual variations.
51 Kurlan R. Neurology 50(6):1530-4, 1998.
Scandinavian Journal of Clinical and Laboratory Investigation
50(4):401-8,1990. 52 Smith CM, Wang X, Hu H et al. A polymorphism in the delta-
aminolevulinic acid dehydratase gene may modify the
27 Trundle D, 1988. Ibid.
pharmacokinetics and toxicity of lead. Environmental Health
28 Rosenman KD, Guss PS. Prevalence of congenital deficiency in Perspectives 103(3):248-53, 1995.
serum cholinesterase. Archives of Environmental Health 52(1):42-
53 Bergdahl IA, Grubb A, Schutz A et al. Lead binding to delta-
4, 1997.
aminolevulinic acid dehydratase in human erythrocytes.
29 Pinto Pereira LM, Clement Y, Telang BV. Distribution of Pharmacology and Toxicology 81(4):153-8, 1997.
cholinesterase activity in the population of Trinidad. Canadian
54 Wetmur JG. Influence of the common human delta-
Journal of Physiology and Pharmacology 74(3):286-9, 1996.
aminolevulinate dehydratase polymorphism on lead body burden.
30 Reiner E, Simeon-Rudolf V, Skrinjaric-Spoljar M. Toxicology Environmental Health Perspectives 102 Suppl 3:215-9, 1994.
Letters 82-83:447-52, 1995.
55 Wetmur JG, Lehnert G, Desnick RJ. The delta-aminolevulinate
31 Trundle D, 1988. Ibid. dehydratase polymorphism: higher blood lead levels in lead
workers and environmentally exposed children with the 1-2 and 2-
32 Brock A, Brock V, 1990. Ibid.
2 isozymes. Environmental Research 56(2):109-19, 1991.
33 Costa LG, Li WF, Richter RJ, Shih DM et al, 1999. Ibid.
56 Claudio L, Lee T, Wolff MS, et al. A murine model of genetic
34 Furlong CE, Li WF, Costa LG et al. Genetically determined
susceptibility to lead bioaccumulation. Fundam Appl Toxicol
susceptibility to organophosphorus insecticides and nerve agents:
35(1):84-90, 1997.
developing a mouse model for the human PON1 Polymorphism.
57 Tomokuni K, Ichiba M, Fujisiro K. Interrelation between urinary
Neurotoxicology 19(4-5):645-50, 1998.
delta-aminolevulinic acid, serum ALA, and blood lead in workers
35 Furlong CE, 1998. Ibid.
exposed to lead. Industrial Health 31(2):51-7,1993.
36 Furlong CE, Richter RJ, Seidel SL, et al. Role of genetic
58 Schwartz BS, Lee BK, Stewart W et al. Delta-Aminolevulinic acid
polymorphism of human plasma paraoxonase/arylesterase in
dehydratase genotype modifies four hour urinary lead excretion
hydrolysis of the the insecticide metabolites chlorpyrifos oxon
after oral administration of dimercaptosuccinic acid. Occupational
and paraoxon. American Journal of Human Genetics 43(3):230-8,
and Environmental Medicine 54(4):241-6, 1997.
1988.
59 Sithisarankul P, Cadorette M, Davoli CT et al. Plasma 5-
37 Furlong CE, Richter RJ, Seidel SL, 1988. Ibid.
aminolevulinic acid concentration and lead exposure in children.
38 Padungtod C, Niu T, Wang Z, Savitz DA, Christiani DC, et al. Environmental Research 80(1):41-9, 1999.
American Journal of Industrial Medicine 36(3):379-87, 1999.
60 Sithisarankul P, Schwartz BS, Lee BK et al. Aminolevulinic acid
39 Trifiletti RR, Packard AM. Immune mechanisms in pediatric dehydratase genotype mediates plasma levels of the neurotoxin,
neuropsychiatric disorders. Tourette鈥檚 syndrome, OCD, and 5-aminolevulinic acid, in lead-exposed workers. American Journal
PANDAS. Child and Adolescent Psychiatric Clinics of North of Industrial Medicine 32(1):15-20, 1997.
America 8(4):767-75, 1999.
61 Plomin R, DeFries JC. The genetics of cognitive abilities and
40 Swedo SE, Leonard HL, Garvey M. Pediatric autoimmune disabilities. Scientific American, May, 1998:62-69.
neuropsychiatric disorders associated with streptococcal
62 Taylor HG. Critical issues and future directions in the
infections: clinical description of the first 50 cases. American
development of theories, models, and measurements for
Journal of Psychiatry 155(2):264-71, 1998.
attention, memory, and executive function. In:Attention, Memory
41 Hollander E, DelGiudice-Asch G, Simon L, et al. B lymphocyte and Executive Function. Eds. Lyon GR, Krasnegor NA. Baltimore:
antigen D8/17 and repetitive behaviors in autism. American Paul H. Brookes Publishing Co., 1996, p. 400-1.
Journal of Psychiatry 156(2):317-20, 1999.
63 Ramey CT, Bryant DM, Wasik BH et al. The infant health and
42 Trifiletti RR, Packard AM, 1999. Ibid. development program for low birthweight, premature infants:
program elements, family participation, and child intelligence.
43 Asbahr FR, Negrao AB, Gentil V et al. Obsessive-compulsive
Pediatrics 89(454-65),1992.
and related symptoms in children and adolescents with
rheumatic fever with and without chorea: a prospective 6-month 64 Ramey CT, Ramey SL. Which children benefit the most from
study. American Journal of Psychiatry 155(8):1122-4, 1998. early intervention? Pediatrics 94(6 Pt 2):1064-6, 1994.
44 Asbahr FR, Ramos RT, Negrao AB et al. Journal of the 65 Ecobichon DJ. Toxic effects of pesticides. In: Casarett and
American Academy of Child and Adolescent Psychiatry Doull鈥檚 Toxicology, Fifth Edition. Ed Klaasses CD. New York:
38(12):1522-5, 1999. McGraw-Hill, 1996.
45 Giedd JN, Rapoport JL, Leonard HL, et al. Case study: acute
basal ganglia enlargement and obsessive-compulsive symptoms
in an adolescent boy. Journal of the American Academy of Child
and Adolescent Psychiatry 35(7):913-5, 1996.
58 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Chapter 6
Known and Suspected
Developmental Neurotoxicants
A large number of chemical important information, it fails to inform
compounds interfere with normal us about the neurodevelopmental effects
brain development, including heavy of exposures to mixtures
metals, alcohol and other solvents, of many different
Every human body
nicotine, opiates, cocaine, marijuana, compounds. Every
contains mixtures of
some pharmaceuticals, pesticides, and human body contains
heavy metals and
others. As described in Chapter 2, mixtures of heavy
synthetic organic
neurodevelopmental toxicants may alter metals and synthetic
chemicals in blood,
brain development and function in organic chemicals in
bone and other
specific and permanent ways. A few blood, bone and other
organs, fat, breast milk,
have been extensively studied (e.g. lead, organs, fat, breast milk,
sperm and expired air.
mer cury, alcohol), while most others sper m and expir ed air .
have undergone minimal examination. Epidemiological research
is complicated by the fact that there are
The following profiles summarize
no unexposed people to serve as controls
what is known about the
for comparison purposes. These
neurodevelopmental toxicity of some
limitations should be kept in mind when
commonly encountered solvents,
reading the following toxicity profiles.
pesticides, nicotine, metals, and
persistent organochlorine compounds. Finally, although the r efer ences cited
We also briefly discuss impor tant do not exhaustively review the available
controversies over the potential literature, they are representative and
neurodevelopmental toxicity of include areas of uncertainty and
compounds that are intentionally added contr oversy . Importantly , many chemical
to drinking water and food 鈥? fluoride compounds with known or suspected
and certain food additives. neurological toxicity have never been
tested for their effects on brain
Experimental toxicity testing usually
development and function. For
involves examining one chemical at a
them, ther e ar e no data to r eview .
time. Although this approach provides
Greater Boston Physicians for Social Responsibility 59
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
METALS In the 1940s, the consequences of
lead poisoning, including poor school
Lead per formance, impulsive behavior , shor t
attention span, and restlessness, were
鈥? Increases in blood lead levels during
reported. 4 Since then neurodevelop-
infancy and childhood are associated
mental damage at lower levels of
with attention deficits, increased
exposure has been well documented. In
impulsiveness, reduced school
fact, there is no evidence of any threshold
performance, aggression, and
for lead-induced cognitive impairment
delinquent behavior .
resulting from early life exposures. 5
鈥? Effects on learning are seen at blood
In one of the earliest studies of lead
lead levels below those currently
effects on intelligence, investigators
considered 鈥渟afe.鈥?
reported a 4-point difference in IQ,
Routes of Exposure
measured by the Wechsler Intelligence
Since lead was removed from most Scales for Children 鈥? Revised (WISC-R),
of the nation鈥? s gasoline supply , most between children with the highest and
current environmental exposures in lowest deciduous tooth-lead levels.6 Other
the US come from lead paint, lead studies have reached similar conclusions.
contaminated dust, and drinking water . In Boston, a cohort of children from
Occupational and hobby exposures middle and upper middle class homes has
also contribute to the lead levels of been followed for years.7 8 Reduced
some adults. Lead tends to be stored performance on the Bayley Mental
in bones, and during pr egnancy , Development Index (MDI) was associated
accelerated maternal bone turnover with elevated umbilical cord blood lead
results in mobilization of lead, leading levels. The difference in scores between
to increased blood lead levels. the high (mean, 14.6 microgm/dl) and low
(mean, 1.8 microgm/dl) blood lead levels
Human Studies
was 4-7 points at 6, 12, and 24 months of
Lead easily crosses the placenta
age. When the children were re-tested at
and enters the fetal brain where it
10 years of age, a 10 microgm/dl increase
interferes with normal development.
in blood lead at 24 months of age was
Many studies report adverse neuro-
associated with a 5.8-point decline in IQ
developmental impacts resulting
as measured by WISC-R. Other studies
from fetal or infant exposures to
show similar results.9
lead, including lowered intelligence,
In the Boston cohort, teachers
hyperactivity, learning and attention
reported behavioral changes in children
disorders, and changes in behavior.
(for example, see 1 2 3 ) Here we summarize that correlated with lead levels. Children
with the higher levels were more
results from several of the larger epide-
distractible, dependent, impulsive, easily
miological studies, omitting most of a
frustrated, not persistent, and unable to
large body of animal research because
follow directions. Attention-deficit
of the relative wealth of human data.
60 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
disorder also correlates with hair lead unique organizational processes are
levels.10 Increased blood level in infancy underway but also because of an
and early childhood may be manifest in immature blood-brain barrier. One study
older children and adolescents as found greater uptake of lead in fetal brain
during gestation than after birth in rats.18
decreased attention span, reading
disabilities, and failure to graduate from
Mercury
high school11 Two studies report that
lead exposure correlates with aggressive, 鈥? Freshwater fish are sufficiently
destructive, and delinquent behavior.12 13 contaminated with methylmercury in
most of the US to necessitate fish
Animal Studies
consumption advisories warning
Animal studies support these
pregnant women or women of
conclusions from epidemiological data.
reproductive age to avoid or limit
Monkeys exposed to lead from birth,
consumption because of threats to
so that blood lead levels are maintained
fetal brain development
at about 15 microgms/dl, show increased
鈥? Large fetal exposures to
distractibility , inappr opriate r esponses
methylmercury cause mental
to stimuli, and difficulty adjusting
retardation, gait and visual
response strategies. 14 A review
disturbances
of animal studies reports deficits
in performance, learning, and 鈥? Smaller fetal exposures may cause
attention associated with low-level lasting impairment of language,
lead exposures. 15 attention, and memory
Mechanisms of Neurotoxicity 鈥? Fetal mercury and PCB exposures
interact to result in magnified effects
Several neurodevelopmental
on neurological development
processes are altered by lead exposure,
leading to abnormal brain development. Routes of Exposure
Intrauterine neurodevelopmental effects
Mercury (Hg) may exist in a number
of lead affect both the cellular structure
of different chemical forms but is usually
of the brain and its chemistry.16
released into the environment as a metal
Structural effects include altered cell
or an inor ganic compound. The US EP A
proliferation, differentiation, synapse
estimates that human activities are
formation, and programmed cell death.
responsible for emissions of approximately
Neurochemical effects include altered
160 tons of mercury annually in the US.19
neurotransmitter levels (acetylcholine,
Major sources are coal-fired power plants
dopamine, glutamate) and altered
and municipal and medical waste inciner-
dopamine receptor density in various
ators. Atmospheric mercury often travels
parts of the brain.17 Lead is also a potent
long distances before being deposited
inhibitor of the NMDA (glutamate)
onto the ear th鈥檚 sur face. Mer cury in
receptor. The fetal brain may be
sediments and water bodies is converted
particularly sensitive not only because
by bacteria into methylmer cury, which
Greater Boston Physicians for Social Responsibility 61
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
How Much Mercury In My Tuna Sandwich?
T he EPA sets 鈥渟afe鈥? reference doses for the
chemicals we are exposed to through our air,
water, and food. Yet it is difficult to translate those
levels, expressed in micrograms and parts per million,
into information that is meaningful for our daily lives.
For instance, how can I determine how much mercury
I am exposed to each time I eat a tuna sandwich?
Some basic information on equivalencies and abbreviations will help you do the
math so you can determine how much of a chemical you may be exposed to.
The first step in determining exposure is converting the various measures into
equivalent units. In the United States we often express our body weight in
pounds or the amount of food we eat in ounces. Environmental concentrations
and exposures, however, are usually calculated using metric units (grams,
kilograms). Note the following equivalencies:
鈥? 1 kilogram (kg) = 2.2 pounds (lb)
鈥? 1 pound = 16 ounces = 454 grams
鈥? 1 ounce = 28 grams (gm)
Because we are often concerned about exposures to very small quantities of
chemicals, it is helpful to know the following units of measure that represent tiny
subdivisions of the gram (gm):
鈥? Milligram (mg) = 1/1000 gm (thousandth)
鈥? Microgram (ug or microgm) = 1/1,000,000 gm (millionth)
鈥? Nanogram (ng) = 1,000,000,000 gm (billionth)
鈥? Picogram (pg) = 1,000,000,000,000 gm (trillionth)
For example, there are 1,000 milligrams in 1 gram, or 1 million micrograms
in that same gram.
We are generally exposed to chemicals that are contained within another
medium such as air, water or food. In order to calculate exposure we must first
calculate the concentration, or the amount of the chemical that is contained in
the water we drink or the food we eat. For example, if 1 gram of fish contains,
on average, 1 microgram (ug) of mercury, we would express the concentration as
1microgm/gm. Since there are a million micrograms in a gram, another way to
express this concentration is 1 part per million, or 1 ppm. The following chart
outlines the equivalencies:
鈥? Gm/kg = mg/g = parts per thousand = ppthousand (1/1000)
鈥? Mg/kg = microgm/g = parts per million = ppm (1/1,000,000)
鈥? Microgram/kg = ng/gm = parts per billion = ppb (1/1,000,000,000)
鈥? Ng/kg = picogm/gm = parts per trillion = ppt (1/1,000,000,000,000)
62 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Since we have determined the concentration of mercury in the tuna fish, we
can determine how much mercury an individual is exposed to when eating the
fish. With a few basic calculations, we can calculate the mercury exposure of a
woman who consumes 7 ounces of tuna per week, given an average tuna
mercury level of 0.2 ppm (Assume she does not eat any other fish
How can I determine
or shellfish, or have any other significant exposures to mercury).
how much mercury I am
鈥? First we convert the ounces into metric units:
exposed to each time I eat
7 oz = 196 gms fish a tuna sandwich?
鈥? Then we multiply the amount of fish consumed/week with
the concentration of mercury in the fish to determine the mercury
exposure per week:
196 gms fish/week x 0.2 microgm mercury /gm fish = 39.2 microgm
mercury/week
How much mercury is that per day?
鈥? Divide by 7, since there are 7 days in a week:
39.2 microgm of mercury /week = 5.6 microgm of mercury/day
= daily mercury exposure
Typically we standardize exposures by dividing
the total exposure by the body mass. Expressing
exposure on a 鈥減er kilogram鈥? basis allows us to
compare exposures among individuals of different
sizes. If we assume the woman eating the sandwich
is of average weight, (132 pounds, or 60 kg), we
divide the total exposure by 60 kilograms:
5.6 microgm/60 kg of mercury/day
= 0.093 microgm/kg
We have determined that the mercury
exposure of a 132 lb woman (60 kg) eating 7
ounces (196 grams) of tuna per week is 0.093
microgms/kg/day. This level of exposure is just at the limit of EPA鈥檚 鈥渟afe鈥?
reference dose of 0.1 microgrm/kg/day.
This calculation is based on the assumption that the woman weighs 132 lbs.
What would the mercury exposure be if a 50 lb child consumed the same amount
of tuna over the course of a week? The child would be exposed to approximately
0.243 microgms/kg/day of mercury.
Greater Boston Physicians for Social Responsibility 63
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Mercury: Inadequate Margin of Safety
level associated with
Measured Exposures
100 harmful effect
Mercury exposures infants (Iraq 1974, high)
DAILY INTAKE FOR EFFECT
associated with harmful
effects have been recognized 10 infants (Japan, 1977)
at progressively lower levels Tapajos River (Brazil, high)
(micrograms/kg/day Hg)
over the past several decades nurses&MDs (U.S., high)
as research meth ods have children (Greenland)
improved. EPA鈥檚 current 1 infants (Alaska, 1976)
1 fish meal/day
advised safe exposure limit, 1 fish meal/day
aboriginal people (Canada)
represented by the triangle, is
1 fish meal/week
exceeded by many groups. It global average
is also exceeded by the global nurses&MDs (U.S.)
0.1
average mercury exposure.
This average, based on a CURRENT EPA REFERENCE DOSE
(below which harm is
report of 559 hair samples considered unlikely) Note: Indicated exposures represent
from 32 locations around the population averages except where
noted as high end of ra nge.
world, reflects a cumulative 0.01
average of levels of fish 1970 1980 1990 2000
YEAR
consumption, and degrees
of fish contamination.1 2 3 4 5
6 7 8 9 10 11
(All indicated
bioaccumulates as it passes up the food behavioral performance, as tested by
exposures were assessed
20
chain. As a result, fish consumed by Fifty-
rewarding for total lever presses.
as hair or blood mercury
levels, except US nurses
pregnant women or women of repro- 60-day-old monkeys born to mothers
and physicians, whose
ductive age may be contaminated with that received 0.04 or 0.06 mg methylHg/
exposures were estimated
by dietary survey.) methylmercury at levels that pose a kg/day for an average of 168 or 747 days
threat to the uniquely vulnerable develop- prior to mating show impaired visual
recognition memor y.21 Autopsy studies
ing brain of the fetus. Forty states have
issued fish advisories warning women of in developmentally exposed animals
reproductive age to limit or avoid show smaller brain sizes, dilated ventricles,
consuming fresh water fish because of and distorted cellular architecture.
mercury contamination. Large predator Human Studies
ocean fish, like swordfish and some tuna,
The devastating effects of
may also be sufficiently contaminated to
methylmercury on the developing human
pose a risk, particularly when eaten
brain after excessive exposure were
regularly . According to EP A estimates,
tragically demonstrated in large-scale
1.16 million women of childbearing
poisonings. In Minamata Bay , Japan,
years eat sufficient amounts of mercury-
during the 1950鈥? s, residents r egularly
contaminated fish to pose a risk of harm
consumed fish contaminated with
to their future children.
methylmer cury from an industrial plant鈥? s
Animal Studies ef fluent in the bay . Infants bor n in the
Studies in animals confirm the late 1950鈥檚 developed characteristic neuro-
developmental neurotoxicity of organic logical findings including mental retardation,
mer cury. Four-month-old rats, exposed disturbances of gait, speech, sucking, and
swallowing, and abnormal reflexes. 22
to 0.008 mg Hg/kg/day on gestational
Mothers of affected children often
days 6-9 show significantly impaired
showed no sign of mercury poisoning.
64 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Another large scale poisoning In the Seychelles, 738 children were
occurred in Iraq in the 1970鈥? s when followed with sequential detailed
residents baked bread with grain neurological testing. Maternal hair levels
intended for planting that had been of mercury averaged 6.8 ppm. At age 2
treated with organic mercury as a years, more highly exposed boys scored
fungicide. Unlike Minamata, this significantly lower on activity level when
represented an acute rather than chronic tested by the Bayley Infant Behavior
Record. 25 Among boys and girls
poisoning. Symptoms were similar in
the two circumstances, but visual combined, the effect of mercury on
disturbances in adults were more severe activity level was significant only at a
in Iraq with actual blindness in several maternal hair level greater than 12 ppm.
instances. 23 The critical effect from Follow up testing at age 5 years showed
prenatal exposure to methylmercury no persistent effect of prenatal mercury
exposure. 26 Neurological testing at 66
was psychomotor retardation with According to EPA
delays in learning to walk and an months of age included the McCarthy estimates, 1.16 million
increased incidence of seizures. Using Scales of Childr en鈥檚 Abilities, Pr eschool women of childbear-
maternal hair mercury levels as a Language Scale, W oodcock-Johnson ing years eat sufficient
measure of prenatal exposure, Applied Pr oblems and Letter and W ord amounts of mercury-
investigators calculated that the lowest Recognition T ests of Achievement, the contaminated fish to
observed adverse effect level (LOAEL) Bender Gestalt T est, and the Child pose a risk of harm to
for psychomotor retardation occurred Behavior Checklist. their future children.
when maternal hair levels of mercury In the Faroe Islands, 917 newborn/
were between 10-20 ppm. 24 Maternal mother pairs were tested at birth for
hair mercury levels are thought to be a maternal hair and umbilical cord blood
fairly accurate indicator of fetal mercury mer cury levels. Childr en whose mother 鈥檚
exposur es during pr egnancy . hair mercury levels were 10-20 ppm
More recently , epidemiological were compared with those whose hair
studies conducted in the Seychelle and levels were less than 3 ppm. Early
Faroe Islands have attempted to identify examination of children showed that the
more subtle developmental neurological most exposed children had subtle
effects of low-dose methylmercury changes in the function of portions of
exposure and to identify a threshold, the brain associated with hearing and
if one exists, below which there is motor skills. As they gr ew older , some
no discer nable toxicity . These study deficits in learning capacity also became
populations were selected because apparent. At age 7 years these children
their fish or marine mammal based underwent extensive neurological testing
diets regularly exposed them to low including the Neurobehavioral
doses of methylmer cury, and mater nal Evaluation System (NES) Finger T apping
hair levels of mercury in these and Hand-Eye Coor dination Test,
populations bracketed the LOAEL Tactual Per formance Test, NES
identified in the Iraq study .
Greater Boston Physicians for Social Responsibility 65
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Continual Per formance Test, W echsler mercury concentration of ocean fish.
Intelligence Scale for Children 鈥? Revised Consequently, it is likely that the Faroese
(WISC-R) Digit Spans, WISC-R experience intermittent spikes of mercury
Similarities, WISC-R Block Designs, exposure that are higher than the
Bender Gestalt T est, Califor nia Verbal Seychellois. The neurodevelopmental
Learning Test, Boston Naming T est, consequences of these two exposure
and the Nonverbal Analogue Profile of patterns may differ. Fourth, pilot whale
Mood States. 27 The studies showed blubber is also contaminated with PCBs
a significant correlation between and other organochlorine chemicals,
impairment in the areas of language, which also affect neurological develop-
attention, and memory and prenatal ment. Though methylmercury is largely
mercury exposure. contained in the whale meat, some resi-
dents also eat whale blubber, resulting in
Investigators in each study controlled
concomitant PCB exposures. PCB levels
for many potentially confounding factors
were measured in the Faroe Island study,
including socioeconomic status, quality of
and investigators used analytical statistical
the home environment, and breast feeding
techniques to control for co-contaminants
status, among others. The differing results
as they looked for effects of prenatal mer-
may be explained by several different
cury exposure. However, some critics
factors. First, some neurological effects do
believe that the other contaminants may
The studies showed a not become apparent until later in child-
explain at least some of the findings. The
significant correlation hood when certain neurological functions
Faroe Islands study team strongly disagrees
between impairment begin to develop. This, however, becomes
and argues that they successfully control-
in the areas of less likely to explain the discrepant find-
led for PCB co-contamination.28 Finally,
language, attention, ings as the Seychellois children approach
the Faroe Islands study identified a relation-
and memory and age 7 and continue to show no lasting
ship between neurodevelopment and cord
prenatal mercury deficits. Second, the testing techniques
blood levels of mercury, rather than
exposure. used in the Faroes may be more sensitive
maternal hair. Umbilical cord blood levels
than those used in the Seychelles. The
may better reflect actual fetal exposures.
