Human variability in hepatic and renal elimination: implications for risk assessment

Abstract

Hepatic metabolism and renal excretion constitute the main routes of xenobiotic elimination in humans. Improving human risk assessment for threshold contaminants requires the incorporation of quantitative data related to their elimination (toxicokinetics) and potential toxic effects (toxicodynamics). This type of data provides a scientific basis to replace the standard uncertainty factor (UF = 10) allowing for the consideration of human variability in toxicokinetics and toxicodynamics. This review focuses on recent research efforts aiming to incorporate human variability in hepatic and renal elimination (toxicokinetics) into the risk assessment process. A therapeutic drug database was developed to quantify pathway-related variability in human phase I and phase II hepatic metabolism as well as renal excretion in subgroups of the population (healthy adults, neonates and the elderly), using data on compounds cleared primarily through each route (> 60% dose). For each subgroup of the population and elimination route, pathway-related UFs were then derived to cover 95-99% of each subgroup. Overall, the default toxicokinetic UFs would not cover neonates, the elderly for most elimination routes and any subgroup of the population for compounds metabolized via polymorphic isozymes (such as CYP2C19 and CYP2D6). These pathway-related UFs allow the incorporation of in vivo metabolism and toxicokinetic data in the risk assessment process and provide a flexible intermediate option between the default UF and chemical-specific adjustment factors (CSAFs) derived from physiologically based pharmacokinetic models. Implications of human variability in hepatic metabolism and renal excretion for chemical risk assessment are discussed.