Significant differences can exist between the metabolic fate of chemicals in the human body and their metabolism during laboratory studies (both in test animals and in vitro), an inconsistency that poses challenges in the hazard and risk assessment process if a human metabolite of possible genotoxic concern is identified. Scientists from two US pharmaceutical companies have now proposed a new approach to this problem that incorporates quantitative ADME data (on absorption, distribution, metabolism and excretion) in humans and rodents such that exposures to a metabolite of genotoxic concern can be estimated at specified doses of the parent compound. “The exposures are then applied to the risk assessment framework, based on known cancer potencies, that allows one to understand the probability of a known or suspect genotoxic metabolite posing a carcinogenic risk in excess of 1 in 100,000” (Dobo K.L. et al., Chemical Research in Toxicology 2009, 22(2), 348; http://dx.doi.org/10.1021/tx8004339) {181366}. Possibly not a good read for the faint-hearted, but if undaunted by this paper, you may wish to browse through other publications appearing in the same special journal issue (No. 2) focussing on human metabolites in safety testing (see http://pubs.acs.org/toc/crtoec/22/2).

The above item was taken from the May 2009 issue of Toxicology and Regulatory News which is sent automatically to members of bibra (click here for more details).

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