Faroe investigators included examination
of some specific areas of neurocognitive Additional studies also show
performance that are more easily and developmental neurotoxicity after oral
accurately detected by detailed computer exposure of humans and non-human
analysis. Third, the exposure pattern is primates to low doses of organic
mer cury.29 30 31 In a New Zealand study ,
likely to have differed in the two groups.
maternal hair mercury levels of 15
In the Seychelles, fish are contaminated
microgms/gm were associated with
with methylmercury at a relatively low
poor er per formance on the W echsler
level and mercury exposure is the result
Intelligence Scale for Children.
of a constant diet of fish. In the Faroe
Islands, however, mercury exposure results Based on the Seychelles study, the
from intermittent ingestion of pilot whale Agency for Toxic Substances and Disease
meat that contains about 10 times the Registry (ATSDR) has established a
66 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
division. 37 In the nervous system,
minimum risk level for oral exposure to
methylmercury at 0.5 microgm/kg/day. mercury interferes with development of
However, the EPA has set the level at 0.1 microtubules, which are small tubular
38
microgm/kg/day. Based on dietary surveys, structures in the neuronal skeleton.
the EPA estimates that about 7% of women Mercury also disrupts cell membrane
in the US of childbearing age consume integrity and alters the chemical
Risk assessments
methylmercury in excess of the 鈥渟afe鈥? dose.32 characteristics of the surface of cells,
or advisories that
However, among women who eat any making them more likely to adhere to
are based on single
fish at all, 50% of those of childbearing one another . This may explain how
hazard analyses
age consume excess methylmercury. cellular migration is affected during
that define safe
brain development. Mercury exposure
The Food and Drug Administration
fish consumption
also disrupts synaptic transmission.
(FDA) established an 鈥渁ction level鈥? for
limits are unlikely
mercury in fish at 1 ppm in 1979. 33 In an in vitro study, methylmercury
to be protective of
However , the FDA鈥檚 action level is a non- and polychlorinated biphenyls (PCBs)
public health.
binding informal guideline, is not legally were reported to interact synergistically,
enforceable, and only serves as discre- with combined exposures resulting in
tionary guidance to FDA and to states lowering of dopamine levels in animal
when deciding when seafood might be brain tissue to a greater degree than would
adulterated. Fish consumption has have been predicted by adding the effects
increased in the US since 1979, and observed when the chemicals were used
individually.39 New data, as yet unpublish-
critics have argued that this action level
is not health-protective. Indeed, FDA ed, from a long term ongoing study of
was quoted in a 1991 General Account- children born to mothers consuming fish
ing Office report as stating that the from Lake Ontario, show that prenatal
agency failed to consider reproductive PCB and mercury exposures also interacted
and developmental toxicity when estab- to reduce performance of 3-year-old
lishing the guideline. 34 Also in 1991, the children on the McCarthy Scales of
Children鈥檚 Abilities.40 Mercury exposures
National Academy of Sciences noted that
the FDA guideline did not adequately protect in this study were quite low, yet they
sensitive populations, including fetuses, combined with PCB exposures to increase
babies and young children.35 (see Spotlight) adverse impacts on neuro-development.
Together, these observations raise important
Mechanisms of Neurotoxicity
questions about the adequacy of fish
Mercury has a high affinity for
consumption advisories based on single
binding to specific chemical structures
chemical analyses. Freshwater fish in
(e.g., sulfhydryl groups) on proteins,
many areas of the US are contaminated
which is thought to explain many of its
with mercury, PCBs, dioxin, and other
biological activities. 36 The result is
toxicants. Risk assessments or advisories
diffuse alteration of cellular function,
that are based on single hazard analyses
inhibition of protein synthesis, and
that define safe fish consumption limits
formation of reactive oxygen species,
are unlikely to be protective of public health.
which can damage DNA and disrupt cell
Greater Boston Physicians for Social Responsibility 67
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Manganese and soy-based infant formula contains
200-300 micrograms Mn/liter.43
鈥? Unlike many other metals, some
Consequently, formula-fed infants
manganese is essential as a catalyst
ingest much more manganese than
in several critically important
those who are breast-fed.
enzymatic processes
An organic form of manganese,
鈥? However , several studies r epor t a
methylcyclopentadienyl manganese
relationship between excessive
tricarbonyl (MMT), is used in a portion of
childhood levels of manganese
the nation鈥檚 gasoline supply as an octane
exposure and hyperactivity or
enhancer. When burned, MMT-
learning disabilities
supplemented gasoline releases several
Unlike mercury and lead, which are
inorganic manganese compounds into the
not required for human health, the
atmosphere, causing small but widespread
metal manganese is essential in trace
inhalation exposures, as well as land and
amounts in order to promote several
water deposition. Animal studies show
critical enzymatic reactions. Manganese
that inhaled manganese compounds may
deficiency may result in abnormalities of
travel along the olfactory nerve directly
connective tissue, cartilage, and bone. In
into the brain, bypassing the general
various species, too little dietary
circulation and the blood-brain barrier.44
manganese causes impaired skeletal
Formula-fed The relevance of this pathway of exposure
development and reproduction,
infants ingest in humans is uncertain.
abnormal carbohydrate and lipid
much more
In adults, only about 3-5%, or
metabolism, and movement disorders.
manganese than
approximately 100 microgms, of ingested
those who are Routes of Exposure
manganese is absorbed into the circulation.
breast-fed.
In non-occupational settings, most Much of this is immediately excreted into
Infants and manganese exposure comes from food. the bile so that adults retain only about
young children The National Research Council 30 microgms daily .45 Animal studies
absorb more estimates a safe and adequate daily show that young animals absorb much
and excrete dietary intake of 2-5 milligrams. The more ingested manganese than adults 鈥?
less ingested ordinary adult dietary intake ranges about 70% in young rats compared to
manganese from 0.52-5.33 milligrams daily with 1-2% in adults. 46 Manganese balance
than adults. 41
an average of 3 milligrams. Infant studies in humans also show that infants
dietary intake of manganese varies and young children absorb more and
dramatically with the source of food. excrete less ingested manganese than
Human breast milk contains about 6 adults. 47 Moreover , the blood brain
micrograms/liter. Infant formula barrier, which keeps many blood-bor ne
contains about 77 micrograms Mn/liter chemicals from entering the brains of
if no manganese has been added and older children and adults, is immature
about 100 micrograms Mn/liter if it has in infants, allowing proportionately
been supplemented.42 Soybean plants more manganese to gain access to and
efficiently extract manganese from soil, lodge in the developing brain.
68 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
has some similarity to Parkinsonism,
Animal Studies
though there are distinct differences.
Despite being an essential trace
element, excessive exposures to Several investigators have attempted
manganese can be harmful to the brain, to detect early signs of neurological
lungs, and reproductive system. Adverse damage from manganese exposure in
reproductive effects, including testicular adults. One describes a continuum of
toxicity and reduced testosterone levels, dysfunction due to manganese exposure,
Emerging evidence
occur in animals exposed to manganese including behavioral and emotional
demonstrates that
during fetal development at levels that effects in addition to the well-known
the brains of fetuses
movement disor der.50 Another used
show no other toxic effects but that are
and newborns are
considerably higher than normal human behavioral methods to look for early
more susceptible to
dietary intake. 48 signs of manganese neurotoxicity after
the toxic effects of
low-level exposures and concluded that
The more critical health effect,
manganese than
there are effects on response speed,
however , that may occur at much lower
adults and that
motor functions, and memor y.51
levels of exposure, is brain damage.
developmental
Emerging evidence demonstrates that Several studies have reported a
exposures may
the brains of fetuses and newborns are relationship between manganese hair
result in unique
more susceptible to the toxic effects levels in children and hyperactivity or
neurological effects.
of manganese than adults and that learning disabilities. One found that the
developmental exposures may result in concentration of manganese in the hair
unique neurological effects. A review of of formula-fed infants increased from
the published literature on manganese 0.19 micrograms/gm of hair at birth to
neurotoxicity in rodents identified seven 0.965 microgms/gm at six weeks,
studies in which animals were exposed declining to 0.685 microgms/gm at four
during development. 49 Three studies months of age. In breast-fed infants, hair
investigated behavioral outcomes, and levels increased only to 0.330 microgms/
each reported increased activity levels gm at four months of age. In this study ,
in offspring. hair levels of manganese in hyperactive
children were 0.434 microgms/gm as
Human Studies
compared to levels of 0.268 microgms/
Respiratory symptoms, pneumonia,
gm in age-matched controls who were
or bronchitis occur in workers with
not hyperactive. 52 Another study
large inhalation exposures to manganese.
reported hair manganese levels of 0.83
Obvious neurological effects of manganese
microgms/gm in hyperactive children
were first noted in workers in manganese
compared with 0.58 microgms/gm in
mines, refineries, and smelters.
controls. 53 This study also found
鈥淢anganism鈥? includes tremor and
elevated lead levels in hyperactive
movement disorders, often preceded by
children. A third study also reports
鈥渕anganese madness,鈥漜haracterized by
higher hair manganese levels in children
compulsive running, fighting, and singing.
with attention deficit hyperactivity
The movement disorder of manganism
disorder than in controls. 54
Greater Boston Physicians for Social Responsibility 69
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Mechanisms of Neurotoxicity
Animals exposed to excessive
manganese early in life show depressed
levels of the neurotransmitters dopamine,
norepinephrine, and serotonin.55 One
study shows that gestational serotonin
depletion in rodents causes much more
extensive structural change in the brains
of offspring than similar depletions in
gasoline octane ratings with lead,
adults, a result that is not surprising, in
population-wide exposures, however
light of the important role of neuro-
low-level they may be, sometimes have
Some studies of 56
transmitters in brain development.
serious, unintended consequences.
children exposed Conclusions
to cadmium
Cadmium
The susceptibility of the developing
have shown
brain to manganese toxicity deserves 鈥? Studies of the neurological effects of
hyperactivity
further attention. Many infant formulas developmental exposure to cadmium
and reduced
are regularly supplemented with manga- report mixed and sometimes
verbal and
nese. Nutritional experts must have conflicting results
performance IQ.
thought that human breast milk is
鈥? In animal tests, cadmium exposure
deficient in this essential element and
causes a mixtur e of hyperactivity ,
that supplements would not be harmful.
reduced activity , and alter ed
Soy-based formulas contain even higher
learning, depending on the timing,
amounts of naturally-occurring manga-
dose, route of exposure, and test
nese. But metabolic studies show that
methods
infants absorb more and excrete less
鈥? Some studies of children exposed to
manganese than adults. Furthermore, in
cadmium have shown hyperactivity and
infants, blood-borne manganese more
reduced verbal and performance IQ
readily enters the brain than in adults.
Animal studies show that developmen- Routes of Exposure
tal exposures to manganese are associ-
Cadmium is a metal with no
ated with hyperactivity . Several studies
essential biological function, but it may
show that hair manganese levels are
interfere with normal neurological
higher in children with hyperactivity
development through a variety of
disor ders than in contr ols. These obser -
mechanisms. Cadmium is released to the
vations call into question the wisdom of
environment from fossil fuel burning,
supplementing infant formulas with this
mining and manufacturing operations,
metal or adding MMT to gasoline, and
sewage sludge, phosphate fertilizers, and
make the case for urgent research to
medical and municipal waste incinerators.
clarify areas of outstanding uncertain-
Cadmium is used for a variety of industrial
ties. As we learned from boosting
70 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
purposes including metal plating, paint guish between direct cadmium toxicity
pigments, plastic stabilizers, and nickel- and nutritional deficiencies from de-
cadmium batteries. creased food and water intake. Finally,
the effect of cadmium on the fetus may be
The largest source of most human
largely an indirect result of impairment of
exposure to cadmium is dietary with an
placental function, enzyme inhibition, or
average adult daily intake of 10-30
alteration of other essential trace metals
microgms. Soil cadmium is readily taken
in the brain rather than a direct toxic
up by leafy vegetables and grain crops,
Soil cadmium is
effect on fetal tissues. For example, metallo-
creating the potential for significantly
readily taken up
thionein induced by cadmium may also
increasing levels in crops grown on soil
by leafy vegetables
bind zinc, an essential trace element,
treated with sewage sludge containing
and grain crops,
resulting in manifestations of zinc defi-
cadmium from industrial sources. 57
creating the potential
ciency, which include birth defects.
Domestic and laboratory animals fed
for significantly
Indirect neurodevelopmental effects are
plants grown on sludge-amended soil
increasing levels in
also inferred from the observation that
may develop cadmium toxicity .58
crops grown on soil
studies of cadmium exposure during
Cadmium also tends to concentrate in
treated with sewage
pregnancy usually fail to find evidence of
shellfish found in contaminated coastal
sludge containing
elevated cadmium levels in the fetal brain.60
waters. Another important source of
cadmium from
cadmium is cigarette smoke; smokers In animals exposed to cadmium
industrial sources.
have blood levels of cadmium approxi- prenatally , a mixtur e of, and sometimes
mately twice that of non smokers. 59 conflicting, neurological effects are
noted. Mor eover , females seem to be
Animal Studies
more sensitive to neurodevelopmental
For several reasons studies of the
effects than males, yet male animals are
neurological consequences of early life
more often studied. Both hyperactivity
exposures to cadmium are more difficult
and reduced activity are noted in
to conduct than studies of lead, for
offspring, depending on the exposure
example. Cadmium is rapidly removed
level, route of exposure, and tests used
from the blood and stored in the kidneys,
to measure activity levels. 61 62 63 The
liver, pancreas, and adrenal glands,
capacity of an animal to learn an
making blood level measurements a poor
avoidance task is also sometimes
indicator of exposure. Chronic cadmium
impaired. 64 In most cases, neurotoxicity
exposure induces the production of a
is noted only when doses are sufficient to
protein, metallothionein, which binds the
alter weight gain and growth. These
metal and reduces its toxic effects.
studies have used maternal exposure
However, intermittent acute exposures to
levels in the range of 0.1-4.0 mg/kg daily
cadmium may escape this mechanism and
during pregnancy via injection, diet,
lead to more severe toxic responses. In
gastric lavage, or inhalation.
laboratory tests, even moderate levels of
In contrast, neonatal exposure to
cadmium exposure may reduce animal
cadmium is potentially more harmful
weight gain, making it difficult to distin-
than prenatal exposure because the
Greater Boston Physicians for Social Responsibility 71
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
blood-brain barrier is not yet fully In a prospective study , a hair sample
developed, and cadmium may have was taken from 26 newborn children
direct access to the developing brain. and their mothers and analyzed for lead
and cadmium. 67 Six years later , the
Microscopic studies show lesions in the
brains of cadmium-treated neonatal rats children were tested by the McCarthy
that are not seen in the brains of treated Scales of Childr en鈥檚 Abilities. Cadmium
adult rats, suggesting that the immature hair levels in children correlated with
blood-brain barrier is an important reduced perceptual and motor
factor in cadmium neur otoxicity . Here, performance. Cadmium hair levels in
too, animal studies show a mixture of mothers correlated with poorer child
hyperactivity , reduced activity , and performance in general cognitive,
altered learning in young animals, perceptual, quantitative, and motor
depending on test methods, dose, and function. Lead levels also correlated
route of exposure. with reduced perceptual performance,
motor, and quantitative scor es.
Human Studies
Mechanisms of Action
Several human studies have
attempted to examine the neurological Cadmium may be directly or
consequences of early exposures to indirectly toxic to the brain of the
cadmium. These are complicated by the developing child. During pr egnancy ,
correlation of lead and cadmium cadmium may interfere with placental
exposures, making it difficult to and essential enzyme function or the
determine the relative contribution of availability of essential trace elements
each metal to observed effects. One study or other nutrients. Neonatal exposures
found a significant correlation between alter neurotransmitter levels, including
elevated hair cadmium and lead levels norepinephrine, dopamine, serotonin,
and hyperactivity in children.65 Another and acetylcholine. 68 Cadmium exposure
study of a rural population of 149 is also associated with increased free
children 5-16 years old found a radical production in tissues resulting in
correlation between hair lead and cell membrane damage and changes in a
cadmium levels and reduced verbal and variety of other physiological functions.
performance IQ when tested by the
Tobacco Smoke and Nicotine
Wechsler Intelligence Scale for
Children.66 This study controlled for 鈥? Children born to women who smoke
gender, age, race, and socioeconomic during pregnancy are at risk for
status. Interestingly, lead and cadmium IQ deficits, learning disorders,
seemed to affect different aspects of and attention deficits
intelligence. Lead levels were more highly
鈥? Children born to women who are
correlated with reduced performance
passively exposed to cigarette smoke
IQ while cadmium levels correlated
are also at risk for impaired speech,
better with reduced verbal IQ.
language skills, and intelligence
72 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
In rats, prenatal nicotine exposure
Routes of Exposure
by maternal low-dose infusion, causes
Cigarette smoke and one of its
hyperactivity in young offspring. 70
components, nicotine, are among the
The effect is most pronounced in males.
most studied neurodevelopmental
Results of testing for effects on learning
toxicants. Many animal studies are
and memory are mixed. Normally
conducted with pure nicotine, which
A number of studies
rodents tend to show increasing interest
easily crosses the placenta, while
of children whose
human epidemiological studies examine in exploring novel environments as they
mothers smoked
age from infancy to adulthood. Rats
the effects of exposure to the complex
during pregnancy
mixture of chemicals in tobacco smoke, exposed to low doses of nicotine in
report adverse effects,
including nicotine. Nicotine exposure in utero showed an opposite effect in that
including diminished
animals, however, produces some of the they tend to explore novel environments
intellectual capacity
same effects in offspring as those seen in more readily in infancy but less after
and achievement
71
children whose mothers smoked during puber ty. Similar changes wer e seen in
into adulthood.
other maze tests. 72 These tests also show
pregnancy, and nicotine is, therefore,
likely to be a substantial contributor to that complicating the task by changing
the testing context sometimes uncovers
the observed effects.
nicotine-induced behavioral changes that
Animal Studies
would not otherwise be apparent.
In animals and humans, nicotine
Human Studies
and tobacco smoke exposure cause
A number of studies of children
growth retardation and other
whose mothers smoked during pregnancy
complications of pr egnancy (pr ematurity ,
report adverse effects, including
placental abnormalities, respiratory
diminished intellectual capacity and
69
distress syndrome). In order to
achievement into adulthood. 73 74 75 76
examine for neurological effects of
prenatal nicotine exposure that are due Effects are apparent immediately after
solely to toxic effects on the developing birth. For example, one study reports
brain and not due to generally retarded that, using Brazelton Neonatal
Behavioral Assessment Scales, infants
growth, it is important to conduct
born to smokers score significantly
animal testing at relatively low-levels
lower at 2, 3, and 14 days postpartum
of exposure. Larger doses that cause
than unexposed infants. 77 Hearing seems
decreased oxygen delivery to the fetus
to be particularly affected. Nicotine
may cause retarded growth and are
exposed infants were able to adapt to
less informative about exclusively
sounds normally but were less able to
neurotoxic effects. Therefore, animal
orient toward the source of the sound.
studies done with low-dose infusion
This finding persisted at 2 weeks of age.
pumps that better mimic the level of
human fetal exposure to nicotine due A large study of 12,000 children
to maternal smoking give extremely followed from birth to 11 years of age
relevant information. showed that those whose mothers
Greater Boston Physicians for Social Responsibility 73
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
smoked more than 10 cigarettes daily Mechanisms of Neurotoxicity
during pregnancy were 3-5 months Animal studies show that gestational
retar ded in general ability , reading and exposure to nicotine at levels that do not
math skills at age 11. 78 Investigators cause growth retardation increases the
corrected for socioeconomic and biolog- number of cholinergic nicotinic neuro-
ical variables in the study population. receptor sites in the fetus and neonate,
One study that followed a cohort of an effect that persists through the postnatal
period of synapse formation. 83 Prenatal
children into adulthood found that, by
age 23, offspring of mothers who nicotine exposure also causes subnormal
smoked during pregnancy had levels of the neurotransmitters dopamine
significantly lower academic achieve- and norepinephrine in the postnatal
ment than unexposed children. 79 This period. 84 Changes in norepinephrine
study controlled for social class, size of utilization persist in some areas of the
family, and birth weight. It did not control brain in adulthood.
for maternal academic achievement. A study of fetal and neonatal rats
Maternal and/or childhood exposure exposed to nicotine showed reduced DNA
synthesis in the brain. 85 This was parti-
to environmental tobacco smoke
(鈥減assive smoking鈥?) also seems to have cularly marked in areas of the brain with
adverse effects. 80 For example, after higher concentrations of nicotinic receptors
correcting for confounding variables, and in areas undergoing rapid cell division.
children at ages 6-9, tested for speech Cigarette smoke, however , is
and language skills, intelligence, and chemically complex and includes carbon
visual/spatial abilities, whose mothers monoxide and cyanide. In addition to the
were exposed to passive cigarette smoke direct action of nicotine on the developing
during pr egnancy , per formed brain, other potential mechanisms of
intermediate between children of toxicity of smoke include low oxygen
smoking mothers and those unexposed levels from carbon monoxide and
.81 Investigators noted attention deficits impaired transfer of nutrients across the
and information processing problems in placenta, resulting in generally retarded
exposed childr en. Testing included the fetal growth.
Wechsler Intelligence Scale for childr en
Conclusions
with three-factor scores including verbal
Tobacco smoke is a complex mixtur e
comprehension, perceptual organization,
of chemicals including nicotine, a
and fr eedom fr om distractibility . In an
neurotoxic substance with lasting effects
animal study of the effects of environ-
on neurological function after fetal
mental tobacco smoke, rats exposed
exposures. Offspring of animals and
only post-natally and not pre-natally
humans exposed to nicotine in utero are
had reduced DNA content in their brains
hyperactive and experience increased
82
when compared to unexposed animals.
tremors and impaired auditory
responsiveness. Children exposed to
74 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
nicotine and other contaminants of 2,3,7,8 鈥? tetrachlorodibenzo-p-dioxin
cigarette smoke during gestation show (with chlorine atoms in the 2,3,7,8
persistent intellectual impairment that positions) has the highest affinity for the
affects performance on neurological Ah receptor and is the most potent
testing and is associated with lower trigger of Ah r eceptor -mediated ef fects.
academic achievement. Environmental Polychlorinated biphenyls (PCBs)
tobacco smoke (鈥減assive smoking鈥?) also are industrial chemicals that were
interferes with brain development. intentionally produced for many years
and used for a variety of purposes
DIOXINS AND PCBS
including as lubricants, coatings, and
鈥? Monkeys exposed to dioxin insulating material in electrical
as fetuses show evidence of transformers. In the US, and in most
learning disabilities other countries, PCB production has been
鈥? Humans and animals exposed
Current Dietary Dioxin Exposures
as fetuses to low levels of PCBs
have learning disabilities
鈥? = 1 pg/kg/day (the advised limit for chronic exposure)
鈥? Children exposed to PCBs
during fetal life show IQ deficits,
hyperactivity , and attention deficits AGE GROUP EXPOSURE
when tested years later
鈥⑩??
Over 20 years 2X
Dioxins are a family of chemical
鈥⑩?⑩?⑩?⑩?⑩?⑩?⑩??
10-14 years 1-16X
compounds unintentionally produced
during a variety of industrial processes, 鈥⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩??
