Physiologically based estimation of in vivo rates of bromodichloromethane metabolism.

Bromodichloromethane (BDCM) is a rodent carcinogen formed by chlorination of drinking water containing bromide and organic precursors. BDCM is a member of the class of disinfection by-products known as trihalomethanes (THMs), compounds that have been shown to be carcinogenic in rodents. A physiologically-based pharmacokinetic (PBPK) model has been developed and applied to provide estimates of the rates of metabolism of BDCM in vivo in rats. The model consists of five compartments (liver, kidney, fat and slowly and rapidly perfused tissues). Tissue partition coefficients were determined using a modified vial equilibration technique and rates of metabolism were estimated by fitting data obtained from stable metabolite (bromide ion, (Br-)) analysis following 4 h constant concentration BDCM inhalation exposure (50-3200 ppm) and closed chamber gas uptake experiments. Metabolism was described using a single saturable pathway representing a high capacity, high affinity process (Vmaxc = 12.8 mg/h/kg; Km = 0.5 mg/l). Rate constants obtained from Br- data adequately described data from gas uptake experiments and literature data on exhalation of 14CO and 14CO2 produced following oral gavage with 14C-BDCM. Pretreatment with trans-dichloroethylene (t-DCE), an inhibitor of CYP2E1, increased the apparent Km from 0.5 to 225 mg/l indicating that CYP2E1 is the major P450 isoform involved in the bioactivation of BDCM to reactive intermediates.

[1]  Melvin E. Andersen,et al.  Gas Uptake Inhalation Techniques and the Rates of Metabolism of Chloromethanes, Chloroethanes, and Chloroethylenes in the Rat , 1990 .

[2]  H J Clewell,et al.  Physiologically based pharmacokinetic modeling with dichloromethane, its metabolite, carbon monoxide, and blood carboxyhemoglobin in rats and humans. , 1991, Toxicology and applied pharmacology.

[3]  M E Andersen,et al.  A physiologically based description of the inhalation pharmacokinetics of styrene in rats and humans. , 1984, Toxicology and applied pharmacology.

[4]  E. Testai,et al.  Bioactivation of chloroform in hepatic microsomes from rodent strains susceptible or resistant to CHCl3 carcinogenicity. , 1992, Toxicology and applied pharmacology.

[5]  E. Testai,et al.  Multiple activation of chloroform in kidney microsomes from male and female DBA/2J mice. , 1994, Journal of biochemical toxicology.

[6]  E. Testai,et al.  Biochemical alterations elicited in rat liver microsomes by oxidation and reduction products of chloroform metabolism. , 1986, Chemico-biological interactions.

[7]  H J Clewell,et al.  Metabolism of inhaled dihalomethanes in vivo: differentiation of kinetic constants for two independent pathways. , 1986, Toxicology and applied pharmacology.

[8]  Division on Earth.  Guide for the Care and Use of Laboratory Animals , 1996 .

[9]  M. W. Anders,et al.  Metabolism of dihalomethanes to carbon monoxide--III. Studies on the mechanism of the reaction. , 1978, Biochemical pharmacology.

[10]  M. Andersen,et al.  Metabolism of inhaled brominated hydrocarbons: validation of gas uptake results by determination of a stable metabolite. , 1982, Toxicology and applied pharmacology.

[11]  H J Clewell,et al.  Applying simulation modeling to problems in toxicology and risk assessment--a short perspective. , 1995, Toxicology and applied pharmacology.

[12]  A. Jeffcoat,et al.  Metabolism and distribution of bromodichloromethane in rats after single and multiple oral doses. , 1990, Journal of toxicology and environmental health.

[13]  H. Vainio,et al.  Different contributions of cytochrome P450 2E1 and P450 2B1/2 to chloroform hepatotoxicity in rat. , 1995, Toxicology and applied pharmacology.

[14]  M. W. Anders,et al.  Metabolism of haloforms to carbon monoxide. I. In vitro studies. , 1977, Drug metabolism and disposition: the biological fate of chemicals.

[15]  M E Andersen,et al.  Development of a physiologically based pharmacokinetic model for chloroform. , 1990, Toxicology and applied pharmacology.

[16]  D J Paustenbach,et al.  Pharmacokinetics of [125I]-2-iodo-3,7,8-trichlorodibenzo-p-dioxin in mice: analysis with a physiological modeling approach. , 1990, Toxicology and applied pharmacology.

[17]  M. Andersen,et al.  GlutathioneS-Transferase-Mediated Mutagenicity of Trihalomethanes inSalmonella typhimurium:Contrasting Results with Bromodichloromethane and Chloroform , 1997 .

[18]  H J Clewell,et al.  A physiologically based simulation approach for determining metabolic constants from gas uptake data. , 1986, Toxicology and applied pharmacology.

[19]  R. Hoover,et al.  Associations of cancer mortality with halomethanes in drinking water. , 1978, Journal of the National Cancer Institute.

[20]  T. Slater,et al.  Activation of chloroform and related trihalomethanes to free radical intermediates in isolated hepatocytes and in the rat in vivo as detected by the ESR-spin trapping technique. , 1985, Chemico-biological interactions.

[21]  N. Whittaker,et al.  Phosgene: a metabolite of chloroform. , 1977, Biochemical and biophysical research communications.

[22]  H A Barton,et al.  Chloroethylene mixtures: pharmacokinetic modeling and in vitro metabolism of vinyl chloride, trichloroethylene, and trans-1,2-dichloroethylene in rat. , 1995, Toxicology and applied pharmacology.

[23]  J. E. Simmons,et al.  Dose-dependent vehicle differences in the acute toxicity of bromodichloromethane. , 1994, Fundamental and applied toxicology : official journal of the Society of Toxicology.

[24]  M. McKenna,et al.  Improved methodology for generating controlled test atmospheres. , 1980, American Industrial Hygiene Association journal.

[25]  W. Humphreys,et al.  Expression of mammalian glutathione S-transferase 5-5 in Salmonella typhimurium TA1535 leads to base-pair mutations upon exposure to dihalomethanes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[26]  M E Andersen,et al.  Determining kinetic constants of chlorinated ethane metabolism in the rat from rates of exhalation. , 1989, Toxicology and applied pharmacology.

[27]  M E Andersen,et al.  Partition coefficients of low-molecular-weight volatile chemicals in various liquids and tissues. , 1989, Toxicology and applied pharmacology.

[28]  Nancy L. Patania,et al.  The occurrence of disinfection by-products in U , 1989 .

[29]  M E Andersen,et al.  A physiologically-based description of the inhalation pharmacokinetics of styrene in rats and humans. , 1983, Developments in toxicology and environmental science.

[30]  R. D. Morris,et al.  Chlorination, chlorination by-products, and cancer: a meta-analysis. , 1992, American journal of public health.

[31]  F. Guengerich,et al.  Role of human cytochrome P-450 IIE1 in the oxidation of many low molecular weight cancer suspects. , 1991, Chemical research in toxicology.