Marchand Axelle, Aranda-Rodriguez Rocio, Tardif Robert, Nong Andy, Haddad Sami
*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.
*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.
Toxicol Sci. 2015 Apr;144(2):414-24. doi: 10.1093/toxsci/kfv009. Epub 2015 Jan 19.
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.
暴露的尿液生物标志物在生物监测研究中被广泛应用。用于芳香族溶剂甲苯（T）、乙苯（E）和间二甲苯（X）的常用尿液生物标志物是邻甲酚、扁桃酸和间甲基马尿酸。吸入暴露后这些生物标志物的毒代动力学尚未通过基于生理的药代动力学（PBPK）模型进行描述。五名男性志愿者在吸入舱中暴露6小时，暴露剂量为每种溶剂时间加权平均暴露值（TWAEV）的1/8或1/4：对血液和呼出气体中的甲苯、乙苯和间二甲苯进行定量，并测量尿液中相应的尿液生物标志物。使用已发表的母体化合物PBPK模型，并将模拟结果与实验性血液和呼出气体浓度数据进行比较。如果存在差异，则对Vmax和Km进行优化。使用文献中发现的参数对尿液排泄进行建模，假设母体化合物代谢的化学计量产率和一级尿液排泄率。还测试了替代模型，用于（1）CYP1A2是唯一与邻甲酚相关的酶的可能性，以及（2）描述扁桃酸系列代谢步骤的两步模型。本研究中适用于尿液排泄的模型将进一步用于解释这些溶剂混合暴露的尿液生物标志物动力学数据。
