title: Application of PBPK modeling in support of the derivation of toxicity reference values for 1,1,1-trichloroethane.
abstract: PBPK modeling has been increasingly applied in chemical risk assessment for dose, route, and species extrapolation. The use of PBPK modeling was explored in deriving toxicity reference values for 1,1,1-trichloroethane (1,1,1-TCE). This effort involved a 5-step process: (i) reconstruction of several published PBPK models for 1,1,1-TCE in the rat and human; (ii) selection of appropriate pharmacokinetic datasets for model comparison; (iii) determination of the most suitable PBPK model for supporting reference value derivation; (iv) PBPK model simulation of two critical studies to estimate internal dose metrics; and (v) calculation of internal dose metrics for human exposure scenarios for reference value derivation. The published model by Reitz et al. [Reitz, R.H., McDougal, J.N., Himmelstein, M.W., Nolan, R.J., Schumann, A.M., 1988. Physiologically based pharmacokinetic modeling with methylchloroform: implications for interspecies, high dose/low dose, and dose route extrapolations. Toxicol. Appl. Pharmacol. 95, 185-199] was judged the most suitable. This model has liver, fat, and rapidly and slowly perfused compartments, contains a saturable process for 1,1,1-TCE hepatic metabolism, and accommodates multiple exposure pathways in three species. Data from a human volunteer study involving acute inhalation exposure [Mackay, C.J., Campbell, L., Samuel, A.M., Alderman, K.J., Idzikowski, C., Wilson, H.K., Gompertz, D., 1987. Behavioral changes during exposure to 1,1,1-trichloroethane: time-course and relationship to blood solvent levels. Am. J. Ind. Med. 11, 223-239] and a chronic rat inhalation study [Quast, J.F., Calhoun, L.L., Frauson, L.E., 1988. 1,1,1-Trichloroethane formulation: a chronic inhalation toxicity and oncogenicity study in Fischer 344 rats and B6C3F1 mice. Fundam. Appl. Toxicol. 11, 611-625] were selected to simulate appropriate internal dosimetry data from which to derive reference value points of departure. Duration, route, and species extrapolations were performed based on internal dose metrics.
authors.affiliation: Quantitative and Computational Toxicology Group, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1681, USA.
authors.forename: Yasong
authors.initials: Y
authors.lastname: Lu
authors.forename: Susan
authors.initials: S
authors.lastname: Rieth
authors.forename: Manupat
authors.initials: M
authors.lastname: Lohitnavy
authors.forename: James
authors.initials: J
authors.lastname: Dennison
authors.forename: Hisham
authors.initials: H
authors.lastname: El-Masri
authors.forename: Hugh A
authors.initials: HA
authors.lastname: Barton
authors.forename: James
authors.initials: J
authors.lastname: Bruckner
authors.forename: Raymond S H
authors.initials: RS
authors.lastname: Yang
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001522:Behavior, Animal / Q000187:drug effects; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D004305:Dose-Response Relationship, Drug; D006801:Humans; D019570:Inhalation Exposure; D051379:Mice; D008815:Mice, Inbred Strains; D015233:Models, Statistical; D051381:Rats; D011916:Rats, Inbred F344; D012016:Reference Values; D018570:Risk Assessment; D012997:Solvents / Q000493:pharmacokinetics* / Q000633:toxicity*; D014018:Tissue Distribution; D014240:Trichloroethanes / Q000493:pharmacokinetics* / Q000633:toxicity*; D014481:United States; D014484:United States Environmental Protection Agency
chemical_list: D012997:Solvents; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane