Chapter 28 - Incorporating mechanistic insights in a PBPK model for arsenic

Abstract

Pharmacokinetic studies with arsenic (As) need to be directly linked with mechanistic studies to match the form of As with specific target tissues and organs. It is essential to select appropriate dose metrics. The ultimate application of any physiologically based pharmacokinetic (PBPK) model is human health risk assessment. While pharmacokinetic and mechanistic studies in animals and human cell lines are necessary and highly valuable for model development, ultimately the model must be evaluated using data from exposed human populations. Clinical and field studies in which exposure is quantitatively evaluated at the level of individual study participant and then matched with the arsenical blood levels and urinary excretion data for that same individual are essential for model evaluation. The importance of methylation and variation in methylation among humans also needs to be quantitatively evaluated. This is because sensitivity analysis has suggested that methylation parameters are highly influential in determining tissue concentrations of methylated species. The development and use of an arsenic PBPK model that has been adequately evaluated help define the relationship between exposure and biologically effective dose at the target tissue level. This knowledge will reduce uncertainties in As risk assessment for exposed human populations.