Increased formic acid excretion and the development of kidney toxicity in rats following chronic dosing with trichloroethanol, a major metabolite of trichloroethylene.
The chronic toxicity of trichloroethanol, a major metabolite of trichloroethylene, has been assessed in male Fischer rats (60 per group) given trichloroethanol in drinking water at concentrations of 0, 0.5 and 1.0 g/l for 52 weeks. The rats excreted large amounts of formic acid in urine reaching a maximum after 12 weeks ( approximately 65 mg/24 h at 1 g/l) and thereafter declining to reach an apparent steady state at 40 weeks (15-20 mg/24 h). Urine from treated rats was more acidic throughout the study and urinary methylmalonic acid and plasma N-methyltetrahydrofolate concentrations were increased, indicating an acidosis, vitamin B12 deficiency and impaired folate metabolism, respectively. The rats treated with trichloroethanol developed kidney damage over the duration of the study which was characterised by increased urinary NAG activity, protein excretion (from 4 weeks), increased basophilia, protein accumulation and tubular damage (from 12 to 40 weeks), increased cell replication (at week 28) and evidence in some rats of focal proliferation of abnormal tubules at 52 weeks. It was concluded that trichloroethanol, the major metabolite of trichloroethylene, induced nephrotoxicity in rats as a result of formic acid excretion and acidosis.
Green
Trevor
T
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, UK. trevor.green@syngenta.com
Dow
Jacky
J
Foster
John
J
D000117:Acetylglucosamine / Q000097:blood; D000818:Animals; D001774:Blood Chemical Analysis; D001973:Bromodeoxyuridine / Q000378:metabolism; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives* / Q000378:metabolism; D005561:Formates / Q000097:blood / Q000652:urine*; D006651:Histocytochemistry; D007674:Kidney Diseases / Q000139:chemically induced* / Q000652:urine; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000652:urine; D008297:Male; D008764:Methylmalonic Acid / Q000652:urine; D011897:Random Allocation; D051381:Rats; D011916:Rats, Inbred F344; D012737:Sex Factors; D014241:Trichloroethylene / Q000378:metabolism / Q000633:toxicity*
D005561:Formates; C030544:formic acid; D014241:Trichloroethylene; D005023:Ethylene Chlorohydrin; D008764:Methylmalonic Acid; C005849:2,2,2-trichloroethanol; D001973:Bromodeoxyuridine; D000117:Acetylglucosamine