Conflicting Views on Chemical Carcinogenesis Arising from the Design and Evaluation of Rodent Carcin

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Research | Mini-Monograph

Conflicting Views on Chemical Carcinogenesis Arising from the Design and

Evaluation of Rodent Carcinogenicity Studies

L. Melnick, a A. Thayer, and R. Bucher

National Institute of Environmental Health Sciences, National Institutes of

Health, Department of Health and Human Services, Research Triangle Park, North

Carolina, USA

Abstract

Conflicting views have been expressed frequently on assessments of human cancer

risk of environmental agents based on animal carcinogenicity data ; this is

primarily because of uncertainties associated with extrapolations of toxicologic

findings from studies in experimental animals to human circumstances. Underlying

these uncertainties are issues related to how experiments are designed, how

rigorously hypotheses are tested, and to what extent assertions extend beyond

actual findings. National and international health agencies regard

carcinogenicity findings in well-conducted experimental animal studies as

evidence of potential carcinogenic risk to humans.

Controversies arise when both positive and negative carcinogenicity data exist

for a specific agent or when incomplete mechanistic data suggest a possible

species difference in response. Issues of experimental design and evaluation

that might contribute to disparate results are addressed in this article.

To serve as reliable sources of data for the evaluation of the carcinogenic

potential of environmental agents, experimental studies must include a) animal

models that are sensitive to the end points under investigation ; detailed

characterization of the agent and the administered doses ; c) challenging doses

and durations of exposure (at least 2 years for rats and mice) ; d) sufficient

numbers of animals per dose group to be capable of detecting a true effect ; e)

multiple dose groups to allow characterization of dose–response relationships,

f) complete and peer-reviewed histopathologic evaluations ; and g) pairwise

comparisons and analyses of trends based on survival-adjusted tumor incidence.

Pharmacokinetic models and mechanistic hypotheses may provide insights into the

biological behavior of the agent ; however, they must be adequately tested

before being used to evaluate human cancer risk.

Key words: dose selection, maximally tolerated dose, mode of action, rodent

cancer bioassay, statistical power, tumor pathology. Environ Health Perspect

116:130–135 (2008) . doi:10.1289/ehp.9989 available via http://dx.doi.org/

[Online 7 November 2007]

http://www.ehponline.org/docs/2007/9989/abstract.html

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This article is part of the mini-monograph " Science for Regulation and

Litigation. "

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