BMJ 2005;331:E389-E391 (15 October), doi:10.1136/bmj.331.7521.E389
BMJ USA October 2005 Animal tests yield misleading results.
Which drugs cause cancer?
FOR Despite President Nixon's War on Cancer, launched in 1971, and
billions of dollars spent since then, cancer remains the second-leading
killer of Americans. Around 40% of us will get cancer, and half of us will
die from it.1 This cease-less tide of human suffering starkly questions the
effectiveness of our strategies, including the accuracy of our methods for
identifying human carcinogens.
Millions of laboratory animals have been sacrificed for this purpose.
Thousands of chemicals, including ever-increasing numbers of therapeutic
drugs, are consequently described as potentially carcinogenic. Yet, are
animal experiments really predictive of human carcinogenicity?
The agency most responsible for protecting Americans from environmental
contaminants is the Environmental Protection Agency (EPA), and the chemicals
of greatest public health concern are described within its Integrated Risk
Information System (IRIS) toxic chemicals database. We recently surveyed
this database to assess the human utility of animal carcinogenicity data.
Most chemicals lack human exposure data and possess only animal
carcinogenicity data. In the majority of cases, however-58.1% (93/160)-we
found that the EPA considered the animal data inadequate to support the
useful human carcinogenicity classifications of probable carcinogen or
But at least the animal data were predictive for 42% of chemicals. Or
were they? A comparison of EPA carcinogenicity classifications with those
assigned by the World Health Organization's International Agency for
Research on Cancer (IARC) yielded disturbing results. For the 128 chemicals
with human or animal data assessed by both agencies, human carcinogenicity
classifications were similar only for those 17 possessing significant human
data. For the 111 primarily reliant on animal data, the EPA was far likelier
than the IARC to assign carcinogenicity classifications indicative of
greater human risk.2
The IARC is widely recognized as the world's leading authority on
carcinogenicity assessments. Such profound differences in carcinogenicity
classifications of identical chemicals between the IARC and the EPA appear
to indicate that in the absence of human data the EPA is over-reliant on
animal carcinogenicity data. Consequently, the EPA tends to over-predict
carcinogenic risk. The questionable reliability of EPA carcinogenicity
assessments was also the topic of a 2000 Congressional investigation.3 It
concluded that despite being advertised as quantitative, science-based
classifications, some were, in fact, more grounded in EPA policy favoring
classifications indicative of greater human risk.
No agency responsible for protecting public health is ever likely to be
sued for excessive caution. As every medical professional is acutely aware,
however, the converse in the case of medical mishap is not true. One cannot
help but sympathize with the concerns of EPA policy-makers in the world's
most litigious nation. Nevertheless, the resultant EPA carcinogenicity
classifications cannot be regarded as generally correct.
On the face of it, the EPA's heavy reliance on animal carcinogenicity
tests seems understandable. There is a longstanding tradition of animal
testing, and virtually all human carcinogens, when tested in sufficient
animal species, have generated positive results.4 However, if enough animal
testing is conducted, it appears that carcinogenesis will eventually occur
in some species regardless of human risk. Of 20 human non-carcinogens
studied in animals, 19 produced carcinogenic effects.5
The problem with animal carcinogenicity tests is not their lack of
sensitivity for human carcinogens, but rather their lack of human
specificity. A positive result has poor predictive value for humans. Reasons
for this include the predisposition of chronic high-dose bioassays for
false-positive results due to the overwhelming of natural tissue repair
mechanisms, and the unnatural elevation of cell division rates during ad
libitum feeding studies.6 Such factors render accurate extrapolation from
animals to humans virtually impossible.
