Effect of dosing vehicle on the developmental toxicity of bromodichloromethane and carbon tetrachloride in rats.
Several halocarbons have been shown to cause full-litter resorption (FLR) in Fischer-344 rats when administered orally in corn oil. Since halocarbons often occur as contaminants of drinking water, we sought to determine the influence of the vehicle, aqueous versus lipid, on the developmental toxicity of two of these agents. In separate assays, bromodichloromethane (BDCM) and carbon tetrachloride (CCl4) were administered by gavage to Fischer-344 rats on gestation days (GD) 6-15 at 0, 25, 50, or 75 mg/kg/day in either corn oil or an aqueous vehicle containing 10% Emulphor EL-620. Dams were allowed to deliver and the litters were examined postnatally. Uteri of females that did not deliver were stained with 10% ammonium sulfide to detect FLR. Effects of both agents on maternal weight gain were slightly more pronounced in the aqueous vehicle at lower doses, but at the highest dose, CCl4 was more maternally toxic in corn oil. Developmentally, both agents caused FLR at 50 and 75 mg/kg in both vehicles. At 75 mg/kg, dams receiving corn oil had significantly higher rates of FLR (83% for BDCM, 67% for CCl4) compared to their aqueous-vehicle counterparts (21% for BDCM, 8% for CCl4). Blood concentrations of BDCM following GD-6 gavage revealed a shorter elimination half-life in the aqueous dosing vehicle (2.7 h) compared to the oil vehicle (3.6 h). Benchmark doses of CCl4 were similar for the oil (18.9 mg/kg) and aqueous (14.0 mg/kg) vehicles. For BDCM, the corn oil vehicle yielded a less conservative (i.e., higher) value (39.3 mg/kg) than the aqueous vehicle (11.3 mg/kg), reflecting different confidence intervals around the estimated 5%-effect dose levels.
Narotsky
M G
MG
Reproductive Toxicology Division, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA. narotsky.michael@epamail.epa.gov
Pegram
R A
RA
Kavlock
R J
RJ
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D006846:Hydrocarbons, Halogenated / Q000008:administration & dosage / Q000097:blood / Q000633:toxicity*; D014677:Pharmaceutical Vehicles; D011247:Pregnancy; D051381:Rats; D011916:Rats, Inbred F344; D013723:Teratogens / Q000633:toxicity*; D022882:Trihalomethanes
D006846:Hydrocarbons, Halogenated; D014677:Pharmaceutical Vehicles; D013723:Teratogens; D022882:Trihalomethanes; C025191:bromodichloromethane; D002251:Carbon Tetrachloride