Toxicity Testing in the 21st Century:
A Vision and a Strategy
Advances in molecular biology, biotechnology, and other fields are pav-
ing the way for major improvements in how scientists evaluate the health risks
posed by potentially toxic chemicals found at low levels in the environment. These
advances would make toxicity testing quicker, less expensive, and more directly
relevant to human exposures. They could also reduce the need for animal testing by
substituting more laboratory tests based on human cells. This National Research
Council report creates a far-reaching vision for the future of toxicity testing.
T
oxicity tests on laboratory effects at lower doses or exposures. Test
animals are conducted to animals are typically observed for overt
evaluate chemicals鈥攊ncluding signs of adverse health effects, which
medicines, food additives, and industrial, provide little information about biological
consumer, and agricultural chemicals鈥攆or changes leading to such health effects.
their potential to cause cancer, birth Often controversial uncertainty factors
defects, and other adverse health effects. must be applied to account for differences
Information from toxicity testing serves between test animals and humans. Finally,
as an important part of the basis for use of animals in testing is expensive and
public health and regulatory decisions time consuming, and it sometimes raises
concerning toxic chemicals. Current test ethical issues.
methods were developed Today, toxicological
incrementally over the evaluation of chemicals
past 50 to 60 years and is poised to take advan-
are conducted using tage of the on-going
laboratory animals, such revolution in biology
as rats and mice. Using and biotechnology. This
the results of animal revolution is making it
tests to predict human increasingly possible
health effects involves a to study the effects of
number of assumptions chemicals using cells,
and extrapolations that cellular components, and
remain controversial. tissues鈥攑referably of
Test animals are often human origin鈥攔ather
exposed to higher doses than whole animals.
than would be expected These powerful new
for typical human approaches should help
exposures, requiring to address a number of
assumptions about challenges facing the
How New Technologies Could Transform
field of toxicity testing. New tests should il-
Existing Approaches
luminate changes at the molecular level, helping
scientists to better predict how chemical expo-
A number of emerging fields and techniques
sures do or do not lead to certain health effects
are contributing major new insights for under-
and how they affect sensitive populations such
standing the biologic responses to chemicals in
as children. They should enable rapid screening
human tissues. For example, new high-through-
of chemicals, which could reduce the backlog
put techniques developed by the pharmaceutical
of the large number of industrial chemicals that
industry use efficient automated methods to test
have not yet been evaluated under the current
certain biologic activities of thousands of chemi-
testing system. They should also reduce animal
cals that used to be studied in animals.
use and suffering.
Emerging fields also include systems biology,
The U.S. Environmental Protection Agency
a powerful approach that uses computational
(EPA), recognizing that the time has come for
models and laboratory data to describe and
more innovative approaches to toxicity testing,
understand biologic systems as a whole and how
asked the National Research Council to develop
they operate. Another impor-
a long-range vision and a
tant field is bioinformatics,
strategy to advance toxicity
which applies computational
testing in the 21st Century.
techniques to vast amounts of
The committee鈥檚 report pres-
data to understand how cells
ents that vision.
and cell systems work.
Current System Has
Vision for the Future of
Resulted in Expensive
Toxicity Testing
Patchwork Approach
Systems biology, bioinfor-
Currently, companies
matics, and rapid assay tech-
seeking to register pesticides
nologies are helping scientists
or federal agencies evaluat-
to better understand how
ing industrial or consumer
cellular networks or pathways
chemicals carry out a series
in the human body carry out
of tests by exposing animals
normal functions that are key
to chemicals to screen for
to maintaining health. When
cancer, birth defects, and
important pathways are sig-
other adverse health effects.
nificantly altered by chemical
In the past, agencies have
exposures, they can cause adverse health effects.
typically responded to scientific advances mostly
But these effects only occur when exposures are
by altering animal-based toxicity tests or adding
of sufficient intensity or duration, or if they oc-
more animal tests鈥攕uch as studying offspring
cur in susceptible individuals or during sensitive
of exposed mothers鈥攖o existing toxicity-test-
life-stages.
ing regimens. That approach has led to a testing
The report envisions a new toxicity-testing
system that is lengthy and costly and that uses
system that relies mainly on understanding 鈥渢ox-
many animals. In combination with the various
icity pathways鈥濃?攖he cellular response pathways
legal authorities under which EPA operates, this
that can result in adverse health effects when
system has resulted in many toxicants not being
sufficiently perturbed. Such a system would
tested at all, despite potential human exposure
evaluate biologically significant alterations with-
to them鈥攅ven as other contaminants receive
out relying on studies of whole animals.
significant research attention and decades of
The key elements of the committee鈥檚 vision
scrutiny.
