Physiologically based toxicokinetic models and their application in human exposure and internal dose assessment

Human populations may exhibit large interindividual variation in toxicokinetic response to chemical exposures. Rapid developments in dosimetry research have brought medicine and public health closer to understanding the biological basis of this heterogeneity. The toxicokinetic behavior of chemicals is, in part, controlled by the properties of the epithelium surrounding organs, some of which are effective barriers to penetration into the systemic circulation. Physiologically based toxicokinetic (PBTK) models have been developed and used to simulate the mechanism of uptake into the systemic circulation, to extrapolate between doses and exposure routes, and to estimate internal dosimetry and sources of heterogeneity in animals and humans. Recent improvements to PBTK models include descriptions of active transport across biological membranes, carrier-mediated clearance, and fractal kinetics. The expanding area of toxicogenetics has provided valuable insight for delineating toxicokinetic differences between individuals; genetic differences include inherited single nucleotide polymorphisms, copy number variants, and dynamic changes in the methylation pattern of imprinted genes. This chapter discusses the structure of PBTK models and how toxicogenetic information and newer biological descriptions have improved our understanding of variability in response to toxicant exposures.