The protracted time frames of animal carcinogenicity studies, and their
substantial drain on human, financial, and animal resources, present other
important disadvantages. Standard rodent bioassays take at least three years
to plan, execute, and interpret.7 They have cost hundreds of millions of
dollars8 and have consumed millions of skilled personnel hours.9 They also
account for many of the animals reported to be experiencing the highest
levels of pain and distress in laboratories.10 Modern alternatives exist,
such as quantitative structure-activity relationship (computerized) expert
systems, which predict biological activity based on chemical structure;
enhanced in vitro assays; and cDNA microarrays, which allow detection of
genetic expression changes long before the development of macroscopic
These methods have the potential to yield superior human specificity
results, in greatly reduced time frames, with greatly reduced demands on
financial, personnel, and animal resources.11
Inexplicably, however, regulatory agencies have been frustratingly slow
to accept modernized testing protocols. With some 400 new drugs now
introduced annually,12 a radical rethinking of our reliance on prolonged
animal testing is required. The development and implementation of rapid and
predictive non-animal assays will minimize cancer losses to society, and
might even restore our faith in the accuracy of the neoplastic warnings
metastasizing throughout our medical formularies.
Andrew Knight, research scientist1, Jarrod Bailey, medical scientist2,
Jonathan Balcombe, research scientist3
1 Animal Consultants International 91 Vanbrugh Court Wincott St London
SE11 4NR, UK,
2 School of Population and Health Sciences University of Newcastle upon
3 Physicians Committee for Responsible Medicine Washington, DC
Correspondence to: A Knight
Competing interests: None declared.
For and against Cancer bioassays William H Farland, chief scientist1,
Bruce Rodan, medical officer (research)1, Peter Preuss, office of research
1 US Environmental Protection Agency Washington, DC Correspondence to:
Informing public health decisions on environmental risks
AGAINST Cancer is a consequence of natural biological processes as well
as potentially being caused or exacerbated by drugs and environmental
chemicals. To perform its public health role regarding potential
environmental carcinogens, the US Environmental Protection Agency (EPA) must
make timely decisions based on available epidemiological, animal, and
mechanistic information. Cancer bioassays with rats and mice remain a
valuable source of data, particularly studies conducted by the National
Toxicology Program under the National Cancer Institute (NCI-NTP) of the US
Department of Health and Human Services (DHHS). Although we recognize the
concerns and sentiments expressed by Knight and colleagues, these opinions
misrepresent EPA's Integrated Risk Information System (IRIS) program, the
value to public health of the cancer bioassay, and the current inability of
alternative laboratory techniques to substitute for cancer bioassays in
human risk evaluations.
EPA is among a number of federal, state, and international organizations
that generate or use cancer bioassay information, including the DHHS with
their Report on Carcinogens, the Food and Drug Administration, the
Occupational Safety and Health Administration, and the World Health
Organization's (IARC) cancer monographs. Bioassay information is included in
EPA's cancer weight of the evidence evaluation of the full array of human,
animal, and mechanistic data, as detailed in the recently published EPA
Guidelines for Carcinogen Risk Assessment.1
Supported by extensive scientific peer review, these guidelines advance
cancer risk assessment methods by moving beyond EPA's previous alphanumeric
cancer classifications to a narrative paragraph with standard descriptors.
The narrative format permits consideration of routes and nature of exposure,
accompanied by a mode of action evaluation of the relevance to humans of
tumors seen in bioassays.
EPA's primary consideration in cancer risk assessment remains the
evaluation of available epidemiological studies, although adequate
epidemiological information is often limited. In addition, epidemiology is
inherently a retrospective science.
Rather than wait for cancer to be demonstrated among exposed humans,
federal agencies proactively use in vivo animal, in vitro, and computer
modeling methods to inform decisions on the prodigious numbers of chemicals
in modern commerce.
EPA's IRIS program serves as a principal source for qualitative and
quantitative hazard characterization and dose-response assessments of these
environmental pollutants. Contrary to the assertion by Knight et al of
negative conclusions from a Congressional investigation, the referenced
independent contractor and Science Advisory Board review spoke to the
usefulness of IRIS for public health and risk assessment, contemporary
quality advances, and ways in which IRIS documentation can be improved.2
The report by Knight et al of "profound" differences when comparing EPA's
IRIS Web site with IARC cancer classifications is also puzzling. The
scientific community, through direct participation and/or independent peer
review, is involved in all cancer hazard characterizations made by EPA, DHHS,
and IARC. The conclusions of these organizations have generally been in
reasonable concurrence, subject to procedural and timing differences.
