Trichloroethylene-induced mouse lung tumors: studies of the mode of action and comparisons between species.
CD-1 mice exposed to 450 ppm trichloroethylene, 6 hr/day, 5 days/week, for 2 weeks showed a marked vacuolation of lung Clara cells after the first exposure of each week and a marked increase in cell division after the last exposure of each week. The damage seen in mouse lung Clara cells is caused by an accumulation of chloral resulting from high rates of metabolism of trichloroethylene but poor clearance of chloral to trichloroethanol and its glucuronide. The activity and distribution of the key metabolizing enzymes in this pathway have been compared in mouse, rat, and human lung. While mouse lung microsomal fractions were able to metabolize trichloroethylene to chloral at significant rates, the rate in rat lung was 23-fold lower and a rate could not be detected in human lung microsomes at all. Immunolocalization of cytochrome P450IIE1 in lung sections revealed high concentrations in mouse lung Clara cells with lesser amounts in type II cells. Lower levels of enzyme could be detected in Clara cells of rat lung, but not at all in human lung sections. Western blots of lung tissues from the three species and of mouse lung Clara cells were entirely consistent with these observations. Consequently, it is highly unlikely that humans exposed to trichloroethylene are at risk from the lung damage/cell proliferation mechanism that is believed to lead to the development of tumors in the mouse lung.
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Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, United Kingdom.
Mainwaring
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GW
Foster
J R
JR
D000280:Administration, Inhalation; D000818:Animals; D015153:Blotting, Western; D002455:Cell Division; D002697:Chloral Hydrate / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D019392:Cytochrome P-450 CYP2E1 / Q000378:metabolism*; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives / Q000378:metabolism; D005260:Female; D005965:Glucuronates / Q000378:metabolism; D006801:Humans; D007124:Immunoenzyme Techniques; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D017208:Rats, Wistar; D012997:Solvents / Q000378:metabolism / Q000633:toxicity*; D013045:Species Specificity; D014241:Trichloroethylene / Q000378:metabolism / Q000633:toxicity*
D005965:Glucuronates; D012997:Solvents; D014241:Trichloroethylene; D002697:Chloral Hydrate; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol; D019392:Cytochrome P-450 CYP2E1; C021100:trichloroacetaldehyde