for the future of toxicity testing are identified in tion of biomonitoring data鈥攕urveying levels
Figure 1 below. The figure encompasses both of chemicals measured in human blood, hair
the assessment of toxicity pathways and 鈥渢ar- or other tissues鈥攊s emphasized. As testing is
geted testing,鈥? which is designed to clarify and developed and refined, other markers of human
refine information from toxicity pathway tests exposure, health effects, and susceptibility will
for use in chemical risk assessments. be identified that can aid public-health authori-
For the foreseeable future, some targeted ties in assessing and responding to chemicals of
testing in animals will need to continue, as it is concern in the environment.
not currently possible to sufficiently understand The report emphasizes the importance of
how chemicals are broken down in the body us- evaluating risk contexts鈥攃ommon decision-
ing tests in cells alone. These targeted tests will making scenarios鈥攆or which toxicity testing
complement the new rapid assays and ensure is being conducted. Some risk contexts require
the adequate evaluation of chemicals. rapid screening of thousands of environmen-
At the bottom of the figure, dose-response tal agents, while others require highly refined
and extrapolation modeling will enable the dose-response modeling for an individual
translation of cellular tests to whole human agent. Defining the risk context can often
systems. Specifically, the modeling will esti- reduce the need to proceed in a stepwise man-
mate environmental exposures that would lead ner from chemical characterization to testing
to significant perturbations of toxicity pathways to dose-response modeling, as set out in the
observed in the cellular tests. figure鈥攁 lengthy process some stakeholder
Population-based and human exposure data groups say has fallen short of addressing public
are also key elements of the vision. Collec- health and environmental problems in a timely
way.
Figure 1. The committee鈥檚 vision for toxicity testing is a process that can include chemical characterization, toxicity
testing, and dose-response and extrapolation modeling as part of broader agency decision-making.
cision-makers without clear guidance concern-
Achieving the Vision: Marshalling the Scien-
ing the potential risks they must address.
tific Community
To advance the science to realize these im-
provements, the committee recommends that a
The report concludes that substantial ben-
new institution be created to foster the kind of
efits will result from achieving the vision but
cross-disciplinary research that will be required
that it will require coordinated efforts and
to achieve the vision. The report says there
resources over the next several decades by sci-
would be far less chance of success within
entists from government, industry, universities,
a reasonable timeframe if the research were
consulting laboratories, and the public interest
dispersed among different locations and orga-
community. EPA has established a National
nizations without a core institute. Although re-
Center for Computational Toxicology that is
sources to support such an institution may seem
developing new software and methods for
limited and current testing practices engrained
predictive toxicology. The National Institute
in some sectors, using these new scientific tools
of Environmental Health Sciences, through the
to generate better information for decision-
National Toxicology Program鈥檚 Roadmap for
making will result in tangible environmental,
the Future has initiated a partnership with the
public-health, and economic benefits.
Chemical Genomics Center of the National In-
The field of toxicity testing is at a pivotal
stitutes of Health to develop and begin carrying
juncture. The vision described in the report
out high- and medium-throughput screening
has the potential not only to improve current
assays to test more chemicals in less time and
approaches, but to fundamentally transform
at less cost. Long-standing problems, such as
them by making them quicker, cheaper, more
the backlog of untested or insufficiently tested
scientific, and more responsive to existing and
chemicals, could be addressed while reducing
new challenges faced by environmental health
the time-, resource- and animal-intensive nature
authorities and the public.
of the current system that sometimes leaves de-
Committee on Toxicity Testing and Assessment of Environmental Agents: Daniel Krewski (Chair), Univer-
sity of Ottawa; Daniel Acosta, Jr., University of Cincinnati; Melvin Andersen, The Hamner Institutes for Health
Sciences; Henry Anderson, Wisconsin Division of Public Health; John Bailar III, University of Chicago;
Kim Boekelheide, Brown University; Robert Brent, Thomas Jefferson University; Gail Charnley, Health
Risk Strategies; Vivian Cheung, University of Pennsylvania; Sidney Green, Howard University; Karl Kelsey,
Harvard University; Nancy Kerkvliet, Oregon State University; Abby Li, Exponent, Inc.; Lawrence McCray,
Massachusetts Institute of Technology; Otto Meyer, The National Food Institute; D. Reid Patterson, Reid
Patterson Conculting; William Pennie, Pfizer, Inc.; Robert Scala, Exxon Biomedical Sciences (retired); Gina
Solomon, Natural Resources Defense Council; Martin Stephens, The Humane Society of the United States;
James Yager, Johns Hopkins University; Lauren Zeise, California Environmental Protection Agency. The
project director was Ellen Mantus.
This report brief was prepared by the National Research Council based on the committee鈥檚
report. For more information or copies, contact the Board on Environmental Studies and
Toxicology at (202) 334-3060 or visit http://nationalacademies.org/best. Copies of Toxicity Testing
in the Twenty-first Century: A Vision and a Strategy are available from the National Academies
Press, 500 Fifth Street, NW, Washington, D.C. 20001; (800) 624-6242; www.nap.edu.
This study was supported by funds from the U.S. Environmental Protection Agency.
Permission granted to reproduce this brief in its entirety with no additions or alterations.
漏 2007 The National Academy of Sciences
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