NOAEL and LOAEL determinations of acute hepatotoxicity for chloroform and bromodichloromethane delivered in an aqueous vehicle to F344 rats.
Chloroform (CHCl3) and bromodichloromethane (BDCM) are generally the two most prevalent disinfection by-products formed during chlorination of drinking water, and both have been shown to be hepatotoxic, nephrotoxic, and carcinogenic in rodents. As the toxicity of these trihalomethanes (THMs) has most often been studied with corn oil as the vehicle of administration, the objectives of this study were to assess hepatotoxicity after exposure to single, low dosages of CHCl3 and BDCM given orally in an aqueous vehicle to estimate a lowest-observed-adverse-effect level (LOAEL) and a no-observed-adverse-effect level (NOAEL) and to compare toxic potency. Ninety-day-old male Fischer 344 rats were gavaged with either 0.125, 0.1875, 0.25, 0.5, 0.75, 1.0, or 1.5 mmol CHCl3 or BDCM/kg body weight in 10% Alkamuls EL-620 (5 ml/kg body weight). At 24 h postgavage, serum was collected for analysis of clinical chemistry indicators of liver damage. Both CHCl3 and BDCM induced dose-dependent hepatotoxicity; serum alanine aminotransferase, aspartate aminotransferase, and sorbitol dehydrogenase were elevated significantly over control at 1.5, 1.0, and 0.5 mmol/kg. At these dose levels after 24 h, the two THMs appeared to be equipotent hepatotoxicants. Additional assessments at later time points demonstrated that BDCM causes more persistent liver damage than CHCl3 (Lilly et al., 1997). At 0.25, 0. 1875, and 0. 125 mmol of either THM/kg, significant increases over control were not detected for any measured endpoint. Therefore, these data indicate that the acute, oral NOAELs and LOAELs for liver toxicity are 0.25 and 0.5 mmol/kg, respectively, for both CHCl3 and BDCM. These determinations should provide a basis to establish new exposure limits for One-Day Health Advisories for these prevalent THMs.
Keegan
T E
TE
Environmental Science and Engineering/Curriculum in Toxicology, University of North Carolina at Chapel Hill, USA.
Simmons
J E
JE
Pegram
R A
RA
D000410:Alanine Transaminase / Q000097:blood; D000704:Analysis of Variance; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D001835:Body Weight / Q000187:drug effects; D002273:Carcinogens / Q000633:toxicity*; D002725:Chloroform / Q000633:toxicity*; D004203:Disinfection / Q000379:methods; D006846:Hydrocarbons, Halogenated / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D014677:Pharmaceutical Vehicles; D051381:Rats; D011916:Rats, Inbred F344; D022882:Trihalomethanes; D014867:Water / Q000737:chemistry*; D014881:Water Supply / Q000592:standards
D002273:Carcinogens; D006846:Hydrocarbons, Halogenated; D014677:Pharmaceutical Vehicles; D022882:Trihalomethanes; D014867:Water; C025191:bromodichloromethane; D002725:Chloroform; D007064:L-Iditol 2-Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase