title: Human inhalation exposures to toluene, ethylbenzene, and m-xylene and physiologically based pharmacokinetic modeling of exposure biomarkers in exhaled air, blood, and urine.
abstract: Urinary biomarkers of exposure are used widely in biomonitoring studies. The commonly used urinary biomarkers for the aromatic solvents toluene (T), ethylbenzene (E), and m-xylene (X) are o-cresol, mandelic acid, and m-methylhippuric acid. The toxicokinetics of these biomarkers following inhalation exposure have yet to be described by physiologically based pharmacokinetic (PBPK) modeling. Five male volunteers were exposed for 6 h in an inhalation chamber to 1/8 or 1/4 of the time-weighted average exposure value (TWAEV) for each solvent: toluene, ethylbenzene, and m-xylene were quantified in blood and exhaled air and their corresponding urine biomarkers were measured in urine. Published PBPK model for parent compounds was used and simulations were compared with experimental blood and exhaled air concentration data. If discrepancies existed, Vmax and Km were optimized. Urinary excretion was modeled using parameters found in literature assuming simply stoichiometric yields from parent compound metabolism and first-order urinary excretion rate. Alternative models were also tested for (1) the possibility that CYP1A2 is the only enzyme implicated in o-cresol and (2) a 2-step model for describing serial metabolic steps for mandelic acid. Models adapted in this study for urinary excretion will be further used to interpret urinary biomarker kinetic data from mixed exposures of these solvents.
authors.affiliation: *Department of Environmental and Occupational Health, ESPUM, IRSPUM, Chair in Toxicological Risk Assessment and Management, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and Exposure and Biomonitoring Division, Environmental Health Sciences and Research Bureau, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0K9 *Department of Environmental and Occupational Health, ESPUM, IRSPUM, Chair in Toxicological Risk Assessment and Management, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and Exposure and Biomonitoring Division, Environmental Health Sciences and Research Bureau, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Axelle
authors.initials: A
authors.lastname: Marchand
authors.affiliation: *Department of Environmental and Occupational Health, ESPUM, IRSPUM, Chair in Toxicological Risk Assessment and Management, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and Exposure and Biomonitoring Division, Environmental Health Sciences and Research Bureau, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Rocio
authors.initials: R
authors.lastname: Aranda-Rodriguez
authors.affiliation: *Department of Environmental and Occupational Health, ESPUM, IRSPUM, Chair in Toxicological Risk Assessment and Management, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and Exposure and Biomonitoring Division, Environmental Health Sciences and Research Bureau, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Robert
authors.initials: R
authors.lastname: Tardif
authors.affiliation: *Department of Environmental and Occupational Health, ESPUM, IRSPUM, Chair in Toxicological Risk Assessment and Management, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and Exposure and Biomonitoring Division, Environmental Health Sciences and Research Bureau, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0K9.
authors.forename: Andy
authors.initials: A
authors.lastname: Nong
authors.affiliation: *Department of Environmental and Occupational Health, ESPUM, IRSPUM, Chair in Toxicological Risk Assessment and Management, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and Exposure and Biomonitoring Division, Environmental Health Sciences and Research Bureau, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0K9 *Department of Environmental and Occupational Health, ESPUM, IRSPUM, Chair in Toxicological Risk Assessment and Management, Université de Montréal, Montreal, Quebec, Canada H3C 3J7, and Exposure and Biomonitoring Division, Environmental Health Sciences and Research Bureau, Health Canada, 50 Columbine Driveway, Ottawa, Ontario, Canada K1A 0K9 sami.haddad@umontreal.ca.
authors.forename: Sami
authors.initials: S
authors.lastname: Haddad
mesh_terms: D000328:Adult; D001555:Benzene Derivatives / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D015415:Biomarkers / Q000032:analysis* / Q000097:blood / Q000652:urine; D001944:Breath Tests; D006801:Humans; D019570:Inhalation Exposure; D008954:Models, Biological; D014050:Toluene / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014992:Xylenes / Q000008:administration & dosage* / Q000493:pharmacokinetics*
chemical_list: D001555:Benzene Derivatives; D015415:Biomarkers; D014992:Xylenes; D014050:Toluene; C004912:ethylbenzene; C031285:3-xylene
keywords: PBPK modeling; biomarkers; ethylbenzene; inhalation; m-xylene; toluene