Saturable metabolism and its relationship to toxicity

Metabolism plays a central role in regulating the toxicity of a variety of chemicals. Relatively innocuous substances can be converted to highly toxic metabolites. Conversely, toxic substances can be biotransformed to less harmful metabolites or be excreted, thus limiting their duration of biological action. Virtually all metabolism and many excretory processes utilize specific binding proteins, i.e., enzymes and carrier proteins. These metabolic and carrier-mediated excretory clearance pathways are capacity-limited, becoming saturated at sufficiently high substrate concentrations. Saturable metabolic clearance processes lead to dose-dependent pharmacokinetics for many chemicals. When dose-dependent pharmacokinetics prevail, internally significant parameters, such as area under the curve for concentration of toxicant at active sites and the amount of metabolite formed during inhalation exposure, are not linearly related to externally significant parameters such as administered dose or inspired concentration. Dose-response curves should relate observed effects to some internally significant parameter. Toxic response should often be indexed to area under the curve relationships or total amount metabolized, instead of dose or inspired concentration. The former parameters are complexly related to the latter. The nature of the relationship depends on the kinetic constants for metabolic and excretory clearance. Pharmacokinetic analyses of dose-dependent clearance mechanisms provide an understanding of how one transforms externally significant parameters to internally significant parameters under various exposure conditions. Consideration of metabolic clearance at the organ level illuminates the importance of physiological factors, showing unequivocally that blood flow may be rate-limiting for metabolism under many exposure conditions. Recognition of the potential for this behavior is essential to the proper design and evaluation of certain toxicological experimentation. Development of comprehensive pharmacokinetic descriptions of the influence of saturable clearance on delivery of active chemical to target sites augurs well for improving both intraspecies and interspecies extrapolation of toxicity data. This is a critical area of contemporary toxicology. Dose selection for chronic studies could also be improved by knowledge of the dose-dependence of pharmacokinetic parameters in proposed test species. The field of toxicology reviewed here represents an interface between pharmacokinetic research and studies on basic mechanisms of toxic action. It entails utilization of quantitative concepts to better understand the physiological and biochemical controls which regulate the expression of the toxicity of various chemicals. Much work remains to be accomplished in this exciting area of toxicological research. Some of the predictions of the pharmacokinetic analyses are still tentative and require more definitive experimentation...