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

在试图预测人体毒性水平时出现的一个问题是，对于给定剂量的毒物，到达目标组织的剂量部分存在个体间差异，从而导致反应的差异。为了充分预测暴露后化合物的毒性，有必要使用适当的工具来估计目标组织中化学物质的动力学。近年来，基于生理学的毒代动力学/药代动力学（PBPK）模型已被用于此目的。为了更好地估计/考虑个体间的可变性，这些模型可以考虑个体内在的因素，这些因素与他们的生理（例如，年龄，性别，肥胖）和遗传学（例如，酶多态性）有关。他们还可以考虑外部因素，如共同暴露于导致毒性动力学相互作用的其他异种抗生素。不同的生活方式有利于反复接触外源性药物，如慢性药物。本研究计划的主要目的是增加我们对调节环境毒物的毒性动力学因素的了解，以便使用PBPK模型改进组织暴露评估的可预测性。拟议的计划旨在：(i)通过使用大鼠和人体材料的体外方法识别和表征药物-污染物代谢相互作用；（ii）利用从大鼠体内暴露中获得的数据，利用药物-污染物毒性动力学相互作用，验证PBPK模型在体外的外推方法；（iii）根据现有的体外数据制定估算人群代谢变异性的方法；（iv）确认和改进脂肪组织体积的可变性估计。开展这样一个研究项目将大大提高我们对药物消费如何影响人体对环境污染反应的可变性的认识。这种基于药物-污染物生理的毒性动力学相互作用模型的发展将导致加拿大人类健康风险评估做法的改进。有了这个项目，加拿大的研究将在PBPK毒性动力学相互作用和个体间变异性建模领域处于领先地位。

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.