The importance of non-linear (dose-dependent) pharmacokinetics in hazard assessment

The chronic toxicity of chemicals is evaluated most frequently in animal species and these results subsequently applied to assessing exposure hazards to man. Initial studies are designed to elucidate target organ effects and to characterize the type of toxicity; therefore, administration of high doses of the test material has been the accepted practice. Inherent in this approach is the assumption that few chemicals are capable of saturating the various biochemical and/or transport processes which determine their fate in the body. However, more recently it has become apparent that the biotransformation, excretion, and protein binding of many chemicals are capacity-limited processes. Since the approach in toxicity testing has been to administer large doses of a test chemical, the probability of encountering saturable processes in animal toxicity tests is high. Deviation from linear, dose-independent to non-linear, dose-dependent pharmacokinetics precludes extrapolating the same toxicity from high to low doses. Toxicity at high doses may be due to saturated detoxification or excretion mechanisms which when fully operative at lower doses do not result in the same toxic response. Therefore, knowledge of the pharmacokinetics of a chemical is essential in evaluating the results of animal toxicity tests. More important, in a prospective sense, is the use of pharmacokinetic data to assist in dose selection for chronic toxicity studies. In both cases, the maximum information is obtained from a well defined dose-response relationship. Therefore, massive doses which result in non-linear pharmacokinetics should be avoided unless those occur at dose levels approximating those experienced in actual conditions of human exposure. If these principles are followed, better judgment could be exercised in using animal data to assess the hazard of exposure in man.