Pharmacokinetic factors influencing risk assessment: saturation of biochemical processes and cofactor depletion

Models generally consider risk to be a function of the hazard (toxicity) and exposure (dose). That function is best described by the dose response of the toxic effect. For any risk assessment system to be effective, it should consider that dose-response relationship. Saturation phenomena often produce nonlinear dose curves, and any risk assessment system should be able to address such effects. Physiologically based pharmacokinetics offer an approach to deal with these nonlinear responses. Some historic risk models and common saturable processes are discussed. The impact of maximum tolerated dose (MTD) on risk evaluation and the kinetics of some saturable processes are considered. Specific examples have been selected to demonstrate the importance of saturation of processes in assessing the hazard of chemicals.