Identification of drug-pollutant interactions and refining predictions of interindividual variability in pollutant toxicokinetics

点击翻译按钮获取中文摘要

A problem that arises when attempting to predict toxicity levels in humans is that, for a given dose of toxicant, there exists interindividual variability in the fraction of dose that attains the target tissue and therefore leading to variability in the response. In order to adequately predict the toxicity of a compound following exposure, it is necessary to use adequate tools to estimate kinetics of the chemical in the target tissue. In recent years, physiologically based toxicokinetic/pharmacokinetic (PBPK) modeling has been used to this effect. In order to better estimate/consider interindividual variability, these models can take into account factors that are intrinsic to individuals which are related to their physiology (e.g., age, gender, adiposity) and their genetics (e.g., enzymatic polymorphisms). They can also consider extrinsic factors such as coexposure to other xenobiotics leading to toxicokinetic interactions. Different lifestyles can favor repeated coexposures to xenobiotics, such as chronic medication. The principal objective of this research program is to increase our knowledge on the factors that modulate toxicokinetics of environmental toxicants in order to refine predictability in tissue exposure assessment using PBPK modeling. The proposed program aims to: (i) identify and characterize drug-pollutant metabolic interactions by in vitro methods using rat and human material; (ii) validate PBPK modeling in vitro-in vivo extrapolation approaches using drug-pollutant toxicokinetic interactions with data obtained from rat in vivo exposures; (iii) develop methods to estimate metabolic variability in population based on available in vitro data; and (iv) confirm and refine variability estimations in adipose tissue volumes. The undertaking of such a research program will greatly enhance our knowledge on how drug consumption can affect the variability in the body's response to environmental pollution. The development of such drug-pollutant physiologically-based toxicokinetic interactions models will lead to improvements in Canadian human health risk assessment practices. With this program, Canadian research will be leading in the field of PBPK modeling of toxicokinetic interactions and interindividual variability.