5-9 years 1-27X
including municipal and medical waste
鈥⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?? 1-32X
1-4 years
incineration, secondary copper smelting,
鈥⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩??
hazardous waste incineration, and Breast-fed Infant 34-53X
鈥⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩?⑩??
chlorine-based pulp and paper bleaching,
among others. Dioxins consist of two * Based on a minimal risk level defined by ATSDR as a level at or below which adverse health effects are not expected to
occur in humans. Chronic exposure is defined as an exposure lasting 1 year or longer.
benzene rings, joined by two oxygen
Dioxin is concentrated in animal fat, and accumulates at higher levels in
atoms, with varying numbers of chlorine
long-lived animals, and animals higher in the food chain. Because human
atoms distributed ar ound the peripher y. food sources vary with age, dioxin intake also varies with age.1 2 Because
The toxicity of a given dioxin molecule dioxin is concentrated in breast milk, the intake of breast-feeding infants is
highest, exceeding ATSDR鈥檚 recommended limit for chronic exposure (one
varies with the number and position of
year or longer) by a factor of 34-53. This limit is exceeded to lesser degrees
chlorine atoms. Most of the toxic in all age groups. According to EPA, if one were to calculate, based on all
human and animal data, a dioxin exposure limit that would protect against
manifestations of dioxin exposure are
noncancer effects, (incorporating uncertainty factors to account for species
mediated through attachment of the differences and sensitive populations, such as the fetus), this exposure limit
dioxin molecule to a cellular receptor would be 鈥渙n the order of 10 to 100 times below the current estimates of
daily intake in the general population.鈥?3
(the Ah receptor), although some
neurodevelopmental effects may be
unrelated to Ah receptor activation.
Within the dioxin family of compounds,
Greater Boston Physicians for Social Responsibility 75
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
banned because of their environmental Animal Studies
persistence, tendency to bioaccumulate, Monkeys exposed gestationally to
and toxicity. However, PCBs still exist in dioxin through a maternal diet containing
many electrical transformers, in landfills, 5-25 ppt dioxin, within the range of
and hazardous waste sites. PCBs are human breast milk contamination, show
structurally similar to dioxins but lack the deficits in discrimination-reversal learning
oxygen atoms between the benzene rings. (retarded learning of shape reversals).86
In this test, animals initially learn to
Routes of Exposure
An adequate margin respond correctly to a particular shape,
Exposure to dioxins and PCBs is
of safety requires several
form, color, or position. Then the correct
largely through dietary sources. Both
orders of magnitude
answer is reversed so that the previous
between the range of
dioxins and PCBs are environmentally
human exposures and
incorrect response now becomes correct.
persistent and tend to bioaccumulate in
the lowest level of
fatty tissue. Consequently, concentrations This requires changing a response
adverse health effects.
Adverse health effects
of each are highest at the top of the food strategy, a task more difficult than simply
of dioxin,1 2 3 4 however,
chain, including beef, pork, dairy products, learning to discriminate initially.
have been demons-
trated in animals at
and fish. Breast milk contains among the Monkeys fed from birth to age
levels of exposure
highest levels of any human tissue because twenty weeks with a PCB mixture and
that approximate
the upper range of of its high fat content, which explains concentration representative of PCBs
human exposures. This
demonstrates the urgent why a nursing infant is exposed to a typically found in human breast milk
substantial portion of a total lifetime dose showed significantly impaired learning and
need to reduce human
exposures by reducing
of each of these families of chemicals performance skills when tested between
or eliminating dioxin
2.5 and 5 years of age.87 In addition to
during the first few months of life.
production and release.
retarded learning, exposed monkeys
showed perseverative behavior (constant
Dioxin: Inadequate Margin of Safety
repetition) and an inability to inhibit
inappropriate responses.88 The affected
DIOXIN
EXPOSURE
monkeys had blood PCB levels of 2-3 ppb,
(picograms/kg/d)
similar to levels in the general human
REPORTED
1,000,000
HEALTH EFFECTS
population. Other investigators report
male reproductive
similar effects on learning and behavior in
single gestational dose
effects (rats)
100,000
monkeys exposed to PCBs shortly after
decreased sperm
single gestational dose
count (rats)
birth, including hyperactivity.89 90
10,000
Rats exposed to PCBs prenatally
increased abortions, 4 year exposure
1,000
CURRENT learning-impaired
show reduced visual discrimination,
(preconception, gestational,
HUMAN offspring (monkey) and lactational)
EXPOSURE increases and decreases in activity level,
altered social 1.3 year exposure
100 behavior in (preconception, gestational,
breastfed infant
and impaired learning. 91 92 Depending
offspring (monkey) and lactational)
child on the particular PCB(s) used in the
10
study , ef fects ar e seen at mater nal doses
teenager
adult
as low as 2 microgms/kg/day every
1
second day from day 10-20 of gestation,
with no no-effect level identified.
76 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Dioxin is unintentionally produced in a variety of industrial Because of their similar chemical properties, PCBs and
processes, including municipal and medical waste incineration.1 dioxin have similar patterns of long range atmospheric transport
Once emitted into the air, dioxin often travels more than a resulting in widespread deposition. Both accumulate in the
thousand miles before settling on pastures and water bodies cattle and fish feeding on contaminated vegetation, and
that produce the global food supply.2 PCBs were produced concentrate further in species eating high on the food chain,
predominantly from the 1920鈥檚 to the 1980鈥檚, for use in a variety including humans. PCBs and dioxin can remain in soil for many
years. 9 10 Laboratory studies in animals have demonstrated
of products including transformers, capacitors, and lubricant
oils.3 While PCB production has been banned in most countries, significant dermal absorption of PCBs, but not of dioxin,
following contact with contaminated soil.11 12 13 However, most
approximately two-thirds of the total amount produced has not
yet been released to the environment.4 PCBs have been human exposure to both PCBs and dioxins occurs through food
consumption.14 15 Because dioxin and PCBs are carried by fat,
introduced into the environment through careless disposal,
leakage from industrial facilities and waste disposal sites, and they are passed during pregnancy from mother to fetus, the
from products in use.5 6 PCBs introduced to land or water bind most vulnerable stage of human development, and continue to
to soil and sediment particles, evaporate at various rates, and, be transmitted during breast feeding. Dioxin and PCBs thus
like dioxin, undergo long range atmospheric transport. 7 8 illustrate one of the unforeseen pathways by which industrial
chemicals may travel from the factory to the fetus.
Greater Boston Physicians for Social Responsibility 77
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
exposed to PCBs prenatally showed
Human Studies
delayed or reduced psychomotor
In the late 1960s and early 1970s
development and poorer performance on
two episodes of accidental human
a visual recognition memory test. 95
exposure to PCB-contaminated rice oil
These children have now been followed
in Japan and T aiwan r esulted in tragic
for more than 11 years. Prenatal PCB
developmental effects in children born
exposure remains associated with lower
to exposed mothers. 93 The developing
IQ scores after controlling for other
fetus was much more sensitive than
factors, including socioeconomic
mothers, and numerous abnormalities
status. 96 Compared with the low
were observed including low birth
exposure group, the most highly exposed
weight, hyperpigmented skin, swollen
children were more than three times as
gums and eyelids, and early tooth
likely to perform poorly on IQ tests and
eruption. Neurological abnormalities
tests designed to measure their attention
were among the most significant
span. They were more than twice as
findings, including mental retardation
likely to be at least two years behind in
among some of the most highly
word comprehension in reading.
exposed. Delayed brain development
According to the investigators, the most
and behavioral abnormalities in the
frequent manifestations of neurodevelop-
children persist for years after the
mental toxicity of PCBs are disturbances
incidents. Exposed children have deficits
in neuromotor activity and attention
on IQ testing, and according to
(deficits in focused and sustained
teachers, are hyperactive and exhibit
attention), impairments of higher
more behavioral problems than those
cognitive functions and learning, and
unexposed. 94
neurodevelopmental delays. These
Although these tragic incidents
disturbances seem likely to persist
exposed children to obviously toxic
throughout the school years.
amounts of PCBs, other studies have
Another group of children in North
examined the neurodevelopmental
Carolina shows similar results. Higher
effects of exposures to levels of PCBs
fetal PCB exposures, as measured by
found in the ambient environment. One
PCB levels in maternal blood, were
group of 212 children in Michigan has
associated with lower scores on
been followed for years. Children were
psychomotor development tests
classified as offspring of fish-eating
(Brazelton) at six and twelve months of
mothers if maternal Lake Michigan fish
97
age than those with lower exposures.
consumption was at least 6-8 oz/month.
Some of the study families, however , In a New York study of several
were not fish eaters. In most cases, but hundred newborn children whose
not all, fetal and nursing PCB exposure mothers ate PCB-contaminated fish
correlated with maternal Lake Michigan from Lake Ontario, those with the
fish consumption before and during higher exposures showed abnormal
pregnancy . The childr en most highly reflexes and startle responses and
78 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
PCBs: Inadequate Margin of Safety
PCB
SERUM LEVELS
(ppb)
REPORTED 20 REPORTED
HUMAN HEALTH EFFECTS
decreased visual recognition when EXPOSURES
compared with the less exposed. 98
Recently , investigators r epor ted that, Great Lakes 15
fish eaters
at 12 months of age, prenatal PCB
exposure was associated with poorer
Great Lakes
per formance on the Fagan T est of Infant 10
non-fish eaters
Intelligence and at 3 years of age with Midwest and
Northeast US women
poorer performance on the McCarthy Michigan mothers
decreased reflexes, memory,
Scales of Childr en鈥檚 Abilities. 99 5
visual discrimination, IQ, attention
North Carolina mothers
Wisconsin women
The development of another group hypotonia and decreased reflexes,
psychomotor development, and
Dutch mothers
of 418 children has been studied neurologic "optimality"
0
prospectively for several years in the (Note: Indicated exposures represent population
averages except where noted as high end of range.)
Netherlands, after measuring PCB/
reported by parents. This study also Prenatal exposure to
dioxin levels in maternal blood during
background levels of PCBs
reported small but significant reductions
the last month of pr egnancy , in umbilical has been shown to adversely
in thyroid hormone levels at 2 weeks and
cord blood, and in breast milk. These effect reflexes, memory
and neurological function
3 months of age in the children with the
exposures were all at ambient
as assessed by physical exam
highest PCB/dioxin fetal exposures. 101
environmental levels and not the result in infants and toddlers.
Adverse effects on attention,
of a large accidental exposure or of Mechanisms of Neurotoxicity memory, intelligence and
excessive fish consumption. Cognitive reading comprehension
The mechanisms of action of
abilities were assessed in 395 of these have been demonstrated
dioxins and PCBs on early neurological in children followed up
children with the Kaufman Assessment
development ar e incompletely under - to age 11.1 2 3 4 5 6 7 8 9 10 11
Battery for Children at 42 months of 12 13 14 15 16 17 18 19 20 21 22
stood. Dioxins and some PCBs share one
age. 100 After adjustment for co-
mechanism of action but differ in others.
variables, maternal PCB blood levels
However , because their chemical charac-
were significantly associated with lower
teristics ar e similar , they tend to co-exist
scores on the overall cognitive and
in biological tissues, making it difficult
sequential and simultaneous processing
to distinguish between their toxic effects
scales of this batter y. Lactational
in human epidemiological studies.
exposures and current exposure to PCBs
Dioxins and dioxin-like PCBs (so-
and dioxin were not related to 42-month
called coplanar or non-ortho PCBs)
cognitive performance, indicating that
share a common mechanism of action by
the adverse effect is the result of fetal
binding to the Ah r eceptor . This complex
exposure to PCBs.
is then further processed and passes into
The investigators also report that
the cell nucleus where it binds to DNA,
umbilical cord and maternal PCB blood
influencing the production and metabolism
levels are significantly associated with
of a variety growth factors, hormones,
less time at high level play . Blood PCB
and hor mone r eceptors. However , many
levels in 42-month old children are
non-coplanar or ortho-PCBs that do not
associated with slower reaction times
readily attach to the Ah receptor also
and more signs of hyperactivity as
have biological activity , which substan-
Greater Boston Physicians for Social Responsibility 79
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
tially contributes to their neurodevelop- decrease dopamine synthesis while non-
mental toxicity . At least some of this ortho PCBs increase dopamine levels
toxicity may result from interference after in utero and lactational exposure in
rats. 106 This effect may also be related to
with thyroid hormone function.
the neurodevelopmental delays described
PCBs may interfere with thyroid
in humans exposed to PCBs in utero.
hormone in a variety of ways. In animal
tests, some PCBs displace thyroxine from Conclusion
its carrier protein, transthyretin, in the Dioxins and PCBs adversely affect
circulation. In many animals, thyroxine, brain development and function at ambient
attached to transthyretin, is the form by levels of exposure. The effects of prenatal
which thyroid hormone gains access to exposure to PCBs appear to be permanent.
the fetal brain. Any chemical that interferes Psychomotor developmental delays,
with this binding has the potential to alter attention deficits, changes in play behavior,
normal brain development. However, in and cognitive impairment, including IQ
humans, another protein, thyroid binding deficits, have been described in large
globulin, is the main carrier protein for human study populations. The mecha-
thyroxine, and their binding is less nism(s) by which these chemicals exert
affected by PCBs. their neurotoxic effects are not fully
Dioxin and PCBs may also interfere understood but probably include
with thyroid hormone function by alterations in neurotransmitter levels
increasing the turnover of thyroxine and thyroid hormone function.
through induction of an enzyme, which
PESTICIDES
facilitates the metabolism and excretion
of the hormone. 102 PCBs may also 鈥? Animal tests of pesticides belonging
interfere with thyroid-hormone-mediated to the commonly used organophos-
gene transcription. 103 A recent report, phate class of chemicals show that
however , shows that, although pr enatal small single doses on a critical day of
PCB exposure does reduce thyroxine development can cause permanent
levels, thyroid-dependent protein changes in neurotransmitter receptor
synthesis in the brain is not affected by levels in the brain and hyperactivity
the doses used. 104 This finding implies
鈥? One of the most commonly used
that the neurodevelopmental effects of
organophosphates, chlorpyrifos
prenatal PCB exposures are not
(Dursban), decreases DNA synthesis
exclusively due to decreased thyroid
in the developing brain, resulting in
hormone levels.
deficits in cell numbers
Some PCBs also alter normal brain
鈥? Some pyrethroids, another
neurotransmitter levels, although the
commonly used class of pesticides,
nature of change depends on PCB
also cause permanent hyperactivity in
structure. 105 For example, ortho-PCBs
animals exposed to small doses on a
single critical day of development
80 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
鈥? Children exposed to a variety of behavioral effects in rats exposed
pesticides in an agricultural during gestation. Pregnant rats given
community in Mexico show chlorpyrifos (6.25, 12.5, or 25 mg/kg/
impaired stamina, coordination, day by injection, gestational days 12-19)
memor y, and capacity to r epr esent had offspring with fewer muscarinic
familiar subjects in drawings cholinergic receptors in their brains and
markedly altered righting reflex and cliff
Many pesticides kill insects because
avoidance tests. 108 When maternal rats
they are neurotoxic. For example, the
are treated with 5 mg chlorpyrifos/kg/
organophosphates and carbamates
day by gavage from gestational day 6-
inhibit acetylcholinesterase, the enzyme
Studies in neonatal
postnatal day 11, offspring have a
responsible for breaking down the
mice show that a
decreased auditory startle response
neurotransmitter acetylcholine. Other
single dose of an
109
families of pesticides including pyrethroids, and decreased brain weight. (For
organophosphate
comparison purposes, the current
pyrethrins, and organochlorines also
pesticide on postnatal
reference dose [RfD] for chlorpyrifos,
exert their toxic action by interfering
day 10 causes
the human dose below which no
with nerve cell function. Routes of
hyperactivity at
adverse ef fects ar e consider ed likely ,
exposure to pesticides are discussed in
4 mos. of age.
is 3 microgm/kg/day)
Chapter 7.
Another organophosphate, diazinon,
Organophosphates was given to pregnant mice at 0, 0.18,
Organophosphates are widely used for or 9.0 mg/kg/day thoughout pr egnancy ,
pest control in the home, on the lawn and and the development of their offspring
110
garden, and on the commercial food supply. was evaluated. Offspring of the
mothers receiving the highest dose grew
Animal Tests
more slowly than those in the lower
Studies in neonatal mice show that exposure groups. Although offspring of
a single dose of an organophosphate those receiving the lowest dose grew
pesticide (1.5 mg diisopropylfluoro- normally, behavioral testing r evealed
phosphate [DFP]/kg body wgt) on delays in development of the contact
postnatal day 10 causes permanent placing r eflex and sexual maturity .
decreases in muscarinic cholinergic Adult offspring of mothers exposed at
receptors in the cerebral cortex and either dose showed impaired endurance
hyperactivity at 4 mos. of age. 107 and coordination. The RfD for
Exposed animals showed persistently diazinon is under r eview by EP A.
increased locomotion (horizontal
movement) and total activity (all types Organochlorines
of movement) when compared to
DDT is an organochlorine pesticide
untreated controls.
no longer used in the US but heavily
Chlorpyrifos (Dursban), one of the used in some parts of the world both in
most heavily used organophosphates, agriculture and for disease vector
also causes neurochemical and control. DDT was banned in the US and
Greater Boston Physicians for Social Responsibility 81
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
other countries because of toxicity to
wildlife and its capacity to
bioaccumulate and persist in the
environment for years. DDT also exerts
its toxic action by interfering with the
stability of nerve cell membranes,
resulting in overstimulation of the
nervous system in exposed animals.
Animal Tests
Newborn mice were given a single
dose of 0.5 mg DDT/kg on day 3, 10, or
19 of life and examined at 4 months of
age for activity level and muscarinic
cholinergic receptors in the brain in a community where pesticides were
cortex. 111 Those animals exposed to regularly used in agriculture whereas the
DDT on day 10 showed significant other came from a community with a
increases in activity level and decreases non-chemical agricultural system. A
in receptor levels at that age. Mice variety of organochlorine pesticides were
exposed on days 3 or 19 did not show measured in the umbilical cord blood
significant changes. These results and breast milk of individuals in the
highlight a short but significant window pesticide-exposed community , though
of vulnerability to a neurotoxic chemical exposure to other classes of pesticides
when exposure may have lifelong effects wer e also likely .
on brain structure and function. Children in the exposed community
Human Studies showed significantly diminished stamina
and coordination when asked to catch a
Reports of the neurological
ball, stand on one foot as long as
evaluation of children exposed to
possible, jump in place, and drop raisins
pesticides are few and are usually limited
into a bottle cap from a distance of 15
to the acute effects of exposures.
cm. Memory in the pesticide-exposed
However , a recent study of childr en in
children was also impaired. They were
Mexico, who are regularly exposed to a
less able to recall what they had been
mixture of pesticides in their largely
promised as a reward (a red balloon)
agricultural community , suggests that
before testing started. Exposed children
many different brain functions may be
were also impaired in their ability to
impaired by pesticide exposure during
draw recognizable representations of
child development. 112 Researchers
people and objects. When asked to
compared two different groups of 4-5
draw a person, exposed children averaged
year old children who came from very
1.6 body parts/drawing in drawings
similar genetic, social, and cultural
considerably more distorted than those
backgr ounds. However , one gr oup lived
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CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Drawings of a Person
of the unexposed children that averaged
4.4 body parts/drawing. Houses and trees by Yaqui children (by age and gender)
drawn by pesticide exposed children
were also more distorted and difficult
to interpret. Exposed children appeared
to be less creative in their play activity. Foothills
(pesticide-free)
Pyrethroids
Naturally-occurring pyrethrins or
synthetic pyrethroids are insecticides that
also exert their toxic action by interfering 54 mos. girl 60 mos. girl
with the electrical activity of nerve cells.
They are sometimes divided into Type I
and Type II compounds. Type I cause
repetitive firing of nerve cells while Type
II cause nerve inexcitability by blocking
cell depolarization.
Animal Tests
55 mos. girl 71 mos. boy
Mice given small doses of
bioallethrin (T ype I) or deltamethrin
(T II) on day 10 of life also show
ype
Valley
reduction in muscarinic cholinergic
receptor levels in the brain cortex as (pesticide-exposed)
adults, along with hyperactivity .113 In an
attempt to better define the dose-
response curve, investigators used doses
of bioallethrin at 0.21, 0.42, 0.70, and
42 mg/kg on day 10 of life. The
hyperactivity of the mice as adults
increased with increasing levels of
54 mos. girl 71 mos. girl
exposure through the 0.70 mg/kg dose,
but then fell sharply with the 42 mg/kg
dose. This observation is particularly
important for pesticide testing in that
testing at higher doses of exposure may
fail to identify an adverse effect seen only
at lower levels of exposure. Current
53 mos. girl 71 mos. girl
methods for dose selection for pesticide
regulatory testing purposes may miss
Illustrations are those by Mexican Yaqui Indian children drawn
this effect and should be re-examined.
during a study of the effects of pesticide exposure on neurological
development. The study was conducted by Elizabeth A. Guillette,
PhD, University of Arizona. Illustrations used with permission.
Greater Boston Physicians for Social Responsibility 83
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Another study of two pyrethroids, brain development, independent of its
fenvalerate and cypermethrin, examined serving as an enzyme to break down the
the effect on neurotransmitter levels in neurotransmitter, acetylcholine. Research
offspring of rats after gestational and shows that the enzyme facilitates neurite
lactational exposures.114 Alterations in outgrowth from neurons and that
levels of neurotransmitter enzymes deficiency of the enzyme reduces neurite
outgrowth.115 In addition, chlorpyrifos
(monamine oxidase and acetylcholin-
esterase) were noted. Dopamine receptor decreases DNA synthesis, independent of
levels in the brain were decreased after its cholinergic mechanism, resulting in
exposure to each of the chemicals and deficits in numbers of cells in the
developing brain.116 117 This latter obser-
muscarinic cholinergic receptor levels
were markedly decreased only after vation is particularly important for two
cypermethrin. reasons. First, the potential for toxicity of
organophosphates is often inferred from
Mechanisms of Neurotoxicity
the degree of cholinesterase inhibition,
The low Organophosphates and carbamates
but the effects of chlorpyrifos on DNA
concentrations inhibit acetylcholinesterase, the enzyme
synthesis and cell numbers show that no
of chlorpyrifos responsible for breaking down the
general conclusions may be drawn from
necessary to impair neurotransmitter acetylcholine at nerve
anticholinesterase activity alone. Neuro-
DNA synthesis and synapses or at the junction of nerves with
toxicity testing has not generally been
cell division are muscles. The result is twofold. In the
designed to measure the effects of organo-
actually lower than short term, the synapse or neuromuscular
phosphates on cell proliferation and
exposure levels of junction is overstimulated and clinical
differentiation. The presumption has been
children under some symptoms result. But in the developing
that cholinesterase inhibition is the most
pesticide home-use organism, as previously noted, neuro-
sensitive endpoint. Second, the low concen-
conditions. transmitters also play important roles in
trations of chlorpyrifos necessary to impair
orchestrating cell proliferation, migration,
DNA synthesis and cell division are actually
differentiation, synapse formation and
lower than exposure levels of children under
apoptosis. Alterations in neurotransmitter
some pesticide home-use conditions.118 119
levels during development have significant
Pyrethroids, pyrethrins, and
effects on the brain that do not occur after
organochlorines also exert their toxic
adult exposures.
action by interfering with nerve cell
Several different mechanisms help
function. By modifying the permeability
explain the neurodevelopmental effects of
of nerve cell membranes to various ions
organophosphates. First, by altering
they may either increase or decrease
neurotransmitter levels (acetylcholine
the excitability of nerve cells causing
and others secondarily) these chemicals
repetitive firing or prolonged inactivity.
interfere with cell replication and
Studies done in developing animals show
differentiation. Second, acetylcholines-
that each of these classes of insecticides
terase itself appears to have a role in
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CHAPTER 6: Known and Suspected Developmental Neurotoxicants
spring of women who are exposed to
these types of chemicals during the latter
part of pr egnancy . One study of childr en
exposed to a mixture of pesticides
during development shows adverse
impacts on a variety of neurological
functions, including stamina,
coordination, memor y, and ability to
conceptualize and draw . These r esults
confirm the need for comprehensive
neurodevelopmental testing of pesticides
before they are licensed for commercial
use. Under cur rent law , the US EP A is
authorized to require such testing but,
with rare exceptions, has failed to
exer cise that authority . (see chapter 7)
SOLVENTS
may also permanently alter neuroreceptor 鈥? Exposure to organic solvents during
levels in portions of the brain and modify development may cause a spectrum
animal behavior as a result. of disorders including structural
birth defects, hyperactivity , attention
Conclusions
deficits, reduced IQ, learning and
Several different classes of pesticides
memory deficiencies.
show unique neurodevelopmental
鈥? As little as one alcoholic drink a
toxicity in animals exposed during
day during pregnancy may cause
gestation or at particular windows of
impulsive behavior and lasting
vulnerability in the neonatal period.
deficits in memor y, IQ, school
Small exposures during those periods of
performance, and social
susceptibility permanently alter brain
adaptability in offspring.
neur oreceptor levels and cause hyper -
activity in the animals as adults. These 鈥? Animal and limited human studies
adverse effects are distinctly unlike those show that exposures to common
seen after adult animal exposures. It is chemicals like toluene, trichloro-
important to note that the stage of brain ethylene, styrene, and xylene during
development in rodents at age 10 days is pregnancy can also cause learning
similar to the same stage in humans deficiencies and altered behavior in
during the last trimester of pr egnancy . offspring, though fairly large
These results, therefore, suggest the exposur es may be necessar y.
potential for similar effects in the off-
Greater Boston Physicians for Social Responsibility 85
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
The Institute of Medicine of
Routes of Exposure
the National Academy of Sciences
Organic solvents are widely used in
Committee to Study Fetal Alcohol
consumer products, hobbies, and indus-
Syndrome has proposed five diagnostic
try. Releases of some or ganic solvents to
categories for fetal alcohol related
the environment from large industrial
121
sources are reported on the Toxics Release abnor malities: 1) diagnosis of F AS
and a confirmed history of maternal
Inventory (TRI). For example, in 1997
alcohol exposur e, 2) diagnosis of F AS
over 115 million pounds of toluene, 75
without a confirmed history of maternal
million pounds of xylene, 46 million
pounds of styrene, and 21 million pounds alcohol exposur e, 3) par tial FAS with
of trichlor oethylene wer e released to air , confirmed alcohol exposure, 4) alcohol
related birth defects, 5) alcohol related
water , and land by the lar gest industries
neurodevelopmental disorders.
required to report their toxic emissions.
