Experimental approaches to the determination of genetic variability

Toxicology is concerned with the interaction between xenobiotics and biological molecules directly or indirectly coded in the DNA, and can be regarded as a branch of genetics. There is genetic variation in these interactions, which has important implications for risk assessment and because it can be used as a tool in studying toxic mechanisms. The genetics of susceptibility can be studied by forward or reverse genetics. Forward genetics involves working from an observed phenotype such as susceptibility to a particular xenobiotic and identifying the susceptibility genes. Often, this involves mapping and identifying quantitative trait loci, as most toxic responses have a polygenic mode of inheritance. The use of inbred strains is almost essential. Reverse genetics involves starting with a known genetic polymorphism and determining its effects on the response to xenobiotics. Studies of 'knockout' animals are a good example, although there are many naturally occurring polymorphisms that may affect toxic responses. In both cases, care has to be taken to ensure that the genetic background is carefully controlled in any comparison between animals thought to be carrying susceptible and resistant alleles.