Unfortunately, the three central references upon which the Knight et al
commentary is based are all unpublished self-citations, which were not
available on request beyond abstracts.
Every known human carcinogen has tested positive in laboratory animals,
and for almost one third of these the bioassay was the first indication of
carcinogenic hazard, including aflatoxins, asbestos, diethylstilbestrol, and
many others.3,4 Rall5 concludes that reports of high positive rates ( 50%)
in early NCI-NTP bioassays were due to targeting of suspected carcinogens,
accompanied by the use of any positive finding as the standard, irrespective
of the strength of association.
Rall's analysis actually concludes that only 7-12% of later NTP
bioassays of chemicals selected on the basis of human exposure potential are
positive under more generally accepted standards.
The Knight et al assertion regarding the poor predictive value of the
bioassay fails to fully convey the analyses in the listed citations.
Referencing these calculations as sensitivity or specificity is also
troubling, absent a gold standard for separating genuine human carcinogens
from non-carcinogens. Given these facts, the assertion that EPA and other
public health agencies are over-predicting human risk should be viewed
Cancer bioassays at US federal facilities must be conducted consistent
with the Animal Welfare Act (7 US C et seq) and rigorous institutional
animal care policies.6,7 The reference by Knight et al to these animals
"experiencing the highest levels of pain and distress in laboratories" is
not reflective of typical test conditions, nor, indeed, is there any mention
of chronic cancer bioassay testing in the cited reference, which excluded
rats and mice from the analysis.8
In providing the above response to Knight et al, our intent is to clarify
the relative merits of the cancer bioassay to inform public health
protection in a weight of evidence framework. We agree that more efficient
test methods are needed. In addition to US federal efforts toward
development of alternative toxicological methods,9 EPA has also created a
National Center for Computational Toxicology to develop methods to
incorporate expanding toxicogenomic and proteomic information into the risk
Cancer is a multisite, multifactorial process of still unknown
mechanistic etiology. The cancer bioassay addresses this in a whole system
model. The additional data obtained from alternative test methods can and do
contribute to the weight-of-evidence cancer evaluations in EPA's IRIS
program, but none of them obviates the continuing need to include bioassay
results in evaluating environmental pollutants for the purpose of protecting
Competing interests: None.
Disclaimer: The views expressed in this commentary are those of the
authors and do not reflect US Environmental Protection Agency policy.
US Environmental Protection Agency. Guidelines for carcinogen risk
assessment. EPA/630/P-03/001F, March 2005.
Versar Inc, 2000. Characterization of data uncertainty and variability in
IRIS assessments, pre-pilot vs pilot/post-pilot.
Huff J. Long-term chemical carcinogenesis bioassays predict human cancer
hazards. Issues, controversies, and uncertainties.
Ann NY Acad Sci 1999;895: 56-79.[Abstract/Free Full Text]
Maronpot RR, Flake G, Huff J. Relevance of animal carcinogenesis findings
to human cancer predictions and prevention. Toxicol Pathol 2004;32(Suppl 1):
Rall DP. Laboratory animal tests and human cancer. Drug Metab Rev
2000;32(2): 119-128.[CrossRef][ISI] NRC. Guide for the care and use of
laboratory animals. Institute for Laboratory Animal Research. National
Academies Press. 1996.
NIH. NIH Office of Animal Care and Use.
Stephens ML, Mendoza P, Weaver A, Hamilton T. Unrelieved pain and
distress in animals: an analysis of USDA data on experimental procedures. J
App Animal Welfare Science 1998;1(1): 15-26.
ICCVAM/NICEATM. The Interagency Coordinating Committee on the Validation
of Alternative Methods/The National Toxicology Program Interagency Center
for the Evaluation of Alternative Toxicological Methods. National Institute
of Environmental Health Sciences.
National Center for Computational Toxicology.
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