A physiologically based pharmacokinetic description of the oral uptake, tissue dosimetry, and rates of metabolism of bromodichloromethane in the male rat.
Bromodichloromethane (BDCM), a trihalomethane (THM) and water chlorination by-product, induces cancer in several tissues in experimental animals, including target tissue sites where increased incidences of human cancer have been linked to consumption of chlorinated water. The purpose of the present study was to examine the effects of vehicle of administration on the pharmacokinetics of orally administered BDCM and to further develop and validate a physiologically based pharmacokinetic (PBPK) model to describe BDCM absorption, tissue dosimetry, and rates of metabolism for both oil and 10% Emulphor vehicles. Estimates of oral absorption rate constants were determined by fitting blood and exhaled breath chamber concentration-time curves obtained following gavage of male F344 rats with 50 or 100 mg BDCM/kg in corn oil or 10% Emulphor using a previously published multicompartmental gastrointestinal tract submodel (Semino et al., Toxicology 117, 25-33, 1997) linked to a PBPK model. Independently estimated oral uptake and metabolic rate constants accurately described kidney BDCM concentrations and plasma bromide ion levels without adjustment. This observation increases our confidence in model structure and values of parameter estimates. Liver BDCM concentrations were simulated, but with less accuracy than kidney dosimetry simulations, following incorporation of BDCM loss to metabolism during sample preparation. This model describes BDCM tissue dosimetry and metabolism following oral gavage and can be utilized in estimating rates of formation of reactive metabolites in target tissues. Estimates of tissue dosimetry and levels of toxic intermediates can be incorporated into a risk assessment model for BDCM-induced toxicity and carcinogenicity.
Lilly
P D
PD
University of North Carolina-Chapel Hill 27599, USA.
Andersen
M E
ME
Ross
T M
TM
Pegram
R A
RA
D000284:Administration, Oral; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001944:Breath Tests; D001965:Bromides / Q000097:blood*; D002273:Carcinogens / Q000493:pharmacokinetics*; D003314:Corn Oil; D006846:Hydrocarbons, Halogenated / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007408:Intestinal Absorption; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009929:Organ Size / Q000187:drug effects; D010938:Plant Oils; D051381:Rats; D011916:Rats, Inbred F344; D014018:Tissue Distribution; D022882:Trihalomethanes
D001965:Bromides; D002273:Carcinogens; D006846:Hydrocarbons, Halogenated; D010938:Plant Oils; D022882:Trihalomethanes; C025191:bromodichloromethane; D003314:Corn Oil