Assessing Human Variability in Kinetics for Exposures to Multiple Environmental Chemicals: A Physiologically Based Pharmacokinetic Modeling Case Study with Dichloromethane, Benzene, Toluene, Ethylbenzene, and m-Xylene

Abstract

The objective of this study was to compare the magnitude of interindividual variability in internal dose for inhalation exposure to single versus multiple chemicals. Physiologically based pharmacokinetic models for adults (AD), neonates (NEO), toddlers (TODD), and pregnant women (PW) were used to simulate inhalation exposure to “low” (RfC-like) or “high” (AEGL-like) air concentrations of benzene (Bz) or dichloromethane (DCM), along with various levels of toluene alone or toluene with ethylbenzene and xylene. Monte Carlo simulations were performed and distributions of relevant internal dose metrics of either Bz or DCM were computed. Area under the blood concentration of parent compound versus time curve (AUC)-based variability in AD, TODD, and PW rose for Bz when concomitant “low” exposure to mixtures of increasing complexities occurred (coefficient of variation (CV) = 16–24%, vs. 12–15% for Bz alone), but remained unchanged considering DCM. Conversely, AUC-based CV in NEO fell (15 to 5% for Bz; 12 to 6% for DCM). Comparable trends were observed considering production of metabolites (AMET), except for NEO’s CYP2E1-mediated metabolites of Bz, where an increased CV was observed (20 to 71%). For “high” exposure scenarios, Cmax-based variability of Bz and DCM remained unchanged in AD and PW, but decreased in NEO (CV= 11–16% to 2–6%) and TODD (CV= 12–13% to 7–9%). Conversely, AMET-based variability for both substrates rose in every subpopulation. This study analyzed for the first time the impact of multiple exposures on interindividual variability in toxicokinetics. Evidence indicates that this impact depends upon chemical concentrations and biochemical properties, as well as the subpopulation and internal dose metrics considered.

Additional information

Funding

Mathieu Valcke’s work is part of his regular tasks as a permanent professional financed by regular budgets from the Ministère de la santé et des services sociaux du Québec. Sami Haddad’s contribution is part of his research program, which is supported by a Discovery Grant from the National Sciences and Engineering Research Council of Canada (NSERC). The authors declare they have no conflicts of interests.