A Review of Analytical Methods

For xenobiotics and their metabolites which form readily reversible interactions with target sites for toxicity (e.g. receptors), the peak level of unbound cornpound present in the immediate vicinity of the target site should be directly related to the biological response over a considerable concentration range. In contrast, for chemicals which form rather stable ligands to their target, including very reactive xenobiotics and their metabolites, the amount of compound present over a period of time is often more important than the peak level. For a number of compounds, a direct correlation between total covalent binding to cellular proteins and the extent of hepatocellular necrosis has been established. Similarly, for several carcinogens, DNA alkylation has been shown to be directly related to their carcinogenic potency, although in some cases (e.g. dimethyl-nitrosamine) such a correlation is not observed with total binding but rather with specific adducts. There are a number of additional reasons why the concentration of a xenobiotic and/or its metabolites that is achieved in a tissue may not correlate with the biological response observed. Common causes are as follows.