Ethanol is consumed in alcoholic beverages. The spectrum of clinical abnormali-
Toluene and xylene ar e in gasoline and ties probably reflects differences in
its vapors, as well as other consumer timing, duration, and level of alcohol
products. Trichloroethylene is commonly exposure during gestation, although the
Clinical used as a degreaser and is a common timing of periods of vulnerability for
manifestations of drinking water contaminant at low each of the various disorders is not well
fetal alcohol concentrations. Because many solvents known. First trimester exposure is
exposure include are volatile, inhalation exposures are probably necessary for the distinctive
hyperactivity and particularly important. physical facial abnormalities seen in
attention deficit. FAS.122 Alcohol exposur e during the
Ethanol (alcohol) second and third trimester alters neu-
ronal cir cuitry. The thir d trimester is a
The neurodevelopmental effects of
particularly vulnerable time for brain
ethanol have been extensively studied.
injury as a result of alcohol exposure. 123
The term 鈥渇etal alcohol syndrome鈥?
Alcohol鈥檚 ef fects on the fetus ar e mor e
(FAS) was first coined in 1973 to
related to the maternal peak blood
describe malformations in the offspring
However , alcohol level than to total alcohol con-
120
of chr onic alcoholic women.
sumed, so that binge drinking is likely to
the consequences of fetal alcohol
be more harmful than equal amounts
exposure had been known long before.
consumed over a longer period of
Affected children show a mixture of
time. 124 One study finds a threshold
craniofacial, limb, and cardiovascular
effect at an average of 0.5 oz. absolute
defects associated with growth and
alcohol per day .125
developmental delays, though the degree
of impair ment can var y considerably . Clinical manifestations of fetal
Cognitive functions may vary from alcohol exposure include hyperactivity
normal to severely disrupted while and attention deficit.126 Memory, speed
physical features may independently vary of information processing, and
from normal to obviously abnormal. arithmetic functioning are also
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CHAPTER 6: Known and Suspected Developmental Neurotoxicants
adversely affected.127 Eating disorders, Mechanisms of Neurotoxicity
bedwetting, sleep disorders, speech Animal studies show that fetal
delay, anxiety, depression, and alcohol exposure causes reduction in
psychotic symptoms may also occur. brain weight, selective loss of certain
Although there is a higher likelihood of cells, impaired maturation of cells, and
cognitive disorders and mental retarded synaptic development.130 131
retardation in FAS children, mental Several different mechanisms probably
function varies and may be normal. contribute to alcohol toxicity. They
A study of 16 pairs of twins heavily include disruption of cell-cell interactions
exposed to alcohol prenatally found by interfering with cell adhesion
molecules132 , reduction of placental
concordance for fetal alcohol syndrome
in five pairs of monozygotic twins and transport of amino acids, glucose, and
in 7 of 11 pairs of dizygotic twins. 128 other nutrients as a result of reduced
oxygen supply133 , and abnormalities
Genetically-determined variations in
of synaptic transmission.134
maternal metabolism of alcohol also
influence the likelihood of F AS in
Other Solvents
offspring, since one of the metabolites
of alcohol, acetaldehyde, is thought Human Studies
to contribute substantially to the
Compared to ethanol, much less is
condition. 129 These observations
known about the effects of other
demonstrate the interaction of
solvents on brain development and
genetic factors with a well-known
function. Occupational exposures to
neurodevelopmental toxicant.
solvents may cause both peripheral and
One of the difficulties encountered central nervous system effects in adult
in studying the results of fetal alcohol workers and are also associated with
exposure is the frequent co-occurrence birth defects, including abnormalities of
of poor maternal nutrition, delayed the central nervous system, in their
prenatal care, and other maternal offspring. 135 136 However , little
substance abuse, including tobacco. information is available about the
These factors complicate efforts to tease neurological development of children
out the clinical features that are solely whose mothers were exposed to solvents
due to alcohol. Moreover, eating and during pr egnancy . One study examined
sleep disturbances, behavioral neurological development of children at
difficulties, and impaired cognitive an average age of 3 years whose mothers
functioning and attention often had been occupationally exposed to
adversely impact the mother-infant solvents during at least some portion of
relationship. Thus, it is difficult to pregnancy .137 No significant ef fect was
know how much future disability is found on evaluation for attention,
attributable to fetal alcohol exposure behavior , sociability , activity , or lear ning.
and how much is due to social factors Developmental milestones were the same
during infancy and early childhood. in exposed and unexposed groups, with
Greater Boston Physicians for Social Responsibility 87
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
the exception of delayed onset of Animal Studies
walking in the children exposed Animal studies also show
throughout pregnancy as compared to neurobehavioral consequences of
unexposed children. (13.3 mos. vs. 12.2 intermittent large prenatal exposures to
mos.) This finding is of uncertain toluene. Pregnant mice were exposed to
significance since the children of 200, 400, or 2000 ppm (parts per
mothers exposed for only the first or million) toluene by inhalation for 60
first and second trimesters of pregnancy minutes, 3 times a day , on gestational
actually began walking sooner than the days 12-17. Offspring from the highest
unexposed. (10.8, 11.6 mos vs. 12.2) exposure group performed more poorly
Maternal exposures in this study were on behavioral tests of righting reflex,
not actually measured, and no attempt 140
grip strength, and inverted screen.
was made to correlate developmental Rats exposed to 1800 ppm toluene 6 hrs/
outcomes with specific solvents. It may , day by inhalation on days 7-20 gestation
therefore, be misleading to draw any gave birth to offspring with impaired
firm conclusions fr om this single study . learning when tested in a Morris water
maze. 141 Occupational safety limits for
Toluene is an or ganic solvent used
in glues, inks, paints, cleaning agents, toluene in the US allow 200 ppm
and gasoline. After large exposures, exposur e for a 40 hr . work week.
such as encountered with maternal (Occupational safety limits may not be
glue snif fing during pr egnancy , offspring enforced. The values are presented here
may be born with craniofacial only for purposes of comparison to
abnormalities resembling those of experimental data.) Mice supplied with
FAS.138 Follow up studies show gr owth drinking water containing 16, 80, or 400
retardation and persistent deficits in mg. toluene/liter (ppm) during pregnancy
cognition, speech, and motor skills. It is and lactation gave birth to offspring
unknown whether or not a threshold with deficient motor skills (rotorod
performance). 142 The highest exposed
level of exposure to toluene exists,
below which no neurodevelopmental group showed decreased habituation in
effects occur in humans. The develop- open-field activity . The EPA鈥檚 maximum
mental effects of toluene so closely contaminant level (MCL) for toluene in
resemble those of alcohol, that some drinking water is 1.0 mg/l (ppm).
investigators believe the mechanism of The offspring of rats supplied with
toxicity is similar .139 As with alcohol, it drinking water containing 312, 625, or
may be the case that even relatively 1250 mg trichloroethylene/liter (ppm)
small exposures to toluene have subtle throughout gestation and lactation were
but important effects on neurocognitive studied. 143 Exploratory behavior was
development, though this has not been increased in 60- and 90-day old male
studied well in humans. rats exposed at any level. Locomotor
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CHAPTER 6: Known and Suspected Developmental Neurotoxicants
activity (running wheel) was higher US allow 50 ppm for a 40 hr . work
in rats exposed to 1250 ppm week. Another study shows an important
trichlor oethylene. The EP A鈥檚 drinking interaction between prenatal styrene
water MCL for trichloroethylene is exposure and dietary protein
deficiency .148 Rats given a pr otein
0.005 mg/l (ppm) The offspring of rats
exposed to 1800 ppm trichloroethylene deficient diet and styrene (100 mg/kg/
by inhalation 6 hr/day , 5 days per week day) during pregnancy gave birth to
for 2 weeks before mating had reduced offspring with lower brain weights and a
body weight but no evidence of behavior marked increase in amphetamine-
abnormalities. 144 The offspring of those induced hyperactivity when compared to
exposed throughout pregnancy had controls, including those exposed to just
marginally reduced activity levels. styrene or only a low protein diet.
Occupational safety limits in the US Conclusions
allow trichloroethylene exposure at
In summar y, many studies show that
100 ppm for a 40 hr . work week.
fetal exposure to relatively small
Xylene exposure by inhalation at Animal tests suggest
amounts of alcohol disrupts normal
500 ppm, 6 hrs/day , on gestational days that, at levels at or
brain development, resulting in
7-20 resulted in rat offspring with below those allowed
hyperactivity , attention and lear ning
decreased brain weight and diminished in the workplace,
disor ders, and impair ed memor y. The
motor performance (rotorod) and xylene and styrene
magnitude of risk of fetal alcohol
learning and memory (Morris water may alter learning,
syndrome depends on both genetic and
maze).145 500 mg/m3 xylene is equivalent behavior, motor
environmental factors and their
to 115 ppm. In another study , the skills, and activity
interactions. Large inhalation exposures
offspring of rats exposed to xylene at levels after fetal
to toluene during pregnancy (glue
500 mg /m3, 6 hrs/day , 5 days/wk, exposure.
sniffing) also carries the risk of
throughout pregnancy showed reduced devastating effects on fetal brain
horizontal movement in open field development, as well as causing
testing and structural changes in brain, structural birth defects. The effects of
hear t, liver , and kidneys. 146 At 50 mg/m3 smaller exposures on fetal brain
offspring showed retarded growth and development are unknown. Other
skeletal abnormalities. Occupational solvents that may be encountered in the
safety limits in the US allow xylene expo- workplace or in consumer products have
sure at 100 ppm for a 40 hr . work week. the potential for disrupting normal brain
Young rats (1-48 days of age) development but usually at relatively
exposed to styrene at 25 and 50 ppm 7 high exposur e levels. However , animal
hrs/day , 6 days/wk. showed significant tests suggest that, at levels at or below
delays in weight gain, decreased activity those allowed in the workplace, xylene
in open field testing, and decreased and styr ene may alter lear ning, behavior ,
avoidance behavior .147 Occupational motor skills, and activity levels after fetal
safety limits for styrene exposure in the exposure. Since volatile solvents are
Greater Boston Physicians for Social Responsibility 89
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
often present in consumer products,
excessive hobby and home exposures
are possible, particularly when products
are used in confined or poorly ventilated
areas. Nutritional factors may also
contribute to neurodevelopmental
impacts of solvent exposure.
Additional Chemicals of Concern
Although assessments for
developmental neurotoxicity are missing
for many chemicals, two very different Association and heralded by the Centers
kinds of substances deserve particular for Disease Control and Prevention as
mention because they are intentionally one of the major public health success
added to water or food, thereby stories of the 20 th centur y. We do not
exposing large populations on a lifetime intend to review the entire controversy
daily basis. Whenever entire populations here. Recent reviews are found
are exposed to any chemical substance elsewher e. 149 150 151 Rather, her e we
through the food or water supply , comment briefly on concerns about
exhaustive safety evaluations should be neurodevelopmental impacts of prenatal
essential prior to initiation of exposure exposure to fluoride.
and as new data become available. The US EPA sets a Recommended
Fluoride Maximum Contaminant Level of 4.0
ppm fluoride in drinking water . The
Since the 1950鈥? s, in many
National Institute for Dental Research
communities throughout the US and
considers fluoride at 1 ppm optimal for
other areas of the world, fluoride has
preventing dental caries. This level may
been added to community drinking
be exceeded in some communities.
water supplies with the intention of
Additional sources of fluoride, including
reducing tooth decay . Controversy
topical fluoride treatments, fluoride
about the safety of that practice centers
tablets, and fluoride toothpaste, add to
around concerns about increased risks
the total fluoride burden.
of tooth staining and brittleness (dental
fluorosis), bone brittleness (skeletal In an animal study , pregnant rats
fluor osis), bone cancer , hormone were given 0.13 mg sodium fluoride/kg
disruption (melatonin), premature by injection on 9 separate occasions
puber ty, and alter ed neur ological from days 14-18 or 17-19 during
developmental. In addition, some critics pregnancy.152 Offspring of tr eated
argue that fluoridating the water supply animals and controls were monitored
has a minimal impact on tooth decay . by videotape that was then computer -
The practice has been staunchly analyzed in order to quantify various
defended by the American Dental behavioral characteristics. Offspring
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exposed to fluoride on days 17-19 Two reports from China identify
of pregnancy showed significant significantly lower childhood IQs in
hyperactivity . They tended to move fr om communities where fluoride exposure is
one activity to another more frequently elevated. In one community, where
than unexposed animals. This study has drinking water naturally contains 4.12
been criticized for using excessive ppm fluoride, IQs were significantly
fluoride exposures. The authors respond lower than in a nearby community with
by noting that the blood levels of fluoride levels at 0.91 ppm. (average IQ
98 vs. 105)156 This difference persisted
fluoride in the treated animals were
similar to the levels measured in people when the study population was controlled
who are exposed through fluoridated for parental educational level. The
Studies in animals
water . Another criticism center ed on the authors describe similar occupations,
and human populations
lack of biological plausibility that the living standards, and social customs in
suggest that fluoride
results would differ in the two groups the two communities. The ecologic
exposure, at levels
exposed at similar times during design of this study imposes some limits
that are experienced
pregnancy .153 The authors, however , on the conclusions that may be drawn
by a significant
point out that vulnerable developmental since the exposure (fluoride) and
proportion of the
stages change rapidly during this time outcome (IQ) were compared on a
population whose
window and argue that the findings are population-wide basis without any
drinking water is
entirely plausible. 154 attempt to associate individual fluoride
fluoridated, may have
exposure levels with individual IQs.
Another study found that the
adverse impacts on
Nonetheless, an IQ shift of 7 points in an
offspring of rats given 5, 15, 50 ppm
the developing brain.
entire population has large population-
fluoride in drinking water during
wide implications, as well as impacting
pregnancy and lactation had significantly
individual members, and these results
elevated acetylcholinesterase levels when
deserve close attention.
tested at 80 days of age. 155 Maternal
acetylcholinesterase levels were also In the other study, investigators
increased. Though not measured in this used dental fluorosis and urinary fluoride
study , a likely r esult of elevated levels to stratify children into four
quartiles.157 Elevated fluoride exposures
acetylcholinesterase activity is decreased
acetylcholine levels. As we have noted, were associated with decreased IQs in this
the enzyme, acetylcholinesterase, and the population. That is, the distribution of IQ
neur otransmitter , acetylcholine, play scores in children in each quartile of fluo-
important roles in brain development. ride exposure shifted progressively down-
Changes in the concentrations of any ward as the fluoride exposures increased.
neurotransmitter during development Conclusion
may have permanent neurological
Studies in animals and human
consequences. The largest effect
populations suggest that fluoride
was seen at 5 ppm, decreasing at the
exposure, at levels that are experienced
higher levels.
by a significant proportion of the
Greater Boston Physicians for Social Responsibility 91
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
population whose drinking water is gland, and an essential link in hormonal
fluoridated, may have adverse impacts regulatory processes, has been most
on the developing brain. Though no final extensively studied.
conclusions may be reached from It is important to note that most of
available data, the findings are the adult brain is protected by the blood-
provocative and of significant public brain bar rier, wher eas the blood-brain
health concern. Perhaps most surprising barrier is not complete in the developing
is the relative sparseness of data human brain until about six months of
addressing the central question of age (3 weeks in rats, an important
whether or not this chemical, which is difference when considering the design
intentionally added to drinking water , of neur otoxicity testing). However , the
may interfere with normal brain hypothalamus is not protected by a
development and function. Focused blood-brain barrier at any time during
research should address this important life and remains in contact with any
matter ur gently . potentially neurotoxic substances
circulating in the blood. 160 Destruction
Food Additives
of hypothalamic cells would be expected
The potential for certain food to disrupt the intricate chemical
additives to alter neurological messenger (hormonal) feedback loops
development, behavior , and lear ning among the hypothalamus, pituitar y, and
capacity has been the subject of lively testes or ovaries.
debate and controversy for many years.
Indeed, studies show that rats treated
Food additives of concern are 1) the
in the neonatal period with large doses of
amino acid, glutamate, present naturally
monosodium glutamate (MSG) have
in many proteins and added to many
significantly smaller accessory sexual
processed foods, 2) the artificial
organs and lower concentrations of
sweetener , aspar tame, which is
testosterone.161 However, the doses of
metabolized into the two amino acids,
MSG used in these studies are often 2-5
aspartate and phenylalanine, and 3) food
gms/kg on several consecutive days, levels
colorings and dyes.
known to cause destruction of
One focus of concern centers around hypothalamic neurons, whereas the upper
the observation that glutamate and bound of human dietary daily intake of
aspartate are the major excitatory amino MSG is approximately 35 mg/kg.162 163
acid neurotransmitters in the mammalian 164
However, Olney argues that blood
brain and that large amounts of glutamate levels, after an oral dose in
glutamate administered to pregnant adult humans, rise 20 times higher than a
rhesus monkeys late in gestation result in comparable dose in adult monkeys and
damage to the fetal brain.158 159 Damage five times higher than in mice.165
to the hypothalamus, the portion of the Therefore, he says, the margin of safety is
brain responsible for sending chemical not what it appears from animal testing.
messages to the underlying pituitary
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CHAPTER 6: Known and Suspected Developmental Neurotoxicants
One study shows that the offspring anecdotal reports, regulators, a publicly
of rats fed diets containing 2%, 4%, or funded research institution, burdens of
6% aspartame during pregnancy and proof, and uncertainty.
lactation showed delays in eye opening, Conclusions
swimming, righting, startle response, and
For about 25 years considerable
walking. 166 Effects were seen at each
controversy has swirled around the
exposure level. Exposure during nursing
degree to which food additives,
had more effect than prenatal exposure.
including artificial sweeteners, flavor
These exposures are approximately 3-9
enhancers, colorings, and dyes, may
gms/kg/day , which is about a thousand
influence childr en鈥檚 brain function.
times higher than expected human
Studies show that exposures
exposur e levels. However , it is impor tant
substantially higher than those in the
to remember the lessons from lead,
human diet are necessary to cause
mer cury, and PCBs - that animal studies
observable adverse effects in animals.
commonly underestimate human
Historical reviews show , however , that
sensitivity to developmental
animal tests frequently underestimate
neurotoxicants by 100-10,000 fold.
the sensitivity of the human brain.
The second focus of concern centers Human studies also show that at least
on the apparent capacity of food dyes and some children appear to be particularly
additives to alter behavior in some sensitive to dietary exposures to these
children diagnosed with ADHD or other additives, with hyperactivity and
attentional disorders. In the 1970鈥檚, decreased attention spans.
Benjamin Feingold sparked considerable
The degree to which these food
interest when he linked food additives to
additives contribute to attentional and
behavior changes in children with
behavioral disorders in the general
hyperactivity, mood, and behavioral
population remains uncertain, though it
disorders.167 Since then, the topic has
seems clear that some children respond
remained highly controversial. A recent
with behavioral changes recognized by
report from the Center for Science in the
parents, teachers, and healthcare
Public Interest reviewed 23 controlled
providers. The link between diet and
studies, some of which were blinded, and
behavior in children with ADHD is
found 17 with evidence that some
uncertain and remains a matter of
children鈥檚 behavior significantly worsens
considerable disagreement. A substantial
after they consume artificial colors or
body of literature concludes that the link
certain foods. 168 The authors also note
exists in some children and raises
that the National Institute of Mental
questions about the origins of a
Health largely dismiss diet as a treatment
heightened sensitivity to these dietary
approach and that the Food and Drug
exposures. Genetic and early-life
Administration denies the effect of diet on
environmental factors must be considered
behavior. This topic is an instructive
as these questions are explored.
intersection of published scientific studies,
Greater Boston Physicians for Social Responsibility 93
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
Toxicants and their Health Effects
Toxicant Health Effects/ Toxicant Health Effects/
Characteristics Characteristics
Metals Solvents
H= Human studies,
Cadmium 鈥? H, A Learning disabilities Toluene 鈥? H, A Learning disabilities
A= Animal studies
Decreased IQ Speech deficits
Motor dysfunction Motor dysfunction
Hyperactivity Craniofacial
Hypoactivity abnormalities
Lead 鈥? H, A Learning disabilities Trichloroethylene - A Increased exploratory
IQ deficit behavior
Attention deficit Hyperactivity
Impulsivity Xylene - A Motor dysfunction
Violence Learning disabilities
Hyperactivity Memory impairment
Aggression Decreased brain weight
Manganese 鈥? H, A Brain damage Pesticides Notes:
Motor dysfunction
Organochlorines 1. Learning disabilities include
Compulsive behavior
dysfunctions in listening,
DDT - A Hyperactivity
Memory impairment
speaking, reading, writing,
Mixture 鈥? H Decreased stamina
Hyperactivity spelling or calculations.
Decreased coordination
Learning disabilities
2. Only neurodevelopmental,
Decreased memory
Attention deficit
learning or behavioral effects
Decreased ability to
of toxicants, or physical
Mercury 鈥? H, A Visual impairment draw familiar objects impairments that lead to
Learning disabilities
them, are listed.
Organophosphates
Attention deficit
(including DFP, Developmental delays 3. Chart information is
Motor dysfunction
chlorpyrifos (Dursban), Hyperactivity synthesized from Chapter 6.
Memory impairment
Please see this chapter for
diazinon) - A Behavioral disorders
(minimal) references to studies on these
Motor dysfunction
At higher levels: chemicals.
