Physiologically based pharmacokinetic modeling with methylchloroform: implications for interspecies, high dose/low dose, and dose route extrapolations.
A unified physiologically based pharmacokinetic (PB-PK) model was developed and used to describe the disposition of methylchloroform (1,1,1-trichloroethane, MC) in three different species (rats, mice, and humans) after four different routes of exposure (inhalation, intravenous injection, bolus gavage, and drinking water administration). Metabolism of MC followed Michaelis-Menten kinetics in each species. Vmax's were calculated from the allometric equation: Vmax = 0.419 BW0.7, and Km appeared to be identical in each species (5.75 mg equivalents/liter). Once the PB-PK model had been developed for young adult animals (1-3 months of age), it was used to study the disposition of MC in older rats and mice (approximately 18.5 months of age). Most of the changes in the pharmacokinetic behavior of MC in older rats could be simulated by increasing the size of the fat compartment in the PB-PK model from 7 to 18% of body weight. However, the pharmacokinetic behavior in older mice was more complex; increasing the size of the fat compartment in this species from 4 to 18% only accounted for part of the observed differences between old and young animals. An appropriate dose surrogate (average area under the liver concentration/time curve) was selected and the PB-PK model was used to make quantitative comparisons between "internal doses" of MC in long term animal studies and "internal doses" associated with human exposures to MC. Values of the dose surrogate in humans consuming 2 liters/day of water with typical levels of MC contamination (1-10 ppb) were four to six orders of magnitude lower than the dose surrogates in the rodent studies at levels of MC exposure which failed to produce adverse effects on the liver (875-1500 ppm, 6 hr/day, 5 days/week).
Reitz
R H
RH
Toxicology Research Laboratory, Dow Chemical Company, Midland, Michigan 48674.
McDougal
J N
JN
Himmelstein
M W
MW
Nolan
R J
RJ
Schumann
A M
AM
D000818:Animals; D001944:Breath Tests; D004326:Drinking; D006801:Humans; D006843:Hydrocarbons, Chlorinated / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D008954:Models, Biological; D051381:Rats; D011916:Rats, Inbred F344; D014240:Trichloroethanes / Q000008:administration & dosage / Q000493:pharmacokinetics*
D006843:Hydrocarbons, Chlorinated; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane