Mechanisms of non-genotoxic carcinogens and importance of a weight of evidence approach.

It is well established that cancer is a multi-step process which involves initiation, promotion and progression. Chemical carcinogens can alter any of these processes to induce their carcinogenic effects. The presence of multiple mutations in critical genes is a distinctive feature of cancer cells and supports the contention that cancer arises through the accumulation of irreversible DNA damage. In the majority of instances, chemical carcinogens, directly or after xenobiotic metabolism, induce DNA damage and act in a 'genotoxic' manner. There is, however, a group of carcinogens that induce cancer via non-genotoxic mechanisms. Non-genotoxic carcinogens have been shown to act as tumor promoters (1,4-dichlorobenzene), endocrine-modifiers (17beta-estradiol), receptor-mediators (2,3,7,8-tetrachlorodibenzo-p-dioxin), immunosuppressants (cyclosporine) or inducers of tissue-specific toxicity and inflammatory responses (metals such as arsenic and beryllium). The diversity of modes of action of non-genotoxic carcinogens, the tissue and species specificity, and the absence of genotoxicity makes predicting their carcinogenic potential extremely challenging. In order to better understand the mechanisms of known human non-genotoxic carcinogens and to illustrate the importance of a weight of evidence approach when evaluating their carcinogenic potential, we will (1) evaluate the proportion of non-genotoxic carcinogens among known, probable and possible human carcinogens classified by the International Agency for Research on Cancer (IARC), (2) estimate the risk of exposure of human non-genotoxic carcinogens through margin of exposure (MOE) evaluation, and (3) discuss potential alternative methods for their detection. Our analysis demonstrated that human non-genotoxic carcinogens were present in 12% (45/371) of IARC's Groups 1, 2A and 2B carcinogens and that a potential hazard was associated with 27% (12/45) of them. Consequently, it is suggested that for all genotoxic chemicals, the mode of action is investigated for hazard and risk evaluation. Further, if negative genotoxic compounds have putative non-genotoxic modes of action, appropriate risk measures should be implemented.