Smaller brain size, Pyrethroids (including
cellular distortions bioallethrin, deltamethrin, Hyperactivity
in brain cypermethrin) - A
Mental retardation Other
Solvents
Nicotine 鈥? H, A Hyperactivity
Ethanol (Alcohol) 鈥? H, A Learning disabilities Learning disabilities
Attention deficits Developmental delays
Memory impairment in cognitive functions
Behavioral disorders Dioxins 鈥? H, A Learning disabilities
Eating and
PCBs 鈥? H, A Learning disabilities
sleeping disorders
Attention deficit
Lower brain weight
Memory impairment
Craniofacial, limb and
Hyperactivity
cardiovascular
Psychomotor dysfunction
abnormalities
associated with various Fluoride 鈥?
growth and A Hyperactivity
developmental delays H Decreased IQ
Mental retardation (ecologic studies)
Styrene - A Decreased activity
Decreased avoidance
behavior
In conjunction
with dietary protein
deficiency: Lower brain
weight, Hyperactivity
94 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
GLOSSARY OF TESTS OF NEUROLOGICAL DEVELOPMENT IN RODENT STUDIES
M LOCOMOTOR ACTIVITY:
any different tests are used to assess
the neurological development of Open field activity 鈥? the animal is placed in the
experimental animals. It is important that these middle of a transparent plastic cage marked off
tests are validated and that they do, in fact, into squares. Numbers of squares entered (total
serve as useful indicators of normal or activity), horizontal and vertical movements (rearing),
abnormal neurological function. Test validation duration of inactivity, description of gait or any
has several components. Investigators must abnormal movements, habituation, and response
conduct testing in very similar conditions using to novel environments may be observed.
standardized testing protocols. If those Rotorod performance 鈥? tests the ability of the
conditions are met, similar results should be animal to maintain its balance on a small
observed in multiple laboratories and should be horizontal cylinder that has a rubberized
replicable in a given laboratory. Any test that is surface and is rotated by a motor at different
not replicable or that shows wide and standardized speeds. This tests balancing
unexplained variability in results has little utility reactions and motor coordination.
for neurological testing. Finally,
Running wheel 鈥? the animal
predictive power and species
is observed running inside a
variability (species concordance) must
rotating wheel
be considered. These issues are
LEARNING AND MEMORY:
particularly important when using
Morris water maze 鈥? the animal capable of
animal tests to predict effects in humans.
swimming is placed in a tank of water with a
The following descriptions are intended to
small platform submerged just below the surface
provide the reader with a skeletal description
at a specific place in the tank. The animal finds
only of the tests mentioned in this report.
the platform and can stand on it. This can be
Standardized protocols for administering the
repeated at various intervals to test learning and
tests are not included.
memory. The position of the platform can be
EARLY REFLEXES:
changed in order to examine the animal鈥檚
Placing response 鈥? the animal is held by the tendency to perseverate or ability to re-learn.
nape of the neck and touched on the chin with
T maze tests 鈥? the animal is placed in a T
a stretched wire. Normally the animal grips the
shaped maze and learns to find the reward in
wire with its forelimbs. This response develops
one arm of the maze. Maze tests, like other tests
within a few days of birth
that require choices, can be reversed so that the
Righting reflex 鈥? the animal is placed on its back animal must learn to change response strategies
and observed for speed and ability to turn upright in order to be rewarded. Changing response
AVOIDANCE: strategies is more complex than learning the
correct response initially and may be a more
Cliff avoidance 鈥? the animal is placed on
sensitive indicator of impaired learning.
a raised platform; the normal response is to
turn away when visual stimulus suggests Visual recognition 鈥? various tests are designed
dangerous depth (height) to test the animal鈥檚 ability to recognize shapes,
colors, or positions, by rewarding a correct
STRENGTH:
response. Discrimination-reversal learning may
Grip strength 鈥? the strength with which
then be tested by reversing the correct answer so
the animal grips a wire with forelimbs
that the previous correct answer is now incorrect.
against resistance
Greater Boston Physicians for Social Responsibility 95
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
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118 Whitney KD, Seidler FJ, Slotkin TA. Developmental
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103 Zoeller RT. Effects of developmental exposure to PCBs on
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107 Ahlbom J, Fredriksson A, Eriksson P. Exposure to an
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109 US EPA. A retrospective analysis of twelve developmental
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110 Spyker JM, Avery DL. Neurobehavioral effects of prenatal
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111 Eriksson P, Ahlbom J, Fredriksson A. Exposure to DDT during
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128 Streissguth AP, Dehaene P. Fetal alcohol syndrome in twins of
112 Guillette EA, Meza MM, Aquilar MG, Soto AD, Enedina I. An
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129 Rutledge JC. Genetic factors in clinical developmental
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114 Malaviya M, Husain R, Seth PK, Husain R. Perinatal effects of
two pyrethroid insecticides on brain neurotransmitter function in
131 Diaz J, Samson HH. Impaired brain growth in neonatal rats
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115 Bigbee J, Sharma K, Gupta J, Dupree J. Morphogenic role for
132 Ramanthan R, Wilkemeyer MF, Mittal B, et al. Alcohol inhibits
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116 Slotkin TA. Developmental cholinotoxicants: nicotine and
133 Yang HY, Shum AYC, Ng HT, et al. Effect of ethanol on human
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134 Broun S. New experiments underscore warnings on maternal 151 CDC. Fluoridation of drinking water to prevent dental caries.
drinking. Science 273:738-739, 1996. MMWR 48:986-993, 1999.
135 Snyder R, Andrews LS. Toxic effects of solvents and vapors. In: 152 Mullenix PJ, Denbesten PK, Schunior A, Kernan W.
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136 Schettler T, Solomon G, Valenti M, Huddle A. Organic 153 Ross J, Daston G. Letter to the editor. Neurotoxicol Teratol
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154 Mullenix P, Denbesten P, Schunior A, Kernan W. Reply.
137 Eskenazi B, Gaylord L, Bracken MB, Brown D. In utero Neurotoxicol Teratol 17(6):687-688, 1995.
exposure to organic solvents and human neurodevelopment.
155 Zhao XL, Wu JH. Actions of
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sodium fluoride on
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139 Pearson M, Hoyme H, Seaver L, Rimsza M. Toluene 156 Zhao LB Liang GH, Zhang DN, et
embryopathy: delineation of the phenotype and comparison with al. Effect of a high fluoride water
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140 Jones HE, Balster RL. Neurobehavioral consequences of
intermittant prenatal exposure to high concentrations of toluene. 157 Li XS, Zhi JL, Gao RO, Effect of
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children. Fluoride 28(4):189-192,
141 Hougaard KS, Hass U, Lund SP, Simonsen L. Effects of
1995.
prenatal exposure to toluene on postnatal development and
behavior in rats. Neurotoxicol Teratol 21(3):241-250, 1999. 158 Olney JW. Excitotoxic food
additives: functional teratologic aspects. Prog Brain Res 73:283-
142 Kostas J, Hotchkin J. Behavioral effects of low-level perinatal
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143 Taylor DH, Lagory KE, Zaccaro DJ, et al. Effect of
trichloroethylene on the exploratory and locomotor activity of 160 Kimmel CA, Buelke-Sam J (eds). Developmental Toxicology.
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1985.
161 Nemeroff CB, Lamartiniere CA, Mason GA, et al. Marked
144 Dorfmueller MA, Henne S, York R, et al. Evaluation of reduction in gonadal steroid hormone levels in rats treated
teratogenicity and behavioral toxicity with inhalation exposure of neonatally with monosodium L-glutamate: further evidence for
maternal rats to trichloroethylene. Toxicology 14(2):153-166, disruption of hypothalamic-pituitary-gonadal axis regulation.
1979. Neuroendocrin 33(5):265-267, 1981.
145 Hass U, Lund SP, Simonsen L, Fries AS. Effects of prenatal 162 Fernstrom JD. Dietary amino acids and brain function. J Am
exposure to xylene on postnatal development and behavior in Diet Assoc 94(1):71-77, 1994.
rats. Neurotoxicol Teratol 17(3):341-349, 1995.
163 Walker R. The significance of excursions above the ADI. Case
146 Mirkova E, Zaikov C, Mikhailova A, et al. Prenatal toxicity of study: monosodium glutamate. Regul Toxicol Pharmacol 30(2 pt
xylene. J Hyg Epidemiol Immunol 27(3):337-343, 1983. 2):S119-121, 1999.
147 Shigeta S, Miyake K, Aikawa H, Misawa T. Effects of postnatal 164 Fernstrom JD. Dietary amino acids and brain function. J Am
low-levels of exposure to styrene on behavior and development in Diet Assoc 94(1):71-77, 1994.
rats. J Toxicol Sci 14(4):279-286, 1989.
165 Olney JW. Excitotoxins in food. Neurotoxicol 15(3):535-544,
148 Khanna VK, Husain R, Hanig JP, et al. Increased 1994.
neurobehavioral toxicity of styrene in protein malnourished rats.
166 Brunner R, Vorhees C, Kinney L, Butcher R. Aspartame:
Neurotoxicol Teratol 13:153-159, 1991.
assessment of developmental psychotoxicity of a new artificial
149 Hileman B. Fluoridation of water. Chem Eng News 66:26-42, sweetener. Neurobehav Toxicol 1(1):79-86, 1979.
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167 Feingold BF. Why your child is hyperactive. New York:
150 Connett P. Fluoride: a statement of concern. Waste Not #459. Random House, 1975.
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century review. Center for Science in the Public Interest.
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adhd_resch_bk02.pdf
Greater Boston Physicians for Social Responsibility 101
CHAPTER 6: Known and Suspected Developmental Neurotoxicants
102 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 7: Chemicals, Regulations & the Environment
Chapter 7
Chemicals, Regulations
& the Environment
Scope of the Chemical Problem the United States by the large, industrial
facilities required to report under TRI.2
S carce information about the health
Of the 20 TRI chemicals
effects of the approximately 80,000
on the list with the largest
chemicals in commercial use, pervasive
total releases, nearly three- Nearly a billion pounds of
human exposures to many toxic chemicals,
these neurotoxicants were
quarters are known or
and seriously inadequate regulatory
emitted by facilities on-site
3
suspected neurotoxicants.
oversight combine to create a global
directly into just the air and
Nearly a billion pounds of
environmental threat to our children.
surface water, with the
these neurotoxicants were
鈥淐hildren today live in a very emitted by facilities on-site potential to be inhaled,
different environment from years ago,鈥? absorbed or otherwise
directly into just the air
said pediatrician Philip Landrigan, MD, and surface water, with the ingested through our food
MSc, Chair of the Department of and water supplies.
potential to be inhaled,
Community and Preventative Medicine absorbed or otherwise
at the Mt. Sinai Medical Center. 鈥淭here ingested through our food and water
are new patterns of illness emerging, and supplies. Additional amounts were
many more chemicals to which children released on and off-site into underground
are exposed. More than 10 million wells, landfills and other disposal facilities,
products contain chemicals. Toxicity bringing the total releases to over 1.2
testing has not even begun to keep pace billion pounds.
with disease. We are conducting a vast
In order of total releases, the top
toxicological experiment on our children
chemicals that are known or suspected
which will affect generations to come,鈥?
neurotoxicants include methanol,
said Landrigan.1
ammonia, manganese compounds,
Toxics Release Inventory Reveals Over toluene, phosphoric acid, xylene, n-
a Billion Pounds of Neurotoxicants hexane, chlorine, methyl ethyl ketone,
Released Into Environment carbon disulfide, dichloromethane,
The Toxics Release Inventory (TRI) styrene, lead compounds, and glycol
reporting for the year 1997 reveals that a ethers. The 1997 TRI also reports metals
total of 2.58 billion pounds of toxic released to the environment. Again, over
chemicals were released nationwide in half of those listed are known or
Greater Boston Physicians for Social Responsibility 103
CHAPTER 7: Chemicals, Regulations & the Environment
and certain industry sectors. For
example, the major sources of mercury,
including coal-fired power plants and
incinerators, were not required to report
to TRI in 1997. Electric utilities and six
other industry sectors will be required to
report emissions beginning with 1998
data, but incinerators and other facilities
will still escape right-to-know reporting
suspected to be toxic to the central
requirements. Other exemptions include
nervous system.4 These include
sources that use less than 25,000 pounds
antimony, arsenic, barium, cadmium,
lead, manganese, nickel, selenium,
thallium, cobalt and mercury.5
Known or suspected neurotoxicants
represent 81 percent of the total top 20
chemicals released to just air and
surface water. They comprise 71 Other
percent of total on-site releases to air, 19%
water and land of the top 20 chemicals.
The 1997 TRI release data include
information on only about 650
chemicals, or less than 1% of the Neurotoxic
80,000 chemicals in commercial use.6 81%
They also do not provide chemical
release information on all industries,
of chemicals. This has important
including small-quantity generators
implications for chemicals shown in this
report to exert adverse effects at
extremely low levels. Due to concern
about these low-level effects, EPA
recently lowered the reporting thresholds
for a number of persistent,
bioaccumulative toxic chemicals (PBTs)
including mercury, dioxins, PCBs and
some pesticides.7 Unfortunately, lead was
not included in this list. A separate rule
to ensure the reporting of lead emissions
has been opposed by the lead industry
and delayed by Congress.8
104 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 7: Chemicals, Regulations & the Environment
occupational exposures, sometimes at
Use of Neurotoxicants High
high levels, and pose additional risks to
TRI does not account for toxic
people in surrounding communities.
chemicals incorporated into products,
which may be a source of significant fetal One of the most disturbing
or childhood exposures. However, toxics observations in the 1997 TURA data is
use information, which is only available in that the use of lead and lead compounds
a few states, provides important additional has risen a dramatic 77 percent from
information regarding potential human 1990-1997 (lead use alone rose 83
percent, lead compounds 75 percent.) 11
exposures to neurotoxicants.
Lead compounds appear in the top 20
An analysis of 1997 data stemming
TURA list for both chemicals shipped in
from the Massachusetts Toxics Use
product and used.12 Products that
Reduction Act (TURA) reveals that over
account for some of the increase include
half of the top 20 chemicals 鈥渟hipped in
use of lead in polyvinyl chloride (PVC)
product,鈥? and half of the top 20
and coated wire products.
chemicals used by industrial facilities
required to report in Massachusetts, are Exposures to Pesticides Pervasive
known or suspected neurotoxicants.9 Although some pesticides were
(鈥淪hipped in product鈥? includes chemicals added to TRI in 1995, requiring
that are incorporated into final products, manufacturers to report releases of listed
such as styrene monomer into chemicals, agricultural and other
polystyrene, and also distribution of commercial users of pesticides are not
chemicals that are themselves the end required to report releases under TRI.
product, such as solvents.) These The U.S. used approximately 1.23 billion
neurotoxicants used by industrial
facilities total over 500 million pounds
and represent over 50 percent by weight
of the top 20 chemicals used, and over
40 percent of the top 20 shipped in
product in Massachusetts for the latest
reporting year.10 Chemicals bound up in
products may not represent a toxic threat
during use, but may be a very real threat
during shipping or handling, or when
they are released during disposal,
including incineration. Chemicals used in
facilities provide opportunities for
Greater Boston Physicians for Social Responsibility 105
CHAPTER 7: Chemicals, Regulations & the Environment
pounds of 鈥渃onventional鈥? organophosphate insecticides, chemically
pesticides in 1997 and a related to more toxic nerve warfare agents
total of about 4.5 billion developed earlier this century. One such
pounds when all types of pesticide, chlorpyrifos (commonly sold as
pesticides are included, Dursban), is among the most widely-used
such as wood preservatives insecticides in homes. A national health
and chlorine/hypochlor- exposure study detected chlorpyrifos
ites. Home pesticide use residues (as the metabolite TCP) in the
accounted for about 76 urine of 82% of a representative sample
million pounds in 1997. 13 of American adults. A more recent study
The EPA estimates that about in Minnesota revealed that an even higher
23 percent of the total U.S. use of pesticides 92% of children had detectable levels of
occurs in nonagricultural areas.14 this metabolite in their urine.16 TCP is
Thirty-seven
also a metabolite of chlorpyrifos methyl,
pesticides The failure to include these
used extensively in grain storage, so it is
registered for intentional environmental pesticide
not possible to fully determine the source
use on foods releases in TRI reporting requirements
of exposure.
are neurotoxic impedes exposure assessment and
organophosphates. prevention efforts. This is troublesome Seventeen organophosphates
since children are among the most (including chlorpyrifos) are registered by
vulnerable to adverse health effects from EPA for 鈥渞esidential鈥? uses, including in
pesticides. The 1993 National Academy homes, on lawns, in schools, and on
of Sciences report, Pesticides in the playgrounds. Children play in the grass
Diets of Infants and Children, where pesticides have been used and on
emphasized that children are not little carpets, which are toxic reservoirs for
adults and that, pound for pound, their garden pesticides, lead dust, and other
toxic substances.17 In a 1999 study on
chemical exposures are often greater
than adults. Children are also frequently the distribution of pesticides and
less able to detoxify substances such polycyclic aromatic hydrocarbons
as pesticides, and their developing (PAHs鈥攆ound in cigarette smoke and the
organs, including the brain, are more products of fuel combustion) in house
vulnerable. Enhanced susceptibility to dust, 14 pesticides and 10 PAHs were
adverse effects combines with relatively detected in residential house dust collected
from a typical North Carolina suburb.18
larger exposures to create substantially
increased risks. Chemicals that might biodegrade quickly
outside when exposed to sunlight, water,
Children eat more fruits and veg-
and microorganisms remain for much
etables than adults, on a weight-adjusted
longer periods of time in carpets.
basis. Twenty million American children
five and under eat an average of eight Schools are another source of pesticide
pesticides every day through food con- exposure for children. Surveys in
sumption.15 Thirty-seven pesticides Massachusetts and Connecticut have
registered for use on foods are neurotoxic shown that more than 80% of schools
106 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 7: Chemicals, Regulations & the Environment
developing human brain.) Implicit in
routinely spray pesticides. A New York
this approach is the assumption that
study found that at least 50 active
animal studies are relevant to humans.
pesticide ingredients are regularly applied
This assumption is widely accepted
in the buildings and on the grounds of
because, with some notable exceptions,
schools in that state. These applications
Animal studies
test animals and humans absorb,
expose our children to hundreds of active
commonly fail
metabolize, respond to, and excrete
pesticide ingredients as well as an array of
to predict the
chemicals in substantially similar ways.
solvents and other chemicals misleadingly
particular
labeled 鈥渋nert鈥? ingredients.19 20 The trend Despite validated and standardized
sensitivity of
is toward increasingly common exposures testing protocols, toxicity testing data
the developing
to organophosphates. For example, for individual chemicals from animal
human brain.
chlorpyrifos detections in urine increased studies are woefully inadequate. For
more than tenfold from 1980 to 1990.21 example, nearly 3,000 鈥渉igh production
volume鈥? (HPV) chemicals are produced
Regulatory Requirements at greater than one million pounds per
Limited Toxicity Data year. Yet, for 75 percent of these top-
volume chemicals, even the most basic
Lack of even the most basic
toxicity testing data are lacking.22 For
information about the health
about three-quarters of these commercial
effects of thousands of chemicals
chemicals, the public record holds no
being made, sold, and emitted has
data reporting the results of toxicity
serious implications for our most
testing in developing animals.23
vulnerable population.
Among the approximately 890
Information that might be used to
registered pesticidal active ingredients,
regulate exposure to chemicals comes
EPA considers about 140 to be
largely from results of toxicity testing in
neurotoxic.24 Between 3 and 5% of non-
whole animals, cell cultures, or
pesticidal chemicals have been estimated
epidemiological studies of exposed
to be toxic to the nervous system.25 Yet
people. However, even for those
the Environmental Protection Agency
chemicals that have undergone some
(EPA) asserts that an overwhelming
degree of examination, studies in both
majority of the materials in commercial
animals and humans have deficiencies.
use have not been tested specifically for
Because of obvious ethical concerns
neurotoxic potential, making this
associated with toxicity testing in
estimate highly speculative.26 Since 1991,
humans, our regulatory system for
for example, EPA has had a validated,
chemicals has historically been based
accepted guideline for assessing a
on toxicity testing in animals, with
chemical鈥檚 toxicity to the nervous system
extrapolation of these results to estimate
in immature or developing animals. By
risks for average adult humans. (However,
December 1998, however, manufacturers
animal studies commonly fail to predict
had submitted results from this
the particular sensitivity of the
Greater Boston Physicians for Social Responsibility 107
CHAPTER 7: Chemicals, Regulations & the Environment
any type is required under TSCA.28
developmental neurotoxicity (DNT)
testing for only 12 chemicals 鈥? nine Instead, toxicity testing of these chemicals
pesticides and just three non-pesticide has largely occurred at the manufacturer鈥檚
commercial chemicals.27 discretion, or after manufacture and use
of the chemical has already raised
Why Data are Lacking questions about its impact on the health
of exposed persons. Though Section 6 of
Animal toxicity testing data are
TSCA authorizes the EPA Administrator
inadequate for a number of reasons.
Laboratory animal
to take action to control risks from toxic
First, the 鈥渃ore鈥? or basic toxicity testing
tests of single
chemicals, in its 20-year history EPA has
requirements necessary for registering
chemicals do not
taken Section 6 regulatory actions against
chemicals are often inadequate. Second,
reflect the real world
only five chemicals or chemical classes.29
鈥渢riggered鈥? or conditional testing
of mixed exposures,
requirements may be incompletely or
and commonly fail to In contrast, pesticides must undergo
ineffectually enforced. Third, when
predict the sensitivity a battery of required toxicity tests prior
additional tests are triggered, the testing
of the developing to their registration, manufacture and
guidelines or protocols themselves may
human brain. use. Of more than 890 pesticide 鈥渁ctive
be deficient. Finally, laboratory animal ingredients鈥? registered with EPA, 523
tests of single chemicals do not reflect are registered for use on food or feeds.30
the real world of mixed exposures, and Regulation of food-use pesticides takes
commonly fail to predict the sensitivity place under the Federal Insecticide,
of the developing human brain. Fungicide and Rodenticide Act (FIFRA),
the Federal Food, Drug and Cosmetic
1. Inadequate 鈥淐ore鈥? or Basic
Act (FFDCA), and since 1996, the Food
Testing Requirements
Quality Protection Act (FQPA). The
The lack of toxicity data for
battery of required toxicology tests for
chemicals currently on the market stems
registering or re-registering a pesticide
directly from the lack of requirements for
used in or on food are found in the Code
testing prior to registration or
of Federal Regulations, last revised in
manufacture of these chemicals. For most
1984. Even the core requirements are
non-pesticidal and non-pharmaceutical
alarming in their omissions. They fail to
chemicals that are regulated under the
include, for example, specific tests of a
Toxic Substances Control Act (TSCA),
chemical鈥檚 toxicity to the function of
manufacturers are required to notify the
the nervous system, the immune system,
EPA of their intent to manufacture a
or the endocrine system. EPA has
new chemical or use an existing chemical
repeatedly acknowledged the deficiency of
in substantially new ways. Yet, there
these testing requirements for pesticides,
are no requirements for performing
particularly in terms of testing their
developmental neurotoxicity (DNT)
potential effects on the nervous system,
testing of the proposed chemical. In fact,
and the agency has signaled its intent to
no pre-manufacturing toxicity testing of
revise them. See sidebar page 110.
108 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 7: Chemicals, Regulations & the Environment
of pesticides tested with it, seventy-eight
2. Inadequate 鈥淭riggered鈥?
percent (7 of 9) were found to have an
or Conditional Testing
Registration of a new pesticide does effect on the developing nervous
42
not require pre-market testing for effects system. Rather, the triggers themselves
are inadequate or not enforced. It would
on the developing or adult brain or
not be unreasonable to expect more than
nervous system. EPA only recommends
nine complete DNT studies over the last
this kind of testing after certain
decade inasmuch as EPA has already
conditions have been met鈥攊n other
words, they are 鈥渃onditionally required.鈥? identified 140 or more of existing
For example, EPA鈥檚 recommendation for pesticides to be neurotoxic.
