IMPLICATIONS OF ARSENIC GENOTOXICITY FOR DOSE-RESPONSE OF CARCINOGENIC EFFECTS

Epidemiological data relating arsenic ingestion and skin and internal cancers strongly suggest a sublinear or threshold relationship. Physio logical saturation of methylation-based arsenic detoxification has bee n proposed as one explanation for a sublinear response. We have evalua ted the molecular bases for sublinearity in Light of new data and hypo theses regarding arsenic genotoxicity and chemical carcinogenesis. A r eview of the dose-response relationships observed in arsenic genotoxic ity assays is presented. With the exception of sister chromatid exchan ges, sublinear dose-response relationships for arsenic-induced chromos omal aberrations were observed repeatedly in different mammalian and h uman cell systems. Arsenic also enhanced the clastogenicity and mutage nicity of other DNA damaging agents with a sublinear dose response. Co nsistent with the dose response of arsenic-induced genetic alterations , arsenic also inhibited DNA ligases I and II, enzymes which play a ro le in DNA repair, with a sublinear dose response. In some cases, prote ctive effects of relatively low exposures to arsenic have been observe d, again consistent with sublinearity. We discuss recent theories on t he mechanism of arsenic carcinogenicity and the potential implications for dose-response modeling and risk assessment. Overall, based on ava ilable arsenic genotoxicity data, we conclude that it is likely that a rsenic indirectly induces genetic damage with a sublinear dose respons e in humans, thus providing a biological basis for a sublinear dose-re sponse relationship for human cancer. Furthermore, these results sugge st that linear dose-response modeling from populations experiencing hi gh arsenic exposures is likely to overpredict cancer risks at relative ly low arsenic levels. (C) 1996 Academic Press, Inc.