Genetic factors in toxicology: implications for toxicological screening

Methods of assessing the toxicity of xenobiotics have improved substantially during the last decade. However, as compounds become generally safer, the problem of individual variation in response assumes increasing relative importance. Environmental factors such as age, health and nutritional status, and interactions with other xenobiotics account for some of this variation, but genetic differences between individuals and races have important implications. In a few cases, Mendelian loci which control drug susceptibility (e.g., to isoniazid) have been described. However, in most cases the exact mode of inheritance has not yet been determined due to the problems of carrying out genetic studies in man. It is well established that many loci that are polymorphic in man are also so in laboratory animals, so much of this genetic variation should be picked up in preclinical screening, and could be used to more accurately predict potential variation in toxicity in man. Unfortunately, most toxicologists use only a single stock of laboratory animals, which does not show whether the response to a given xenobiotic is under genetic control. The design of animal tests would be improved by using more than one strain of genetically defined animals, and by paying more attention to genetic variation in responses to xenobiotics, both in animals and man.