DNT testing is contingent upon the In 1998 a working group of EPA
fulfillment of certain criteria, or scientists looked at the agency鈥檚 track
鈥渢riggers,鈥? that were decided upon at a record on DNT testing and concluded:
decade-old workshop sponsored by both
It is impossible
鈥淚n the past, developmental neurotoxicity
EPA and the National Institute for Drug
to predict how
study was based on criteria or triggers
Abuse. From highest to lowest priority,
many neurotoxic
from both adult and developmental
these triggers include chemicals that are:
agents will show
toxicity data and a weight-of-the-evidence
CNS/behavioral teratogens (and
developmental
review of all available data for each
structural analogues), adult neuropathic
neurotoxicity.
chemical. Such triggers were probably a
agents, adult neuroactive agents, reasonable place to start; however, they
hormonally鈥揳ctive compounds, and were based on experience with a limited
developmental toxicants that do not number of agents. More recent
necessarily produce CNS effects.40 41 information suggests that these triggers
After nearly a decade, EPA鈥檚 tiered may not be inclusive enough to signal all
or triggered system for making chemicals that have the potential to
recommendations for developmental produce developmental neurotoxicity.
neurotoxicity testing has prompted Based on the data currently available, it is
manufacturers to submit just nine impossible to predict how many neuro-
complete DNT tests out of 890 toxic agents will show developmental
registered pesticides. The explanation neurotoxicity, nor do we currently have
for this record is multifaceted. sufficient information to predict how many
It is not that there is a lack of agents that are not neurotoxic or that do
accepted methods for testing not show CNS malformations will cause
developmental neurotoxicity. EPA has developmental neurotoxicity.鈥?43
had validated, 鈥渁ccepted鈥? guidelines for More generally, the concept of tiered
performing DNT tests since 1991. or 鈥渢riggered鈥? toxicity testing itself is
Moreover, tests using these validated probably flawed, at least with respect to
DNT guidelines appear to be somewhat the nervous system. Under existing EPA
sensitive at detecting neurotoxicity in regulations the trigger for a 鈥渃onditional鈥?
developing animals. Of the small number requirement that a chemical undergo
Greater Boston Physicians for Social Responsibility 109
CHAPTER 7: Chemicals, Regulations & the Environment
DEVELOPMENTAL NEUROTOXICITY memorandum鈥攋ointly signed by the heads of
AS A CORE TESTING REQUIREMENT EPA鈥檚 Office of Prevention, Pesticides and Toxic
Substances (OPPTS), the Office of Research and
A s early as 1994, EPA recognized that its
Development, and the Office of Children鈥檚
toxicology testing requirements for
Health Protection鈥攁ffirmed the agency鈥檚
registering new pesticides were inadequate,
intention to accept this recommendation and
particularly with respect to testing for toxicity to
the nervous system. In that year, EPA finished, and expand the core requirements for all new
pesticides to include DNT testing.37 The memo
asked its FIFRA Scientific Advisory Panel (SAP) to
referred to the long-delayed revisions which
review proposed revisions to these requirements,
The data call-in
鈥渁re expected to go to OMB (Office of
found in part 158, subpart F, of section 40 of the
fails to answer
Code of Federal Regulations. EPA鈥檚 1994 proposed Management and Budget) in November
the need for
(1998), and which are scheduled for public
revisions would have made it a core requirement
neurotoxicity
notice and comment in Spring 1999.鈥?38
for newly registered pesticides to be screened for
testing for new
Neither step occurred.
neurotoxicity, including acute and subchronic
pesticides being
One thing that did happen in August 1999
testing in adult animals.31 The SAP generally
registered.
is that EPA announced an imminent 鈥渄ata
32
endorsed the proposal. But EPA has failed
call-in,鈥? or DCI, for about 140
repeatedly to issue a proposed rule and finalize
already registered pesticides
these revisions, even after repeated public
considered to be neurotoxic.
33 ,34
announcements of its intention to do so.
The DCI鈥檚 first phase鈥攊nitiated
In the intervening years, however, EPA鈥檚
September 10, 1999鈥攆ocuses on just 34
proposed revisions have expanded. In March
cholinesterase-inhibiting organophosphate
1998, for example, the entire FIFRA SAP
recommended to EPA that it consider requiring insecticides. It requires manufacturers of these
chemicals to conduct and submit tests of
developmental neurotoxicity (DNT) testing for
acute, subchronic and developmental neuro-
all neurotoxic insecticides, with a portion of
toxicity to EPA within two years.39 EPA has not
the panel urging a developmental neurotoxic-
estimated how long it will take to complete
ity testing requirement for all pesticides,
period.35 An internal EPA working group then the entire DCI for all 140 pesticides.
Although this DCI begins the process of
reexamined the agency鈥檚 core testing require-
collecting neurotoxicity data, it is limited to
ments for pesticides, and concluded 鈥?40 CFR
pesticides already identified as neurotoxic.
Part 158.340 (Subpart F) should be updated as
More importantly, the DCI only applies to
soon as possible to include the adult and
chemicals already on the market; it fails to
developmental neurotoxicity guidelines and to
answer the need for neurotoxicity testing for
refer to the newly revised two-generation
new pesticides being registered. Until this
reproduction and prenatal developmental
need is met, most new pesticides and other
toxicity testing guidelines.鈥?36 This recommen-
chemicals will continue to enter the market
dation differs from EPA鈥檚 1994 proposed
before any testing is done to predict toxicity
revisions with the addition of DNT as a
to the brain and nervous system.
basic core requirement. An October 1998
110 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 7: Chemicals, Regulations & the Environment
basic screening for nervous system
toxicity hinges on results from other,
less specific, toxicological testing that
generally does not involve the nervous
system. Yet, as has been pointed out
by Dr. Deborah Rice, an EPA
neurotoxicologist, the triggers for
recommending a DNT study in some
cases depend on information best
obtained from the DNT study itself.44
Finally, it is critical to note that even
when prior testing triggers a recommen-
dation for DNT testing, a chemical
manufacturer is under no obligation to the risks of chemical exposure to the
perform such testing.45 Thus, while 12 nervous systems in children. For
complete DNT studies had been submit- example, a March, 1998 panel of the
ted to EPA by December 1998, various EPA鈥檚 Scientific Advisory Panel (SAP)
agency scientific review committees had reviewed the DNT guideline. It
recommended DNT testing of an additional unanimously agreed that this guideline
A complete DNT
26 chemicals. Though some of these 鈥渕ust be further refined to develop more
study can be
recommendations date back more than sensitive endpoints which are relevant to
planned and
six years, none of the recommended significant outcomes in humans such as
completed in less
testing has ever been completed. A learning disabilities and behavioral
than 2 years.
issues.鈥?46 In addition, Tilson and others
complete DNT study can be planned
and completed in less than 2 years. have identified the exposure period in
the current DNT guideline as being far
3. Deficient Guidelines for
too short to reflect the entire vulnerable
Performing Toxicity Testing
period of brain development in children.47
Another problem with some of EPA鈥檚
The current DNT guideline requires that
current guidelines for performing toxicity
test animals be dosed with a chemical
testing in animals is that they omit key
through the 10th postnatal day. Yet the
measures of toxicity. For example, manu-
critical period of rapid growth in the
facturers of organophosphate and carba-
human brain, extending from the 3rd
mate insecticides, specifically designed to
trimester through the second year of life,
inhibit acetylcholinesterase, a key enzyme
corresponds to the first 21-28 days of life
for the development and function of the
in rats or mice鈥攏ot ten days.48
nervous system, are not currently required
Omissions like these led the National
to submit studies that will quantify the
Academy of Science to conclude in 1993
level of cholinesterase inhibition stem-
that EPA鈥檚 鈥渃urrent testing protocols do
ming from exposure to their product.
not, for the most part, adequately address
Similarly, the current DNT guideline
the toxicity and metabolism of pesticides
eventually must be revised to better assess
Greater Boston Physicians for Social Responsibility 111
CHAPTER 7: Chemicals, Regulations & the Environment
in neonates and adolescent animals or the Scientific Advisory Panel concluded that
effects of exposure during early 鈥渁ny pesticide that works by poisoning the
developmental stages and their sequelae in nervous system鈥? should be considered for
later life鈥?.49 In the first phase of its data developmental neurotoxicity testing 鈥渂y
call in for 34 registered organophosphate the most sensitive validated methods
available.鈥?52 The current DNT guideline
insecticides, EPA has taken steps to ensure
that more useful neurotoxicity infor- is EPA鈥檚 most sensitive validated means
mation is collected. For example, the of doing so.
agency鈥檚 recent DCI specifically requires 4. Laboratory Conditions Do Not
that a comparative evaluation of Reflect the Real World, Animal
cholinesterase inhibition in both adult and Studies May Underestimate
young animals be included. It further Sensitivity of Human Brain
requires that animals in the DNT study
Animal testing typically assesses the
be dosed from day 6
toxic effects from exposure to only one
There is as yet no requirement of gestation through
chemical at a time. This fails to provide
that new pesticides be postnatal day 21,
information about the cumulative and
routinely tested for any significantly beyond
interactive effects from exposure to
neurotoxicity, including the 10th postnatal day
multiple chemicals that often occur in real
developmental neurotoxicity. required under the current
life settings.53 For example, a five-year
guideline.50 However,
study led by Dr. Warren Porter at the
the DCI thus far applies to relatively few
University of Wisconsin, identified signifi-
pesticides, many of which have already
cant shortcomings in toxicological testing
been on the market for two or three
requirements currently used to register
decades or more. As noted above,
pesticides in the United States. The study
however, there is as yet no requirement
suggests that combinations of commonly
that new pesticides be routinely tested
used agricultural chemicals, in levels
for any neurotoxicity, including
typically found in groundwater, can
developmental neurotoxicity.
significantly influence immune and endo-
The flaws in the current DNT guide- crine systems as well as neurological
line do not make it worthless. On the health. Tests in laboratory animals
contrary, the 1998 EPA review of 12 showed that combinations of the pesti-
DNT studies revealed that 鈥淭he develop- cides aldicarb and atrazine, along with
mental neurotoxicity study protocol nitrates, each widespread contaminants of
(OPPTS 870.6300) includes unique groundwater in the U.S., resulted in
endpoints which are not examined in any altered immune, endocrine, and nervous
other standard toxicity testing protocol, system function.54 The study identified
enabling the detection of effects on additional deficiencies in EPA鈥檚 core
nervous system development of the requirements for registering pesticides,
offspring following pre- and/or postnatal including the lack of testing for low dose
exposure.鈥?51 And a March 1998 exposures, no testing for endocrine and
112 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 7: Chemicals, Regulations & the Environment
Autism Cluster Sparks Study of Environment
A t the National Institutes of Health state of the science meeting on autism held
in 1995, the phrase 鈥渆nvironmental cause鈥? was never mentioned.1 Yet only
three years later the Centers for Disease Control (CDC) and the Agency for Toxic
Substances and Disease Registry began compiling information on potential
environmental pollution contributors to a purported autism cluster in Brick
Township, New Jersey. According to the New Jersey Bergen Record, this is
鈥渦ncharted territory鈥? for the CDC.2 At the same time the CDC began studying
autism and its potential environmental connections in a region around Atlanta.
Why the dramatic turnaround?
One catalyst was surely Bobbie Gallagher, Brick Township resident and 1
London E. Looking at Hard
Topics in Autism.
mother of two autistic children. Frustrated by a lack of information about the
Environmental Influences
cause of her children鈥檚 disabilities, she began to look for causes in the on Children conference, NY
Academy of Medicine, May
environment. What she found were plasticizers in the water supply and a nearby 24-25 1999.
Superfund site at the local landfill oozing a toxic soup of chemicals. She also 2
McEnery R. CDC Studying
link between environment
discovered about 30 other children in the area who had been diagnosed with and autism. Bergen Country
autism. It was small comfort to know that she was not alone.3 (At least 42 Record, November 8 1999.
3
Gallagher B. Looking at
children have subsequently been identified with autism in Brick Township,
Hard Topics in Autism.
population 76,000.) Environmental Influences
on Children conference, NY
Gallagher teamed up with the National Alliance for Autism Research (NAAR) Academy of Medicine, May
24-25 1999.
in Princeton, New Jersey, which proposed to the CDC that five new Centers for 4
Boyle C. Epidemiologic
Research in Autism Epidemiology be established. As a result of this proposal, Perspective on Autism.
Environmental Influences
studies in Brick Township looking at drinking water and also the Metedeconk on Children conference, NY
River are now underway, as is a study in five counties around Atlanta, Georgia. Academy of Medicine, May
24-25 1999.
According to Dr. Eric London, medical director of NAAR, epidemiologic 5
California Department of
Developmental Services.
studies from around the world have shown a steady increase in the prevalence of Changes in the Population
autism, from around 4/10,000 in the early Eighties to about 12/10,000 in the of Persons with Autism and
Pervasive Developmental
Nineties. (The CDC fact sheet on autism spectrum disorders estimates prevalence Disorders in California鈥檚
Developmental Services
may be as high as 20/10,000 children). Other evidence suggesting that autism
System: 1987 through 1998.
may be increasing dramatically includes a recent study done by the California A Report to the legislature,
Mar 1999.
Department of Developmental Services released in March 1999. The study looked 6
London E. Looking at
at pervasive developmental disorders (PDDs) from 1987 through 1998 and Hard Topics in Autism.
Environmental Influences
showed a 210 percent increase in cases entered into the autism registry during on Children conference, NY
those years.4 5 If the incidence of autism is increasing, and or clusters of autism Academy of Medicine, May
24-25 1999.
are being discovered, an environmental influence is likely.6 7
Hollander E.
Environmental Factors in
Evidence indicating the environment as a contributing factor to autism is the Development of
mounting. Studies suggest there are both genetic and environmental components Autism. Environmental
Influences on Children
to the disorder.7 However, definitive causes of autism remain elusive. Brick conference, NY Academy of
Medicine, May 24-25 1999.
Township, New Jersey may provide some important missing pieces to the puzzle.
Greater Boston Physicians for Social Responsibility 113
CHAPTER 7: Chemicals, Regulations & the Environment
immune functions, and no tests of allow neurotoxic and other toxic
commonly found mixtures of substances substances to be emitted into air, drinking
that represent real-world exposures. water, food, and onto land. For example,
although the SDWA requires the EPA to
Neurotoxicity studies submitted to
set Maximum Contaminant Levels
EPA, typically in adult rodents, often
(MCLs) for certain listed chemicals, the
vastly underestimate the sensitivity of the
level that is actually set to protect health is
developing human brain. For example,
based on considerations that include costs
based on comparisons of animal and
of water treatment and also best available
human data, animal studies of lead,
water treatment technology. Some
mercury and PCBs predict a 鈥渟afe鈥?
standards are obsolete due to a decline in
exposure level in humans that is 2-4
the toxic threshold for a previously
Costs incurred by orders of magnitude (100-10,000 fold)
recognized effect. Others are obsolete
industry, as a higher than levels that actually cause
because recent evidence has revealed
result of proposed effects in humans.55 These limitations
altogether new effects such as endocrine
regulation, must must be kept in mind as we use the
disruption that occur at lower levels of
be factored into results of animal testing to estimate
exposure than previously noted.56
decision-making. 鈥渟afe鈥? human exposure levels.
Except for food-use pesticides,
Additional Regulatory Authority
FIFRA and TSCA require cost-benefit
and Weaknesses
analyses of the impact of proposed
Besides TSCA and FIFRA, other
standards, in addition to health
major federal laws with regulatory
evaluations. This means that costs
authority over chemicals include the
incurred by industry, as a result of
Clean Air Act (CAA), the Clean Water
proposed regulation, must be factored
Act (CWA), and the Safe Drinking Water
into decision-making.57
Act (SDWA). Each has weaknesses that
1 Dr. Philip Landrigan quoting Dr. Herbert Needleman. 7 Federal Register October 29, 1999, Vol 64:209, Rules
Toxics Release Inventory and Right-to-Know Conference, and Regulations, Page 58665-58753.
Washington, DC. September 9, 1997.
8 Personal communication with Paul Orum, Right-to-
2 U.S.EPA,1997 Toxics Release Inventory Public Data Know Network. January 31, 2000.
Release. May 13, 1999. 9 Environmental Defense Fund 鈥淪corecard鈥?
3 Environmental Defense Fund 鈥淪corecard鈥? (www.scorecard. org) health effects of chemicals - Ibid.
(www.scorecard.org) health effects of chemicals -
10 Massachusetts Department of Environmental
neurotoxicity-compiled from 21 databases or references Protection, Bureau of Waste Prevention, in conjunction
including EPA, National Institute for Occupational Safety
with the Office of Technical Assistance for Toxics Use
and Health鈥檚 Registry of Toxic Effects of Chemical
Reduction, Toxics Use Reduction Institute, Massachusetts
Substances, NJ Dept. of Health Services TRI Fact Sheets
Executive Office of Environmental Affairs. 1997 Toxics
and Casarett and Doull鈥檚 Toxicology, the Basic Science of
Use Reduction Information Release, March 23, 1999.
Poisons, edited by C. Klaassen, M. Amdur and J. Doull, 5th
11 Personal communication with Liz Harriman,
Ed. Pergamon Press, NY 1996.
Massachusetts Toxics Use Reduction Institute. 12/29/99.
4 Ibid.
12 Massachusetts Department of Environmental
5 U.S. EPA. 1997 Toxics Release Inventory Public Data
Protection, Bureau of Waste Prevention, in conjunction
Release. May 13, 1999. with the Office of Technical Assistance for Toxics Use
6 U.S. EPA, Office of Prevention, Pesticides and Toxic Reduction, Toxics Use Reduction Institute, Massachusetts
Substances. Endocrine Disruptor Screening and Testing Executive Office of Environmental Affairs. 1997 Toxics Use
Advisory Committee. Final report. Washington DC, 1998. Reduction Information Release, March 23, 1999.
114 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 7: Chemicals, Regulations & the Environment
32 U.S. EPA, Final Report
13 U.S. EPA. OPPTS. Pesticides Industry Sales and Usage,
from the FIFRA Scientific
1996 and 1997 Estimates. 733-R-99-001, November 1999.
Advisory Panel, A Set of
14 U.S. EPA, OPPTS, Pesticides and National Strategies for Scientific Issues Being
Health Providers, Workshop Proceedings, April 23-24 Considered by the Agency in
1998. EPA 735-R-98-001, July 1998 Connection with the 40 CFR
Part 158 Proposed Rule:
15 Environmental Working Group. How Bout Them
Pesticide Registration Data
Apples? Pesticides in Children鈥檚 Food 10 Years After Alar.,
Requirements, December 19,
Washington DC. 2/25/99.
1994.
16 U.S.EPA, Chlorpyrifos:HED Preliminary Risk Assessment for
33 U.S. EPA, Office of
the Reregistration Eligibility Decision Document. 10/18/99.
Pesticide Programs Annual
17 Raloff J. Home carpets: Shoeing in toxic pollution. Report for 1994, EPA 735-
Science News, 138:86, 1990. R-95-001, http://
www.epa.gov/oppfead1/
18 Lewis R, Fortune C et al. Distribution of pesticides and
annual/1994, January 1995.
polycyclic aromatic hydrocarbons in house dust as a function
of particle size. Enviro Health Perspect, 107:9, 1999. 34 U.S. EPA, Memorandum
to the Administrator from
19 Johnston L. Primary Exposure: Pesticides in MA Schools.
Lynn Goldman, Henry
MASSPIRG Education Fund, 1996.
Longest II, and Ramona
20 Dr. John Wargo. New Directions for Children鈥檚
Trovato, Update and
Environmental Health Law and Policy. Environmental
Implementation Plans for
Influences on Children, Brain, Development & Behavior
the Child Safety Factor of
Conference, New York Academy of Medicine, NY, May 1999.
the Food Quality Protection
21 Schettler T, Solomon G. et al. Generations at Risk: Act, October 14, 1998.
Reproductive Health and the Environment. MIT Press,
35 U.S. EPA, Office of Science Coordination and Policy,
Cambridge, MA. July 1999. Pg. 225.
Final Report: Scientific Advisory Panel (SAP) March 1998
22 Roe D, Pease W., Florini K, Silbergeld E. Toxic Meeting, at http://www.epa. gov/scipoly/sap/1998/march/
Ignorance: The Continuing Absence of Basic Health fqpa_10x.htm/, page 5.
Testing for Top-Selling Chemicals in the United States,
36 U.S. EPA, Toxicology Data Requirements for Assessing
Environmental Defense Fund, 1997.
Risks of Pesticide Exposure to Children鈥檚 Health, Draft
23 Ibid. Report of the Toxicology Workgroup of the EPA 10X Task
Force, November 30, 1998, p. 29.
24 Federal Register. 64(151):2945-42947, 1999.
37 U.S. EPA, Memorandum to the Administrator from
25 Office of Technology Assessment, Neurotoxicity:
Lynn Goldman, Henry Longest II, and Ramona Trovato,
Identifying and Controlling Poisons of the Nervous
Update and Implementation Plans for the Child Safety
System, OTA-BA-436, Washington, DC: U.S. Government
Factor of the Food Quality Protection Act, October 14,
Printing Office, April 1990, p.3.
1998.
26 U.S. EPA, Guidelines for Neurotoxocity Risk Assessment,
38 Ibid., p. 2.
April 30 1998, EPA/630/R-95/001Fa.
39 Federal Register. 64(151):42945-42947, 1999.
27 Makris S, Raffaele K, Sette W, Seed J. A retrospective
analysis of twelve developmental neurotoxicity studies 40 Claudio L, Kwa WC, Russell AL, Wallinga D. Testing
submitted to the U.S. EPA Office of Prevention, Pesticides, methods for developmental neurotoxicity of
and Toxic Substances (OPPTS), draft, 11/12/98. environmental chemicals, Toxicol. Appl. Pharmacol., 164.
(accepted January 4, 2000).
28 Schettler T. et al. Generations at Risk: Reproductive
Health and the Environment. MIT Press, Cambridge, MA. 41 Francis, EZ, Kimmel, CA, Rees, DC, Workshop on the
July 1999. Pg. 240. qualitative and quantitative comparability of human and
animal developmental neurotoxicity: Summary and
29 Roe D, Pease W., Florini K, Silbergeld E. Toxic
Implications. Neurotoxicol and Teratol. 12:285-292
Ignorance: The Continuing Absence of Basic Health
(1990).
Testing for Top-Selling Chemicals in the United States,
Environmental Defense Fund, 1997. Pg. 28. 42 U.S. EPA, Dr. Hugh Tilson, Environmental Influences on
Children, Brain Development & Behavior Conference, NY
30 U.S. EPA. OPPTS. Pesticides Industry Sales and Usage,
Academy of Medicine, May 1999.
1996 and 1997 Estimates. 733-R-99-001, November 1999.
43 U.S. EPA, Draft Report of the Toxicology Workgroup of
31 U.S. EPA, Changes to 40 CFR. Part 158, September 14,
the EPA 10X Task Force, Toxicology Data Requirements for
1994, Presented to the FIFRA Scientific Advisory Panel
Assessing Risks of Pesticide Exposure to Children鈥檚 Health,
(SAP), November 29-30, 1994.
April 28, 1998, p. 12.
Greater Boston Physicians for Social Responsibility 115
CHAPTER 7: Chemicals, Regulations & the Environment
44 Statement by Dr. Deborah Rice, Seventeenth 51 Makris S, Raffaele K, Sette W, Seed J. A retrospective
International Neurotoxicology Conference: Roundtable analysis of twelve developmental neurotoxicity studies
Discussion 鈥? Do the EPA Developmental Neurotoxicity submitted to the U.S. EPA Office of Prevention, Pesticides,
Guidelines Detect Human Developmental Neurotoxicity?, and Toxic Substances (OPPTS), draft, 11/12/98.
Little Rock, AK, October 20, 1999.
52 U.S. EPA, Office of Science Coordination and Policy,
45 Ibid., presentation by David Wallinga, M.D. Final Report: Scientific Advisory Panel (SAP) March 1998
Meeting, at http://www.epa.gov/scipoly/sap/1998/march/
46 U.S. EPA Report of the FIFRA Scientific Advisory Panel
fqpa_10x.htm/.
Meeting, December 8, 1998, held at the Sheraton Crystal
Hotel, Arlington, VA, SAP Report No. 99-01B, January 22, 53 Schettler T, Solomon G et al. Generations at
1999, p. 18. Risk:Reproductive Health and the Environment. MIT Press,
Cambridge, MA. 1999. Pgs. 21-48.
47 Tilson, HA, The concern for developmental
neurotoxicology: Is it justified and what is being done 54 Porter WP, Jaeger JW, Carlson IH. Endocrine, immune
about it? Environ. Health Perspect. 103(6):147-151. and behavioral effects of aldicarb (carbamate), atrazine
(triazine) and nitrate (fertilizer) mixtures at groundwater
48 Claudio L, Kwa WC, Russell AL, Wallinga D. Testing
concentrations. Journal of Toxicology and Industrial
methods for developmental neurotoxicity of
Health 15:133-150, 1999.
environmental chemicals, Toxicol. Appl. Pharmacol., 164.
(accepted January 4, 2000). 55 Rice D, Evangelista de Duffard A, Duffard R et al.
Lessons for neurotoxicology from selected model
49 National Research Council, Pesticides in the Diets of
compounds: SGOMSEC joint report. Environ Health
Infants and Children, National Academy Press:
Perspect 104(suppl 2):205-215, 1996.
Washington, D.C., 1993.
56 Olsen E. Think Before You Drink:The Failure of the
50 U.S. EPA, Letter to Registrants from Lois Rossi, Director,
Nation鈥檚 Drinking Water System to Protect Public Health.
Special Review and Reregistration Division with multiple
NRDC, 1993. pg. V.
attachments, OPPTS, September 10, 1999.
57 Schettler T, Solomon G et al. Generations at
Risk:Reproductive Health and the Environment. MIT Press,
Cambridge, MA. 1999. Pg. 236.
