Conflicting Views on Chemical Carcinogenesis Arising from the Design and Evaluation of Rodent Carcinogenicity Studies
Melnick, Ronald L., Thayer, Kristina A., Bucher, John R., Environmental Health Perspectives
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; b) 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].
Over the past several years, problems related to conflicts of interest in peer review have received considerable attention in the scientific literature and national press (Harris and Berenson 2005; Steinbrook 2005; Waldman 2005). In response, several scientific journals and international agencies overseeing expert scientific review panels have added stringent rules to reveal real or apparent financial conflicts of interest by individuals or commercial entities (Cogliano et al. 2004). The determination of a real or apparent conflict of interest may result in limitation or disqualification of individuals from participation on expert panels.
In contrast to these circumstances, conflicts of interest are an inherent component of science-based litigation and generally include presentations and interpretations of studies that are fashioned to appear consistent and favorable with the position of the sponsor. This situation puts an enormous burden on judges and juries, forcing them to wade through disguised biases in order to decipher assertions from facts. Because of uncertainties in extrapolations of toxicologic findings from studies in experimental animals to human risk and uncertainties in the costs associated with reduction or elimination of human exposures to those agents, numerous conflicts have arisen and continue to arise over the reliability of identified health effects of specific substances. In one view, precautionary health measures to prevent disease are advocated in spite of uncertainties of the magnitude of potential human risks, whereas the alternative perspective argues that additional costs for exposure reduction are not warranted until adverse health effects are clearly demonstrated in humans. Conflicting views on the relative importance of toxicologic research seem to originate largely from concerns of predictability and impacts on human health risks versus impacts on costs and profits. …