Paul White - How Much Is Too Much? The Shifting Paradigm for Genetic Toxicity Assessment

Paul White, Environmental Health Science & Research Bureau, Health Canada, Ottawa, ON, Canada

Interpretations of genotoxicity test results have traditionally been restricted to hazard identification (i.e., dichotomous screen and bin). This qualitative data interpretation paradigm is predicated on three main assumptions: exogenous genotoxic substances are rare, there are no safe levels of genotoxic substances, genotoxicity can only be used to identify potential carcinogens (i.e., genetic toxicity is not a bona fide toxicological endpoint).
These assumptions are now being reconsidered. Exposures to a variety of exogenous mutagens (e.g., natural substances in foods) have been well documented. Numerous studies have illustrated how compensatory responses (e.g., DNA repair) can dramatically affect in vivo dose-response patterns; indicating that exposure limits associated with negligible human risk can be defined. Several authoritative organizations have noted that genetic damage induced by exogenous agents can be manifested as a variety of adverse health effects. Consequently, a paradigm shift is now advocating use of quantitative methods to analyse and interpret genetic toxicity dose-response data. For example, the Benchmark Dose approach has been employed to analyse in vitro and in vivo dose-response datasets; the results being employed for compound potency ranking, examinations of
covariates related to cell type, tissue, and sampling time, and determinations of PoD (point of departure) values for risk assessment and regulatory decision-making. Case studies of noteworthy mutagens in food, pharmaceutical products and occupational settings are currently underway. The analyses collectively demonstrate the utility of quantitative dose-response analyses for regulatory assessments of genotoxic substances, particularly ubiquitous substances that have never been tested for carcinogenic activity

Keywords: EMGS History, Risk assessment, Thresholds