The complementary roles of in vitro and in vivo tests in genetic toxicology assessment

Risk of genetic alteration (genetic toxicity) in humans as a consequence of exposure to exogenous agents is determined in large degree by the results of specific laboratory tests. Although the individual test procedures are uniform and standardized, there is often confusion when effects observed in vitro are not confirmed in vivo. This in vitro/in vivo difference is commonly misrepresented as demonstrating the insensitivity of in vivo genetic toxicology tests. Consideration of the mechanistic bases of the tests leads to a more rational interpretation: In vitro procedures, by avoiding pharmacokinetic limitations and many confounding interactions, are best able to detect the potential for an agent to affect genetic fidelity, while in vivo procedures, specifically because they are influenced by pharmacokinetics and competing reactions, are more suitable for determining the probability of genetic alterations occurring in an intact, dynamic organism. Expectations that in vivo test results should always confirm in vitro findings are unwarranted, as are comparisons of perceived sensitivities for detecting genetic toxicity. Human risk estimation should be based principally on the results of in vivo genetic toxicology tests, as is the case with other, nongenetic endpoints, and the in vivo tests must be sufficiently vigorous to detect genetic injury, including substantiation of the relevancy of the target cells monitored and documentation of their exposure. In contrast, the primary role of in vitro tests should be to guide in the design and selection of in vivo tests, as well as to assist in their interpretation and assessment of adequacy.