Carcinogenesis and Carcinogens that are also Genotoxic

Abstract

The definition of a carcinogen in an experimental context is an agent which increases the incidence of any neoplasm irrespective of whether it is lethal, potentially lethal or benign. As genetic factors are fundamental in carcinogenesis these are briefly reviewed. A description of some of the problems associated with carcinogenicity experiments and the interpretation of their results is presented. Particular emphasis is given to so-called genotoxic carcinogens. ‘So-called’ because there are unresolved difficulties in defining the weight and strength of evidence required for concluding that genotoxicity is indeed the mode of carcinogenic action (MOA), rather than simply concluding that the MOA is unknown. A genotoxic MOA that is based on reactivity with DNA may lead currently to the unverifiable and therefore counter-scientific default assumption that there is no dose without an effect on cancer incidence. Carcinogenicity test design, including the use of the maximum tolerated dose, is briefly discussed. This is followed by consideration of issues and challenges presented in the interpretation of results by the basic pathology, the grouping of tumours for statistical analysis, the use and abuse of historical control data, interpretation of high-dose effects, the use of transgenic animals and the identification of noncarcinogens. Finally, division of the roles of risk assessors and risk managers is outlined. Keywords: carcinogen; carcinogenesis; chemical; dose; false positive; genotoxic; historical control; maximum tolerated; metabolism; mouse; nongenotoxic; noncarcinogen; oncogene; pathology; rat; risk; statistic; transgenic