Capturing and modeling human interindividual differences for health risk assessment: hepatic bioactivation of chloroform.
Lipscomb-JC; Du-JT; Swartout-JC; Mahle-DA; Snawder-JE; Kedderis-GL
Toxicologist 2004 Mar; 78(S-1):362
Chloroform (CF) is a volatile drinking water contaminant. Risks via the oral, but not inhalation route have been estimated. This study was conducted to adjust inhalation dosimetry between animals and humans and assess the impact of variability in some factors which may predispose humans to toxicity. CF partition coefficients were determined in tissues from young and mature rats, and in blood from adult and pediatric patients. CF metabolic rate constants and hepatic CYP2E1 protein concentrations were determined in liver tissue from adult rats and human adult and child organ donors. Vmax was extrapolated to intact tissue and scaled to body weight. The distribution of hepatic blood flow (HBF) as percent of cardiac output was determined from a total of 59 published individual values in human adults. These data were incorporated into physiologically based pharmacokinetic (PBPK) models constructed for mice; rats; and human adults, preadolescents and infants. Because of the relevance of the inhalation reference concentration to chronic, lifetime exposures, constant exposure to CF was simulated until steady state was reached rather than simulating intermittent exposure scenarios. Toxicity studies with mice demonstrate a duration-adjusted NOAEL (liver effects) of 0.9 ppm CF. Simulations indicated that the human equivalent exposure concentration, based on hepatic CF metabolism, was approximately 6 ppm. Among adults, increases in CYP2E1 content and activity, blood:air partitioning, and HBF produced approximately 1, 4 and 17% increases in CF metabolism, respectively. Children converted as much as 34% more CF to metabolites than equivalently exposed adults. These findings will be useful in determining the magnitude of PK variability in the risk relevant PK outcomes between species and among humans.
Bioactivation; Risk-factors; Risk-analysis; Water-analysis; Toxic-effects; Toxins; Blood-sampling; Laboratory-animals; Animals; Animal-studies; Models; Humans
Research Tools and Approaches: Exposure Assessment Methods
The Toxicologist. Society of Toxicology 43nd Annual Meeting and ToxExpo, March 21-25, 2004, Baltimore, Maryland