Acute, short-term, and subchronic oral toxicity of 1,1,1-trichloroethane in rats.
1,1,1-Trichloroethane (TRI) is a widely used solvent that has become a frequent contaminant of drinking water supplies in the U.S. There is very little information available on the potential for oral TRI to damage the liver or to alter its P450 metabolic capacity. Thus, a major objective of this investigation was to assess the acute, short-term, and subchronic hepatotoxicity of oral TRI. In the acute study, male Sprague-Dawley (S-D) rats were gavaged with 0, 0.5, 1, 2, or 4 g TRI/kg bw and killed 24 h later. No acute effects were apparent other than CNS depression. Other male S-D rats received 0, 0.5, 5, or 10 g TRI/kg po once daily for 5 consecutive days, rested for 2 days, and were dosed for 4 additional days. Groups of the animals were sacrificed for evaluation of hepatotoxicity 1, 5, and 12 days after initiation of the short-term experiment. This dosage regimen caused numerous fatalities at 5 and 10 g/kg, but no increases in serum enzymes or histopathological changes in the liver. For the subchronic study, male S-D rats were gavaged 5 times weekly with 0, 0.5, 2.5, or 5.0 g TRI/kg for 50 days. The 0 and 0.5 g/kg groups were dosed for 13 weeks. A substantial number of rats receiving 2.5 and 5.0 g/kg died, apparently due to effects of repeated, protracted CNS depression. There was evidence of slight hepatocytotoxicity at 10 g/kg, but no progression of injury nor appearance of adverse effects were seen during acute or short-term exposure. Ingestion of 0.5 g/kg over 13 weeks did not cause apparent CNS depression, body or organ weight changes, clinical chemistry abnormalities, histopathological changes in the liver, or fatalities. Additional experiments did reveal that 0.5 g/kg and higher doses induced hepatic microsomal cytochrome P450IIE1 (CYP2E1) in a dose- and time-dependent manner. Induction of CYP2E1 activity occurred sooner, but was of shorter duration than CYP2B1/2 induction. CYP1A1 activity was not enhanced. In summary, 0.5 g/kg po was the acute, short-term, and subchronic NOAEL for TRI, for effects other than transient CYP2E1 induction, under the conditions of this investigation. Oral TRI appears to have very limited capacity to induce P450s or to cause liver injury in male S-D rats, even when administered repeatedly by gavage in near-lethal or lethal dosages under conditions intended to maximize hepatic effects.
Bruckner
J V
JV
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, Georgia 30602-2352, USA. bruckner@rx.uga.edu
Kyle
G M
GM
Luthra
R
R
Acosta
D
D
Mehta
S M
SM
Sethuraman
S
S
Muralidhara
S
S
D000284:Administration, Oral; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D007064:L-Iditol 2-Dehydrogenase / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008136:Longevity / Q000187:drug effects; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D009929:Organ Size / Q000187:drug effects; D009954:Ornithine Carbamoyltransferase / Q000097:blood; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000008:administration & dosage / Q000633:toxicity*; D018675:Toxicity Tests; D014240:Trichloroethanes / Q000008:administration & dosage / Q000633:toxicity*; D015430:Weight Gain / Q000187:drug effects
D012997:Solvents; D014240:Trichloroethanes; C024566:1,1,1-trichloroethane; D003577:Cytochrome P-450 Enzyme System; D007064:L-Iditol 2-Dehydrogenase; D009954:Ornithine Carbamoyltransferase; D000410:Alanine Transaminase