116 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 8: Conclusion
Chapter 8
Conclusion
S everal important themes emerge from this were not the case, considering the
the research reviewed in this report. unique capacities and complexities of
the human nervous system.
1. Neurodevelopmental disabilities
are widespread, and chemical exposures 4. Regulatory policy has repeatedly
are important and preventable failed to protect children from
Generations of
contributors to these conditions. widespread harm due to exposures to
children are at risk,
Reductionist analyses that separately developmental neurotoxins. Due to the
and often harmed,
address environmental and genetic extremely slow rate at which proof of
before an adequate
factors may illuminate important details safety or harm materializes, generations
regulatory response
but fail to acknowledge the complexities of children are at risk, and often harmed,
can occur.
of multiple, interacting factors that before an adequate regulatory response
ultimately influence neurological can occur. Timely action can be ensured
development. Both genetic factors only by regulatory processes that are
and environmental factors must be capable of responding during the
simultaneously considered to properly extended period between the earliest
understand these disabilities. evidence and more complete scientific
understanding of the danger.
2. Our initial understanding of the
impacts of neurotoxic substances 5. The failure of the regulatory
regularly underestimates the potential system to protect public health can often
for harm. So called 鈥渟afe鈥? exposure be traced to the influence of vested
thresholds regularly become obsolete as economic interests upon the regulatory
research methods improve. process. Special interests commonly use
a variety of tactics to delay or diminish
3. Carefully conducted, long-term
the regulatory response to public health
epidemiological studies have proven to
threats. One obstacle to timely action is
be much more sensitive measures of
the frequent presumption that chemical
developmental neurotoxicity than
exposures are harmless until a complex,
animal studies. Thus, animal models
expensive, and rigid process for
may greatly underestimate true human
identifying toxicity and health threats
risks. Indeed, it would be surprising if
is completed.
Greater Boston Physicians for Social Responsibility 117
CHAPTER 8: Conclusion
6. Neurodevelopmental disabilities combine. For the purposes of
impose social and economic costs upon comprehensive understanding,
impacted families and the economy as prevention, and public health
a whole. Preventing these disabilities protection, these isolated factors must
has the potential to provide major be conceptually reassembled and
economic benefits. considered as an integrated whole.
7. Special interests are not merely
Neurodevelopmental Disabilities
tolerated but are actually an integral part
Are Expensive Not Only For Families,
of the regulatory process. If we are to
But For Society As A Whole
successfully respond to the threats posed
Learning and behavioral disabilities
by the use and environmental releases of
are associated with early drop out from
neurotoxic chemicals, we must find a
high school, substance abuse, unemploy-
way to insulate public health decision-
ment, teen-parenting, welfare dependence,
making from conflicts of interest that
and incarceration. The enormous
can corrupt it.
financial costs of these problems are
Simplistic Analysis Fails To borne by families, schools, local and
Address The Complex Causes national governments, and by businesses
Of Developmental Disabilities faced with workforce disabilities and
rising health insurance premiums.
Genetic and environmental factors
Regulatory decisions that affect the
interact in complex ways to cause the
neurodevelopment of children impact
learning disabilities and cognitive
not only health, but all aspects of society,
disorders discussed in this report. Yet, in
including the economy as a whole. Indeed,
keeping with current toxicological,
healthy families and a healthy workforce
genetic, and epidemiological research
are essential pillars of a vibrant economy.
strategies, most research continues to
focus on one domain at a time, as if
Regulatory Policy Has Repeatedly
comprehensive understanding would
Failed To Protect Children鈥檚 Health
emerge by simply adding up the
An historical review of our
contributions of each.
understanding of the risks of
This reductionist approach to
neurotoxic chemicals reveals a
complex problems characterizes
disturbing pattern. As a rule, these
biomedical research in the 20th century.
chemicals are recognized as harmful
Though dissecting problems into
long after their use has become routine
component parts helps to illuminate
and exposures have become
important details, a broader integration
widespread. Because the fetus and
must be accomplished before we can
developing child are most sensitive to
truly understand the infinitely more
the effects of these insidious exposures,
complex real world, where genetic,
children bear the burden of regulatory
environmental, and social factors
118 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 8: Conclusion
policies that largely consider chemicals
safe until proven harmful. After a
century of intensive study, the harm
from perhaps the single most-studied
neurotoxicant can be characterized with
fair certainty. Since childhood lead
exposure has been ongoing since lead
paint was first introduced in the 1890s,
five generations of children have been
injured while science slowly advanced to
where it is now capable of appreciating
the magnitude of the problem. This
system often serves special economic
same pattern of 鈥渁fter-the-fact鈥? recog-
nition of harm has been repeated for interests at the cost of children鈥檚 health.
With thousands
mercury, PCBs, pesticides, alcohol, and Individual chemicals or classes of
of potentially
nicotine. In each instance, what we initially chemicals, for which there is plausible
neurotoxic
believed to be a 鈥渟afe鈥? exposure level evidence of toxicity, should not be
chemicals in
steadily dropped as understanding improved. considered innocent until fully proven
widespread use,
guilty. Rather, such chemicals ought to
With thousands of potentially
our snail鈥檚 pace
neurotoxic chemicals in widespread be regulated in a precautionary manner,
approach to
use, our snail鈥檚 pace approach to much as we regulate pharmaceutical
regulation clearly
chemicals - shifting the 鈥渂urden of
regulation clearly sets children in a
sets children in a
minefield of uncertainty and potential proof 鈥? so that some basic evidence
minefield of
harm, where the full extent of current of safety is required before public
uncertainty and
exposures are permitted. Pharmaceu-
hazards will be unknown for the
potential harm
foreseeable future. Meanwhile, ticals are bioactive chemicals, which
thousands of new chemicals come into people take by choice and which have
favorable risk/benefit profiles. Environ-
production and use, creating new
exposure hazards. Even when there is mental chemicals, on the other hand, are
substantial evidence of hazard, bioactive substances that people usually
do not take by choice, but are often
chemicals continue to be inflicted on
the unsuspecting public for decades, exposed to, in varying amounts, without
as painstaking scientific study slowly their knowledge or consent. In addition,
environmental chemicals that carry risks
clarifies precise magnitudes of risk and
cellular mechanisms of harm. Without do not, as a rule, provide countervening
such information, the regulatory health benefits. Clearly, the public
deserves the same measure of protection
system does not easily respond. Rigid
adherence to an inflexible standard from involuntary environmental
for justifying action prevents timely exposures, which may be hazardous,
as from voluntary pharmaceutical
regulatory response to public health
threats. As a result, the regulatory exposures that have therapeutic benefit.
Greater Boston Physicians for Social Responsibility 119
CHAPTER 8: Conclusion
Tip of the Iceberg
current
& proven damage
The regulatory process addresses those few
current & chemicals for which there is rigorous proof of harm,
but such harm is likely to be the tip of the iceberg.
partially proven
There is a deeper level at which emerging harm
can be identified but is not fully proven, despite
yet to be recognized or clear warning signs. Below this, there are damages
that occur with long latency periods, in which
yet to appear
harmful exposure has occurred but the manifestation
of the damage has yet to appear. And below this
there are exposures that are harmful but which will
never be recognized due to the difficulties of detection.
forever unrecognized
There are approximately 80,000 chemicals in
the U.S. inventory, with one-to-two thousand new
chemicals introduced each year. Since chemical
exposures proliferate much faster than their neuro-
developmental toxicities can be understood, the true
dimensions of the toxic threat will always be under-
estimated by 鈥渃urrently available knowledge鈥?.
Finally, risks and benefits often an expected part of the regulatory
accrue to very different groups and are process. Advocates for public health
typically not equitably distributed. and representatives of special, corporate
While manufacturers and particular interests routinely lock horns in the
groups of consumers may benefit from course of scientific deliberations, in
an industrial product or process that which the parties are considered
utilizes or releases neurotoxic 鈥渟takeholders鈥? of equal importance.
substances, the risks of toxic exposures This process allows voices into public
are often borne by others, such as health decision making that are obviously
cultural minorities or economically financially conflicted and often willing
disadvantaged or socially marginalized to expend considerable sums of money
groups. For example, children of urban to ensure that a particular financially
inner cities or children of migrant farm advantageous action is taken. The failure
workers are disproportionately exposed of the regulatory process to guard against
to pesticides or other neurotoxic these influences contributes to the lack of
substances. Subsistence fishing among children鈥檚 health protection. Allowing
less affluent ethnic communities, due financially conflicted interests a central
both to economic necessity and cultural role in the regulatory arena creates a
tradition, results in increased exposure steeply tilted playing field favoring
to fish-borne neurotoxicants, including corporations with enormous political and
mercury, dioxin, and PCBs. economic influence.
Corporate influence on the regulatory
Conflicts Of Interest Are An Accepted
process may include a range of pervasive
Part Of The Regulatory Process
political and financial pressures, including
In environmental public health
political lobbying, campaign contribu-
decision making, the strong influence
of vested economic interests is currently tions, well-financed public relations
120 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
CHAPTER 8: Conclusion
campaigns, biased interpretation of profit by undermining or resisting
scientific evidence, and selectively safeguards. The role of special interests
funded research. Unfortunately, in the regulation of environmental
public agencies widely perceived as chemicals is an important matter for
the defenders of public health are public debate, as it has direct relevance
often compelled by political pressures to the neurological development of
to assume the role of mediator between children now and in the future.
public and corporate interests, rather Taking Our Children Back
than advocating on behalf of a safe, Out Of Harm鈥檚 Way
healthy environment. It is no surprise
We should not need to identify
that these agencies, thus compromised,
with certainty exactly how much and
are incapable of fully protecting the
through what mechanism a neurotoxic
health of our children.
pesticide impairs brain development
In the absence of public understand- before coming to the conclusion that
ing and involvement, critical decisions public health is not protected when the
regarding public health are likely to be urine of virtually every child in this
dictated by narrow special interests that country contains residues of these
have as a core concern neither public chemicals. We can become more
health nor the welfare of the economy discriminate in home use of pesticides
as a whole. These decisions should not and modify agricultural systems so that
be dictated by the special interests that we rely less on pesticides that are toxic
Burden of Proof
Consider a substance for which there is some
unknown threshold at which harm occurs. At any
given state of knowledge, there is an exposure that
"Prove Harm" has been proven to be harmful. This is the upper
curve in the figure.
Permitted Exposure
There is also an exposure level for which
injuries evidence of safety exists. This is the lower curve in
to health the figure.
occur If we decide to allow the regulatory process to
follow the upper curve, we will allow exposure
Actual
(but unknown)
until proof of harm accumulates. Then the exposure
Threshold
unnecessary level will be lowered to reflect the new evidence of
of Harm
precautions harm. This approach guarantees that health will be
harmed as knowledge is accumulated. If we decide
taken
that the regulatory process should follow the lower
"Prove Safety" curve, human health will be protected. As
knowledge of toxicity is gained, it may be found
that the standards can be relaxed.
100%
0% 20% 40% 60% 80%
Completeness of Knowledge
Fi A 08
Greater Boston Physicians for Social Responsibility 121
CHAPTER 8: Conclusion
opportunities to mitigate environmental
factors. Fifty years into the post war
chemical revolution, sufficient evidence
has accumulated to permit better
understanding of the hazards of chemical
exposure and the costs to human health.
Protecting children from harmful
exposures to environmental chemicals is
well within our grasp. Residual uncertain-
ties can not be an excuse for inaction
when the weight of evidence establishes
the likelihood of harm.
Many different disciplines bring
their own special expertise to bear
on understanding the origins of the
and ubiquitous in the environment.
developmental disabilities we have
We do not need to exhaustively
discussed. Toxicologists, epidemiologists,
understand the mechanism by which
Protecting
behavioral geneticists, psychologists,
methylmercury interferes with normal
children from
social workers, teachers, parents, and
harmful exposures fetal brain development before
health care providers each have
to environmental concluding that it is not acceptable for
important roles and responsibilities.
freshwater and many ocean fish to be
chemicals is well
within our grasp. sufficiently contaminated with mercury We hope this report will help empower
to threaten developing brains. We know them and everyone else who cares
about our young and vulnerable to
how to reduce the environmental
releases of mercury so that fish are once better understand the insidious risks
to children鈥檚 health that result from
again safe to eat regularly. We can
widespread, repetitive chemical
modify manufacturing practices so that
exposures. An informed and motivated
lead use in products goes steadily down
public is critical to freeing our public
instead of up. We can eliminate or
agencies from the influence of financial
modify outmoded technologies that
conflicts of interest. This will permit
produce the dioxin that contaminates
these agencies to exercise their intended
fetuses and breast milk. We know how
to do these things. What is often lacking role as guardians of public health and
strengthen democratic, participatory
is the political will to do them.
decision-making. In so doing, we can
Though we can do little about
restore a margin of safety for our current
genetic contributions to many of these
and future children, and take them back,
disorders, we have enormous
out of harm鈥檚 way.
122 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
APPENDIX: Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
Appendix
Clinical Spectrum of
Learning, Development and Behavior
Disorders: Selected Definitions
T he following learning, develop- learning disabilities may be an under- HISTORICAL
mental and behavioral disorders recognized risk factor in adolescent DEFINITIONS OF
LEARNING
suicide.4 Learning disabilities are often
represent a broad spectrum of cognitive,
DISORDERS (*)
motor, perceptual and behavioral disorders. referred to as hidden handicaps because
1861
They describe a set of complex and they frequently go undetected by Early studies of aphasia by
Broca (difficulty in producing
divergent disorders whose descriptions teachers, physicians and parents. or comprehending speech
have evolved/changed over time. The caused by brain damage
There are three definitions of rather than produced by
definitions used in this appendix will deafness or simple motor
learning disabilities worth noting. deficit). Stemmed from
largely reflect the current criteria as stated The first definition was incorporated observations of adults with
acquired brain damage.
in the Diagnostic and Statistical Manual by the National Advisory Committee 1877
of Mental Disorders IV (1994) published on Handicapped Children in 1968 Kussmaul proposed word
by the American Psychiatric Association. blindness (loss of ability to
and is used in the Education for All read).
Handicapped Children Act of 1975 1895-1917
Learning Disorders (formerly Congenital word blindness is
(PL-142). Another definition was used
Academic Skills Disorders) described as a congenital
by the Joint Committee on Learning defect occurring in children
with an otherwise normal or
The term 鈥渓earning disability鈥? Disabilities (NJCLD, 1981) and undamaged brain,
characterized by a disability
covers a variety of disorders in the modified by the Interagency Committee in learning to read.
areas of listening, speaking, reading, on Learning Disabilities (ICLD) in 1987. 1922-1925
math and reasoning. These disabilities Post-Influenzal Behavior
The last definition is described in the Syndrome: children were
interfere with a person鈥檚 ability to store, Diagnostic and Statistical Manual of observed to have a disorder
characterized by anti-social
process, or produce information. These Mental Disorders IV published by the behavior, irritability,
impulsiveness, emotional
difficulties are unexpected, given the American Psychiatric Association. lability, hyperactivity and
person鈥檚 general level of ability.1 As well learning problems. First time
The three definitions are listed below: that structural deficits
as primary difficulties with academics, involving certain parts of the
a.) The Education for All Handicapped central nervous system were
a learning disability can also result in related to behavioral
Children Act of 1975 (PL - 142) states problems. A diagnosis of
secondary problems in social and
that 鈥渢he term specific learning disability structural brain damage was
emotional areas.2 Studies have reported given to children who
means a disorder in one or more of the displayed behavioral and
that children with learning disabilities learning symptoms similar to
basic psychological processes involved in those found in post-
have been found to have lower self- influenzal encephalitis.
understanding or using language, spoken
concept, more anxiety and lower peer
or written, which may manifest itself in *Hagw. RA, Silver AA. Disorders
acceptance than normally-achieving of Learning in Childhood. John
an imperfect ability to listen, speak, read, Wiley and Sons, New York, 1990.
children.3 It has also been suggested that
Greater Boston Physicians for Social Responsibility 123
APPENDIX : Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
write, spell, or do mathematical c.) The Diagnostic and Statistical
HISTORICAL
calculations. The term includes such Manual of Mental Disorders (DSM IV,
DEFINITIONS
conditions as perceptual handicaps, brain 1994) is a manual for psychiatric
continued
injury, minimal brain function, dyslexia, diagnoses and classification of mental
1928
and developmental aphasia. Such terms disorders. The DSM IV provides a
Strephosymbolia: five
do not include children who have learning definition of a disorder and describes the
major symptom complexes:
developmental alexia,
difficulties which are primarily the result parameters within which a certain
writing disability,
developmental word
of visual, hearing, or motor handicaps, of diagnosis is made. Each disorder is
deafness, motor speech
delay and developmental
mental retardation, of emotional conceptualized as a clinically significant
apraxia. These syndromes
disturbance, or of environmental, behavioral or psychological syndrome or
represented a delay or
difficulty in establishing
cultural, or economic disadvantage鈥?.5 pattern that occurs in an individual. Each
cerebral dominance for
language function. The term
disorder is associated with distress (painful
for reading disability is b.) The National Joint Committee of
labeled strephosymbolia.
Learning Disabilities states that learning symptom) or disability (impairment in
1929
one or more important areas of functioning),
disabilities is a generic term that refers
Congenital Auditory
or with a significantly increased risk of
Imperception
to a heterogeneous group of disorders
1934
suffering death, pain, disability or an
manifested by significant difficulties in
Organic Driveness: a
important loss of freedom.7 In addition,
hyperkinetic behavior
the acquisition and use of listening,
disorder related to brain
speaking, reading, writing, reasoning, or the syndrome or pattern must be more
stem pathology.
mathematical abilities, or of social skills. than an expected or culturally-sanctioned
1941
Developmental Lag
response to an event.
These disorders are intrinsic to the
1943-1947
individual, presumed to be due to The DSM IV states that 鈥渓earning
Brain-Injured or Damaged
Child: described perceptual
central nervous system dysfunction, and disorders are diagnosed when the
differences between
retarded children whose
may occur across the life span. Problems individual achievement on individually
history suggested pre-, peri-
in self-regulatory behavior, social administered, standardized tests in
or postnatal brain injury and
those retarded children who
perception and social interaction may reading, mathematics, or written
did not have such histories.
Studies stressed the
exist with learning disabilities but do expression is substantially below that
importance of perceptual
functioning (auditory and
not in themselves constitute a learning expected for age, schooling, and level of
visual) in the diagnosis of
brain-injured children. disability. Learning disabilities may intelligence. The learning problems
Diagnosis of brain damage
occur concomitantly with other significantly interfere with academic
could be given based on the
presence of neuro-
handicapping conditions such as sensory achievement or activities of daily living
psychological disturbance in
perceptual or conceptual
impairment, mental retardation, social that require reading, mathematical, or
thinking.
and emotional disturbances, or with writing skills... Substantially below is
1947
socio-environmental influences such as usually defined as a discrepancy of more
Minimally Brain-Damaged
Child
cultural differences, insufficient or than two standard deviations between
1960
achievement and I.Q. (p.46).鈥?8 However,
inappropriate instruction, and psychogenic
Psychoneurological Learning
Disorders
a smaller discrepancy (between one and
factors. A learning disability may occur
1962
two standard deviations) is sometimes
concomitantly with an attention deficit
Term 鈥淟earning Disability鈥?
first defined by Kirk as a
used when another disorder or a general
disorder. Although all of these
substitute for labels such as
medical compromises the I.Q test.
handicapping conditions may cause
brain injured, perceptually
handicapped or minimal
learning problems, a learning disability
brain dysfunction.
The specific learning disorders listed
is not the direct result of these conditions.6 in the DSM IV are expressive language
124 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
APPENDIX: Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
disorder, mixed receptive-expressive with MR are three to four times more HISTORICAL
language disorder, phonological disorder, likely than the general population to DEFINITIONS
reading disorder, mathematics disorder, have another mental disorder. continued
disorder of written expression, and 鈥淢ental retardation has many
learning disorder not otherwise specified. different etiologies and may be seen as a 1962-1963
Minimal Brain Dysfunction
final common pathway of various
Developmental Delays (MBD): represented a
pathological processes that effect the syndrome of childhood and/
or behavioral problems
Mental Retardation (MR) functioning of the central nervous stemming from some form of
common but unknown brain
system (p.39).鈥?10 Mental retardation
The essential feature of mental dysfunction. Included in the
MBD diagnosis were children
may be associated with a general
retardation (MR), which affects whose basic symptoms were
medical condition (e.g., Down鈥檚 neuropsychological even
nearly 1% of the population, is a though no other evidence of
syndrome). According to the DSM IV,
significantly sub-average general damage to the brain was
reported by history of clinical
etiological factors may be primarily
intellectual functioning that is observation.
biological, psychosocial, a combination
accompanied by a significant limitation 1964
Developmental Dyslexia
of both, or unknown. DSM IV current
in daily adaptive functioning.9 Both of
1967-1968
estimates are that for approximately
these factors must be present for Specific Learning Disabilities
30% - 40% of mental retardation the defined
a diagnosis of mental retardation.
1969
cause is unknown, approximately 5% is
General intellectual functioning is First citation of specific
from heredity (inborn errors of
usually defined by I.Q. and is obtained 鈥淟earning Disabilities鈥?
(Public Law 91-230).
metabolism such as Tay-Sachs, single-
by administering one or more 1971
gene abnormalities such as tuberous
standardized, individually administered Psycholinguistic Learning
Disabilities
sclerosis, and chromosomal aberrations
intelligence tests such as the Weschler
1977
such as fragile x syndrome),
Intelligence Scale (children and adults), Learning Disabilities (Public
approximately 30% results from Law 94-142).
Stanford-Binet, etc. In order to be
1980
alterations of embryonic development
diagnosed as mentally retarded an Specific Developmental
including chromosomal changes or
individual must have an I.Q. of 70 or Disorders (Diagnostic and
Statistical Manual of
prenatal damage due to toxins (maternal
below, which is two standard deviations Mental Disorders -DSM-,
Third Edition). Describes
alcohol consumption, infections),
below the mean (average I.Q. is from disorders that are
approximately 10% is due to pregnancy characterized by inadequate
90-110). There are four different ranges development of specific
and prenatal problems (fetal
of mental retardation that reflect the academic, language,
speech, and motor skills
malnutrition, prematurity, hypoxia,
level of intellectual impairment. The not due to physical or
neurologic disorders, a
trauma, viral and other infections),
classifications are mild mental pervasive developmental
approximately 5% is due to general delay, mental retardation,
retardation (I.Q. 50 to 70 and the or educational deficits.
medical conditions acquired in infancy
largest segment of MR - 85%),
or childhood (infections, poisoning
moderate mental retardation (I.Q. 35 to
{lead}, and trauma, and approximately
50), severe mental retardation (I.Q. 20
15% to 20% is due to environmental
to 35), and profound mental retardation
influences and other mental disorders
(I.Q. below 20). The onset of mental
(deprivation of nurturance and of social,
retardation must occur before an
linguistic, and other stimulation and
individual is 18 years old. In addition,
severe mental disorders such as autism).
according to the DSM IV, individuals
Greater Boston Physicians for Social Responsibility 125
APPENDIX : Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
It is usually problems in adaptive Developmental Disorder not Otherwise
functioning (communication, self-care, Specified (used when the criteria are not
health, safety) and/or personal met for a specific PDD). These disorders
independence, rather than low I.Q., that are described briefly below:
identify an individual as mentally Autism
retarded. Examples of such difficulties
Autism prevalence rates are
may include problems handling personal
estimated to be 2 per 1,000 individuals,
finances, obtaining and keeping employ-
with males four to five times more likely
ment, managing issues related to hygiene,
to be autistic.11 12 Autism is a disorder of
health, and safety, and/or living indepen-
socialization, as it involves severe
dently (shopping, cleaning, etc.). Of
impairments in an individual鈥檚 ability to
course, as with any other disorder, the
relate to others in a reciprocal manner.13
severity of difficulties and different
In addition to problems in social and
personality and behavioral features
emotional reciprocity, individuals with
associated with mental retardation are
autism also have deficits in
on a continuum. For example, some
communication skills and often exhibit
individuals with mental retardation are
repetitive and purposeless behaviors such
passive and/or dependent, while others
as motor mannerisms (rocking back and
may be aggressive and/or impulsive. Also
forth). In most cases Autism is apparent
an individual with mental retardation
from very early childhood and is often
may be capable of limited employment,
accompanied by mental retardation
but have difficulties living independently,
(75%).14 Leo Kanner first described
while another individual with mental
autism in 1943. It probably is the most
retardation may be able to live independently
researched disorder of early childhood.
with outside supports but not be capable
Autism is sometimes referred to as early
of employment without supervision.
infantile autism, childhood autism, or
Kanner鈥檚 autism.15
Pervasive Developmental
Disorders (PDDs) According to the DSM IV, individuals
PDDs are characterized by severe and with autism have markedly abnormal or
pervasive impairments in several areas of impaired development in three areas:
social interactions, communications skills,
development including reciprocal social
interactions, communication skills, and/or and a restricted repertoire of activity and
the presence of stereotyped behavior. The interests with stereotyped patterns of
impairments are deviant from the individual鈥檚 behaviors, interests, and activities. In
developmental level or mental age. These order to be diagnosed with autism an
disorders may present differently for each individual must have a total of six
individual and they are on a continuum of problems in the above-mentioned areas,
with at least two problems in social
severity. The disorders, according to the
DSM IV, are Autistic Disorder, Asperger鈥檚 interactions, at least one problem in
communication skills, and one problem
Disorder, Rett鈥檚 Disorder, Childhood
with repetitive and stereotyped behaviors.
