Application of PBPK modeling in support of the derivation of toxicity reference values for 1,1,1-trichloroethane.
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.
Lu
Yasong
Y
Quantitative and Computational Toxicology Group, Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, CO 80523-1681, USA.
Rieth
Susan
S
Lohitnavy
Manupat
M
Dennison
James
J
El-Masri
Hisham
H
Barton
Hugh A
HA
Bruckner
James
J
Yang
Raymond S H
RS
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
D012997:Solvents; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane