THE COMPLEMENTARY ROLES OF IN-VITRO AND IN-VIVO TESTS IN GENETIC TOXICOLOGY ASSESSMENT

Risk of genetic alteration (genetic toxicity) in humans as a consequen ce of exposure to exogenous agents is determined in large degree by th e results of specific laboratory tests. Although the individual test p rocedures 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 insens itivity of in vivo genetic toxicology tests. Consideration of the mech anistic bases of the tests leads to a more rational interpretation: li t vitro procedures, by avoiding pharmacokinetic limitations and many c onfounding interactions, are best able to detect the potential for an agent to affect genetic fidelity, while in vivo procedures, specifical ly because they are influenced by pharmacokinetics and competing react ions, are more suitable for determining the probability of genetic alt erations occurring in an intact, dynamic organism. Expectations that i n vivo test results should always confirm in vitro findings are unwarr anted, as are comparisons of perceived sensitivities for detecting gen etic toxicity. Human risk estimation should be based principally on th e results of in vivo genetic toxicology tests, as is the case with oth er, nongenetic endpoints, and the in vivo tests must be sufficiently v igorous to detect genetic injury, including substantiation of the rele vancy of the target cells monitored and documentation of their exposur e. 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. (C) 1995 Academic Pre ss, Inc.