Toxicokinetic Models: Where We've Been and Where We Need to Go!

Abstract

Toxicokinetic (TK) models have many uses, some of which are now regarded as almost routine, in areas related to pharmaceutics, toxicology, and chemical risk assessment. These TK models span a range from simple empirical curve-fitting analyses of blood/tissue time courses to physiologically based toxicokinetic (PBTK) models that incorporate anatomical, physiological, and biochemical properties of laboratory animals and humans. While the PBTK models require more effort to develop and validate than do data-based compartmental models, the biological detail in these descriptions permits extrapolation to different doses, different exposure conditions, and different species, including humans. Efforts to develop PBTK models are frequently rewarded with reduced work on subsequent compounds, since the physiologic structure, once developed for a particular life stage and class of compounds, is not expected to change for other compounds in the class. A review of the literature shows that TK models have had many uses in occupational health and industrial hygiene; however, they have not been widely or systematically employed in these disciplines. This overview discusses the history of uses of TK models in occupational health areas and suggests future possibilities for these models. Notably, TK models and especially PBTK models could play much more important roles in establishing occupational exposure limits such as the U.S. Occupational Safety and Health Administration's Permissible Exposure Limits based on either animal or human studies; in assessing the range of susceptibility of diverse human populations based on individual variability; in interpreting epidemiological and biomarker studies for various exposure situations; in developing common methods to assess risks for exposures to both the general population and to worker populations; and in assessing exposures to chemical mixtures.