Development of a physiologically based pharmacokinetic model for chloroform.
A physiologically based pharmacokinetic model describing the disposition of chloroform in mice, rats, and humans was developed. This model was designed to facilitate extrapolations from high doses, such as those used in chronic rodent studies, to low doses that humans may be exposed to in the workplace or the environment. Kinetic constants for mice and rats were derived from in vivo experiments. Enzymatic studies conducted with samples of rodent and human tissues provided a rational basis for estimating human in vivo metabolic rate constants. Incorporation of physiological descriptions of the processes of absorption, distribution, metabolism, and excretion allowed extrapolation between different routes of exposure as well. The model was validated by comparing model predictions with experimental data gathered in mice, rats, and humans after inhalation, oral, or intraperitoneal administration of chloroform. Consistent with previous reports, the metabolic activation of chloroform to toxic intermediates was shown to occur most rapidly in the mouse, less rapidly in the rat, and most slowly in humans. Estimates of the "delivered dose" of chloroform metabolites to internal organs sensitive to chloroform toxicity were calculated. This model may be used to develop refined dose estimates for human populations exposed to low levels of chloroform in the environment.
Corley
R A
RA
Toxicology Research Laboratory, Dow Chemical Company, Midland, Michigan 48674.
Mendrala
A L
AL
Smith
F A
FA
Staats
D A
DA
Gargas
M L
ML
Conolly
R B
RB
Andersen
M E
ME
Reitz
R H
RH
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D002250:Carbon Radioisotopes; D002725:Chloroform / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D006224:Cricetinae; D004326:Drinking; D005069:Evaluation Studies as Topic; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008954:Models, Biological; D051381:Rats; D011919:Rats, Inbred Strains; D014867:Water
D002250:Carbon Radioisotopes; D014867:Water; D002725:Chloroform