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

Journal of Toxicology and Environmental Health. Part a
Mathieu Valcke, Sami Haddad

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-base...Continue Reading

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Citations

Oct 31, 2015·Journal of Toxicology and Environmental Health. Part a·Sung Ha RyuKyu-Bong Kim
Oct 16, 2015·Journal of Toxicology and Environmental Health. Part a·Nataša BrajenovićAleksandar Bulog
May 11, 2016·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·Inês PaciênciaEduardo de Oliveira Fernandes
Oct 27, 2018·Journal of Toxicology and Environmental Health. Part a·Honesty TohonSami Haddad
Oct 21, 2016·Journal of Toxicology and Environmental Health. Part B, Critical Reviews·M Ariel Geer WallaceJoachim D Pleil
Mar 10, 2017·Journal of Toxicology and Environmental Health. Part a·Fernando Barbosa
Dec 2, 2020·International Journal of Environmental Research and Public Health·Carol J MillerBridget B Baker

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