Modeling blood/plasma concentrations in dosed feed and dosed drinking water toxicology studies.
A computer model for predicting blood/plasma concentrations of test chemicals in dosed feed and dosed drinking water toxicology studies was developed. The model was constructed based on linear theory. The animal's feeding and drinking habits and the linear disposition kinetics of the test chemical obtained after a bolus gavage dose were built into the model. Blood/plasma concentrations of oxazepam and pentachlorophenol in dosed feed and dosed drinking water studies were predicted and compared with the experimentally determined data. The model proved highly reliable in predicting the blood/plasma concentrations of test chemical in dosed feed and dosed drinking water studies. The results suggest that if the kinetics of test chemicals fit a one-compartment model then bioaccumulation of the test chemical will occur in dosed feed or in dosed drinking water studies when absorption half-lives are less than 1.38 hr and elimination half-lives are longer than 5 hr. The extent of accumulation is mainly dependent on the elimination half-lives. For chemicals with absorption half-lives less than 1.38 hr and elimination half-lives less than 2 hr, the extent of bioaccumulation will be minimal. Blood/plasma concentrations of test chemicals in rats and mice will fluctuate daily and a quasi-steady state will be achieved after ad libitum exposure to dosed feed or dosed drinking water for approximately 4 days. If a daily 12-hr light cycle is used with the light cycle starting at 7:00 AM, the expected peak and trough blood concentrations in dosed feed studies will occur approximately in the early morning (5:00 AM) and in the late afternoon (4:00 PM), respectively. Similar results were obtained for dosed drinking water studies. The model should be applicable to dosed feed and dosed drinking water studies using other species.
Yuan
J
J
National Toxicology Program, National Institutes of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
D000818:Animals; D001835:Body Weight; D003198:Computer Simulation; D004435:Eating; D005260:Female; D006207:Half-Life; D008297:Male; D051379:Mice; D010076:Oxazepam / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D010416:Pentachlorophenol / Q000008:administration & dosage / Q000097:blood* / Q000493:pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D014116:Toxicology / Q000379:methods*; D014867:Water / Q000737:chemistry
D014867:Water; D010076:Oxazepam; D010416:Pentachlorophenol