Disintegrative Disorder, and Pervasive
126 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
APPENDIX: Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
The impairments in social
interactions are gross and sustained.
According to the DSM IV, they are
evidenced by marked impairment in the
use of multiple nonverbal gestures (eye-
to-eye gaze, facial expression, body
postures, and ability to regulate social
interactions), failure to develop peer
relationships appropriate to develop-
mental age, lack of spontaneous seeking
to share enjoyment, interests, or
achievements, and lack of social and
emotional reciprocity. The impairments
abnormalities in the development of
in communication are evidenced by
cognitive skills. However, usually the
delay in, or lack of, the development of
development of cognitive skills is
spoken language (not accompanied by
uneven, regardless of the general level
attempts to compensate through other
of intelligence.
ways of communication like gestures
or mime), impairment in the ability to Manifestations of the disorder vary
initiate speech if an individual does greatly depending on the developmental
speak, stereotyped and repetitive use level and chronological age of the
of language, and a lack of varied and individual, and they may change over
spontaneous make believe play or time. For example, infants may exhibit a
social imitative play appropriate to failure to cuddle or failure to respond to
developmental level. The repetitive their parents鈥? voices, whereas a young
and stereotyped behavior is evidenced child may cling to an adult or essentially
by preoccupation with one or more treat the adult as if they were not there.
stereotyped and restricted patterns of An autistic person does have the
interest that are abnormal either in capacity for insight, and although
intensity or focus, inflexible adherence impaired in one area, he or she may
to specific, nonfunctional routines or have the cognitive and communicative
rituals, stereotyped and repetitive motor ability to hold a responsible job.17
mannerisms (hand or finger flapping or According to the DSM IV, those
twisting, complex body movements).16 with autism may exhibit a range of
According to the DSM IV, rates of behavioral symptoms including
the disorder are 4 to 5 times higher in hyperactivity, short attention span,
males but females are more likely to impassivity, aggressiveness, self-injurious
have more severe mental retardation. behaviors and temper tantrums. Also,
The onset of autism is prior to three additional symptoms may include odd
years of age typically with no periods of responses to sensory stimulation (high
normal development. Also, there may be threshold for pain, oversensitivity to
Greater Boston Physicians for Social Responsibility 127
APPENDIX : Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
sound or being touched). Those with diagnosed with Asperger鈥檚 syndrome may
autism may have eating disorders have problems with empathy and
(limiting food intake to particular modulation of social interactions.
foods), sleep disorders, abnormalities Difficulties in social interactions (not age-
in mood or affect (giggling or weeping appropriate) may become more apparent
for no reason), and/or lack a sense of at school age, along with the
danger or fear. Finally, autism is development of a fascination with
sometimes observed in association unusual topics and learning vast amounts
of factual information about them.21
with neurological or other general
medical conditions (encephalitis, Also, motor delays or motor clumsiness
phenylkentouria, tuberous sclerosis, may be observed in the preschool period.
fragile X syndrome, anoxia during According to the DSM IV, the condition
birth, maternal rubella). must cause clinically significant
impairment in social, occupational or
Asperger鈥檚 Syndrome
other areas of functioning. In addition,
Prevalence rates of Asperger鈥檚
those diagnosed with Asperger鈥檚
syndrome are estimated to be from 1 to 3
syndrome show no clinically significant
per 1000 school-age children, with boys
delays in language, cognitive
appearing to out number girls by 5:1 to
development, or age-appropriate self-help
15:1.18 Hans Asperger first described
skills, adaptive behaviors and curiosity
Asperger鈥檚 syndrome in 1944. It received
about the environment. Asperger鈥檚
its status as a syndrome in 1981.19 In
syndrome strictly represents problems in
contrast to autism, Asperger described a
social interactions.
condition he was observing as more of a
The DSM IV reports that there
personality style that gave individuals the
appears to be an increased frequency of
20
appearance of being eccentric or loners.
Asperger鈥檚 syndrome among family
He described a cluster of individuals,
labeled as autistic, who had normal I.Q.s, members of individuals who have the
disorder. Research has suggested a rather
less delayed speech problems, more
significant genetic component, with at
motor deficits and later onset. All his
least 50% of affected cases having a close
initial cases were male. Asperger鈥檚
relative with Asperger鈥檚.22
syndrome is currently a separate mental
health disorder at the higher functioning Asperger鈥檚 syndrome is sometimes
referred to as a social learning disability.23
end of the autistic continuum.
An adult or child with Asperger鈥檚
According to the DSM IV, to be
diagnosed with Asperger鈥檚 syndrome an syndrome would commonly exhibit the
individual must present with severe and following essential symptoms: a) poor
social interactions as evidenced by: a
sustained impairment in social
paucity of empathy; naive, inappropriate,
interaction and the development of
one-sided social interaction; little ability to
restricted, repetitive patterns of
form friendships; lack of appreciation of
behavior, interest and activities. Those
social cues, and consequent social
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APPENDIX: Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
isolation; b) poor nonverbal the understanding of Asperger鈥檚
communication (limited use of gesture, syndrome, more individuals are now not
clumsy/gauche body language; limited only being appropriately diagnosed, but
facial expression; inappropriate are also being identified earlier.
expression; peculiar, stiff gaze); c) Rett鈥檚 Disorder
absorption/preoccupation limited/narrow
According to the DSM IV, this
topics or with interests such as weather,
disorder is much less common than
facts about TV, etc., which are learned in
autism and has been reported only in
a rote fashion and reflect poor
females. The essential feature of Rett鈥檚
understanding, conveying the impression
Disorder is the development of multiple
of eccentricity. Associated features include
specific deficits following a period of
a) some language issues such as delayed
normal functioning after birth. Those
development; superficially perfect
with Rett鈥檚 have an apparently normal
expressive language; formal, pedantic
prenatal and perinatal development with
language; odd prosody; peculiar voice
normal psychomotor development
characterizations; impairment of
through the first 5 months after birth.
comprehension including misinter-
However, in the first or second year of
pretations of literal/implied meanings
life, and after a period of normal
and b) clumsy ill-coordinated movements
development, there is regression in
and postures.24
development, which is distinctive and
Until this decade adults and children significant. The disorder is usually
with Asperger鈥檚 syndrome did not come diagnosed prior to age 4. The
to the attention of mental health developmental regression is evidenced by
professionals, since they were regarded a deceleration of head growth between
as odd and even aloof, not perceived as five and 48 months, loss of previously
having a diagnosable mental disorder, or acquired purposeful hand movements
given some other diagnosis such as between five and 30 months with the
obsessive-compulsive, learning disabled, development of stereotyped hand
etc. It is easy to understand how movements (hand-wringing or hand
proficient verbal skills, adequate I.Q., washing), loss of social engagement
and a solitary life could easily mask the rather early (although often social
marked social problems of an adult with interaction develops later), appearance of
Asperger鈥檚 syndrome. Children were poorly coordinated gait or trunk movements,
even less likely to be diagnosed with and severely impaired expressive and
Asperger鈥檚 syndrome as the nature of the receptive language development with
social and emotional problems (delayed severe psychomotor retardation.
developmental milestones such as
The DSM IV reports the duration of
marriage and family) associated with
the disorder is lifelong and the loss of
Asperger鈥檚 syndrome made it more likely
skills is usually persistent and
that they would not be identified until
progressive. Recovery is very limited,
adulthood. With the advancements in
Greater Boston Physicians for Social Responsibility 129
APPENDIX : Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
although some individuals may make The DSM IV reports that in most
modest developmental gains. Rett鈥檚 cases, the onset of this disorder is
Disorder is usually associated with between ages three and four. Onset may
severe or profound mental retardation. be insidious or abrupt. Signs can include
increased activity levels, irritability, and
Childhood Disintegrative
anxiety followed by a loss of speech and
Disorder (CDD)
other skills. The disorder is lifelong.
According to the DSM IV, cases of
Limited improvement is unlikely, but
CDD appear to be very rare, more
may occur. Although it appears likely
common in males, and are usually
that the condition is the result of an
associated with severe mental
insult to developing nervous system, no
retardation. The essential feature of
precise mechanism has been identified.
childhood disintegrative disorder is a
regression in multiple areas of Behavioral Disorders
functioning after at least two years of
The DSM IV classifies two
apparently normal development as
childhood behavioral disorders,
evidenced by the presence of age-
Conduct Disorder and Oppositional
appropriate verbal and non-verbal
Defiant Disorder. Attention Deficit
communication, social relationships,
Hyperactivity Disorder (formerly called
play and adaptive behavior. After the
Attention Deficit Disorder), whose
first two years (but before age ten) there
symptoms may include both behavioral
is a clinically significant loss of
and cognitive problems, is also
previously acquired skills in at least two
described below.
of these areas: expressive or receptive
Attention Deficit Hyperactivity
language, social skills or adaptive
Disorder (ADHD)
behavior, bowel or bladder control,
play, or motor skills. Individuals with Attention Deficit Hyperactivity
this disorder demonstrate social Disorder (ADHD) is the most
problems (failure to develop peer commonly diagnosed childhood
relationships and lack of social or psychiatric disorder in the United
emotional reciprocity), communication States.25 Prevalence rates vary from less
problems (delay or lack of spoken than 1% to as much as 14% of the
language, inability to initiate or sustain school-age population depending on the
a conversation, stereotyped and study.26 Subsequent studies using more
repetitive use of language, lack of varied sophisticated methods report prevalence
make believe play), and behavioral rates of 6.7% to 9.5%.27 The DSM IV
problems (restricted, repetitive, and reports that prevalence rates are from
stereotyped patterns of behavior, 3%-5% of school age children with
interests, and activities, including prevalence data on adolescence and
motor stereotypes and mannerisms) adults more limited. The disorder is
usually observed in autism. more frequently diagnosed in males than
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APPENDIX: Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
in females, with male-to-female ratios level of development. The current
ranging from 4:1 to 9:1, depending on diagnostic criteria requires the
the setting (general population or demonstration of at least 6 symptoms of
clinics). It is very difficult to diagnosis either inattention or hyperactivity -
ADHD in children younger than four or impulsivity that were present before the
five years old because children that age of seven years (although many
young are not often in situations that individuals are diagnosed after the
require sustained attention. Also, it is a symptoms have been present for a
little more difficult to distinguish age- number of years). In addition, symptoms
inappropriate play from that of a must have persisted for more than six
normal overactive toddler. Therefore, months, manifested in two or more
ADHD is usually diagnosed in school- settings (school, home, work), and
aged children between the ages of six impair developmentally appropriate
and nine. In addition, more than 70% academic, social, or occupational
functioning.29 The symptoms usually get
of children diagnosed with ADHD
symptoms will continue to have worse in situations that require sustained
difficulties throughout adolescence attention (class, homework) and may be
and adulthood.28 absent or minimal when the person is in
a one-to-one situation, under strict
There are three subtypes of ADHD.
The first is Attention Deficit Hyperactivity control, or in a novel or especially
Disorder, Combined Type, which includes interesting situation.
six or more symptoms of inattention and The DSM IV states that inattention
six or more symptoms of hyperactivity- is demonstrated by failing to give close
impulsiveness. Second is Attention Deficit attention to details or making careless
Hyperactivity Disorder, Predominantly mistakes in school work or other
Inattentive Type, which includes six or activities. Inattention is also
more symptoms of inattention but fewer demonstrated by having difficulty
than six symptoms of hyperactivity- sustaining attention in tasks, play or
impulsiveness. Finally, there is Attention activity (homework or paperwork) and/
Deficit Hyperactivity Disorder, or finding it difficult to follow through
Predominantly Hyperactive-Impulsive on instructions or persist with tasks until
Type, which includes six or more they are completed. Other examples of
symptoms of hyperactivity-impulsiveness inattention include not listening,
but less than six of inattention. difficulty with organization, being easily
distracted by extraneous stimuli (car
According to the DSM IV, the
honking, background conversation),
essential feature of Attention Deficit
and/or being frequently forgetful in daily
Hyperactivity Disorder is a persistent
activities (missing appointments,
pattern of inattention and/or
forgetting to bring lunch). In social
hyperactivity-impulsivity that is more
situations, changing the flow or content
frequent and severe than is typically
observed in individuals at a comparable of the conversation, not keeping focused
Greater Boston Physicians for Social Responsibility 131
APPENDIX : Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
on the conversation, and/or not sequelae of an insult to the brain might
following the rules of games or activities include inattention, hyperactivity and
impulsivity.30 However, by the 1960s it
may evidence inattention.
became clear that in the large majority of
The DSM IV states that
cases ADHD revealed no evidence of any
hyperactivity is evidenced by fidgeting
(squirming in one鈥檚 seat or leaving one鈥檚 brain damage, but rather of the brain
not functioning the way it should. Over
seat when one is expected to remain
seated), excessive running or climbing in time, the concept of ADHD has
situations where it is inappropriate, and/ undergone many changes. The DSM - II
published in 1968 first described the
or difficulty playing or engaging in
leisure activities. Hyperactivity may also disorder as a 鈥渉yperkinetic reaction to
childhood鈥? and focused on excessive
be demonstrated by talking excessively
motor activity.31 The DSM - III published
and/or always appearing to be in
in 1980 focused on attention and
motion. As expected, the symptoms of
concentration and the distinction
hyperactivity vary with an individual鈥檚
between inattention without hyper-
age and developmental level. For
activity (ADD/noH) and ADD with
example, a toddler or preschooler with
hyperactivity (ADD/H). It also described
ADHD may be constantly on the go as
symptoms in three areas (inattention,
demonstrated by 鈥済etting into
impulsivity, and motor hyperactivity).
everything鈥?, darting back and forth,
The DSM - III - R eliminated the distinction
running through the house, or jumping
on furniture. School-aged children with between inattention, impulsivity, and
motor hyperactivity, and required the
ADHD, however, may have difficulty
presence of 8 out of 14 symptoms.
staying in their seat or sitting still.
During the past decade, there has
Impulsivity may look like impatience
been an increase in the diagnosis and
as evidenced by difficulty delaying
treatment of ADHD.32 Stimulants have
responses, blurting out answers before
been used to treat hyperactivity and
the questions have been completed,
inattention since the 1930s even though
difficulty awaiting one鈥檚 turn,
prior to the 1960s hyperactivity and
commenting out of turn, failing to listen
attention deficits were rarely noticed or
to directions, grabbing objects or
treated as a medical condition. 33 34
touching things they are not supposed
Stimulants work by increasing the
to, or clowning around. Impulsivity
production of dopamine and norepine-
may result in accidents (knocking over
phrine, two of the brain鈥檚 neurotransmitters
objects, running into people, grabbing
(messengers). The medications increase
something hot) or in more potentially
dangerous situations (running into traffic). nervous system alertness, thereby improving
attention and reducing restlessness.35
The concept of Attention Deficit
The use of stimulants to treat
Hyperactivity Disorder (ADHD) came
hyperactivity and attention deficits
from studies of brain damage where the
began to increase dramatically after the
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APPENDIX: Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
Food and Drug
Administration (FDA)
approved Ritalin for use in
children with behavioral
problems in 1961. Since 1971
the use of Ritalin has doubled
every 4 to 7 years.36 It has
been estimated that in 1975,
150,000 children in the
United States were being
prescribed drugs to reduce their impairment in social, academic, or
hyperactivity.37 By the late 1980s occupational functioning in a variety of
Ritalin was regularly used by about 1 settings (home, school, work). The onset
million children in the United States.38 of this disorder may occur as early as
It is estimated that the use of Ritalin has five or six years, but it usually diagnosed
increased from 2.5 times to 5 times in late childhood or early adolescence.
between 1990 and 1995.39 The The earlier the onset, the worse the
production of Ritalin has increased prognosis. Onset is rare after the age of
seven fold in the past eight years, with sixteen. The disorder is not diagnosed in
90% of it consumed in the United individuals over eighteen, as those over
States. 40 Although other medications, eighteen usually meet the criteria for an
such as Cylert and Dexedrine, are used antisocial personality disorder.
to treat ADHD, currently Ritalin is According to the DSM IV, the
prescribed as a treatment for ADHD in prevalence of the disorder appears to
about 90% of all cases.41 The U.S. have increased over the last decades and
Drug Enforcement Administration may be higher in urban than in rural
estimates that by the year 2000, 15% settings. Prevalence rates for males under
of school age children or an estimated 8 eighteen range from 6% to 16% and for
million children will use Ritalin.42 females from 2% to 9%. There are two
subtypes of this disorder, each of which
Conduct Disorder
can occur at a different level of severity
According to the DSM IV, the
essential feature of a conduct disorder is (mild, moderate, or severe). In addition,
the nature, developmental course, and
a repetitive and persistent pattern of
prognosis of the conduct problem differ
behavior in which the basic rights of
for the two subtypes. The first subtype,
others or major age-appropriate social
Childhood-Onset Type, occurs before the
norms or rules are violated. These
behaviors must have been present during age of ten and the individual must exhibit
one of the conduct problems presented
the past 12 months, with at least one
below. Individuals diagnosed with this
present in the past six months. In
type frequently display physical
addition, the behaviors must
aggression towards others, have disturbed
demonstrate clinically significant
Greater Boston Physicians for Social Responsibility 133
APPENDIX : Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
peer relationships, and are usually male. (鈥渃onning鈥? others), and/or stealing items
The second sub-type, Adolescent-Onset without confronting the victims
Type, is characterized by the absence of (shoplifting, forgery). Examples of
any symptoms before the age of ten serious violations of rules include
years. These individuals are less likely to staying out at night despite parental
exhibit aggressive behaviors, tend to have prohibitions (before age 13), running
more normal peer relationships, and are away from home at least twice, and
less likely to have these problems being truant at school (before age 13).
continue in adulthood. The ratio of males Children with a conduct disorder
to females is lower for this subtype. seem to have little empathy (little guilt
The DSM IV reports that the or remorse) for others and may
problematic behaviors of this disorder frequently misperceive the intentions of
fall into four main categories: aggression others as hostile or threatening. In
toward people or animals, destruction of addition, those with a conduct disorder
property, deceitfulness or theft, and/or may have a lower than average I.Q. and
serious violations of rules. The may be more likely to use illegal drugs,
aggressiveness must cause or threaten to have an earlier onset of sexual activity,
cause physical harm to other people or have difficulty with academics (i.e. a
animals. Examples of aggression include learning disorder, ADHD), and may
bullying, threatening or intimidating have lower self-esteem (higher suicide
others, initiating physical fights, and/or rates and attempts).
using a weapon that can cause serious Oppositional Defiant Disorder
physical harm to others (bat, knife, gun,
According to the DSM IV,
etc.). Additional examples of aggression
prevalence rates of ODD are estimated
include being physically cruel to people
to be from 2% to 16%, with males
or animals, stealing while confronting a
diagnosed more often before puberty
victim (mugging, extortion, robbery,
and males and females diagnosed at the
armed robbery), and/or forcing someone
same rate after puberty. According the
into sexual activity. The physical
DSM IV, the essential feature of
violence may take the form of rape,
oppositional defiant disorder is a
assault, or in rare cases homicide.
recurrent pattern of negativistic, defiant,
According to the DSM IV, examples disobedient, and hostile behavior toward
of destruction of property include authority figures that persists for at least
deliberately setting fires with the 6 months. Negative and defiant
intention of causing serious damage or behaviors include persistent
deliberately destroying other鈥檚 property stubbornness, resistance to directions,
(not including fire-setting). Deceitfulness and unwillingness to compromise or
or theft includes breaking into someone negotiate with adults or other children.
else鈥檚 house, building, or car, lying to get Defiance may include deliberate or
goods or favors to avoid obligations persistent testing of limits, usually by
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APPENDIX: Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
ignoring, arguing, or blaming others for doing things that will annoy others,
misdeeds. Hostility is evidenced by blaming others for their own mistakes
deliberately trying to annoy others or by or misbehaviors, being easily annoyed
verbal aggression. Onset of this disorder by others, being angry and resentful, or
is usually before eight and no later than being spiteful or vindictive. Behaviors
early adolescence. Onset is usually must occur more frequently than is
gradual, occurring over months and typical in those of comparable age or
years. Also, symptoms tend to first developmental level and must lead to
emerge in the home, with individuals the significant impairment in social,
child knows well, and the number of academic, or occupational functioning.
symptoms seems to increase with age. Children with this disorder often have
low self-esteem, mood lability, low
The DSM IV states that in order to
frustration tolerance, inappropriate
be diagnosed with oppositional defiant
language (swearing), and use of alcohol
disorder a child must exhibit at least
and drugs. ADHD and learning
four of the following behaviors: losing
disorders also tend to be associated
temper, arguing with adults, actively
with this disorder.
defying or refusing to comply with the
requests or rules of adults, deliberately
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In Harm鈥檚 Way:
APPENDIX: Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
Toxic Threats
to Child TOXICANTS
GENETICS
Development
A REPORT BY
Greater Boston Physicians
SOCIAL
for Social Responsibility ENVIRONMENT
Prepared for a Joint Project with
Clean Water Fund
Release date: May 2000
N early one in five (17%) children in the
United States has been diagnosed with one
or more developmental, learning or behavioral
disability. There is a growing consensus
Human development
Included in the report are:
that disorders including Attention Deficit
takes place within
Hyperactivity Disorder (ADHD) and autism
complex physical, 鈥? A 鈥減rimer鈥? on normal brain development,
are increasing in frequency. These
genetic, social and and how toxic chemicals can alter that
disorders have widespread societal
cultural environments. development
impacts, from health and education costs
The role of toxic 鈥? The spectrum of developmental disabilities
to the repercussions of criminal behavior.
chemicals deserves and their multiple causes, including genetics
Research demonstrates that pervasive
special scrutiny because and gene-environment interactions
substances such as mercury, lead, PCBs,
it is a preventable 鈥? Profiles of known and suspected
dioxins, pesticides, and others, are toxic to
cause of harm. developmental neurotoxicants
the developing child鈥檚 brain (neurotoxic.)
鈥? The scope of the chemical problem
Human exposure to neurotoxic substances is
global. Tests on humans show that these 鈥? And much more including charts, graphs,
chemicals now reside in our bones and other illustrations and 鈥渟potlight鈥? features on such
organs, blood, breast milk, sperm, fatty tissue and things as community activism around autism
urine. As our knowledge about the toxicity of and others
these chemicals has increased, the 鈥渟afe鈥?
threshold of exposure has been continuously
Don鈥檛 miss this groundbreaking new report
revised downward.
with a wealth of information for parents,
Human development takes place within educators, scientists, advocates, public health
complex physical, genetic, social and cultural and public policy professionals.
environments. This report examines the This report has been prepared as part of a joint education project
with Clean Water Fund. Funding has been provided by the John Merck
contribution of toxic chemicals to developmental,
Fund, the Jessie B. Cox Charitable Trust, the W. Alton Jones Foundation,
learning and behavioral disabilities. the Mitchell Kapor Foundation and the Alida R. Messinger Charitable
Lead Trust.
Note: We will make this report
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APPENDIX : Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
138 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
APPENDIX: Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
Greater Boston Physicians for Social Responsibility 139
APPENDIX : Clinical Spectrum of Learning, Development and Behavior Disorders: Selected Definitions
140 I N H A R M 鈥? S W A Y : To x i c T h r e a t s t o C h i l d D e v e l o p m e n t
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