Pulmonary toxicity and carcinogenicity of trichloroethylene: species differences and modes of action.
Trichloroethylene (TCE) is both acutely toxic and carcinogenic to the mouse lung following exposure by inhalation. In contrast, it is not carcinogenic in the rat lung and is markedly less toxic following acute exposure. Toxicity to the mouse lung is confined almost exclusively to the nonciliated Clara cell and is characterized by vacuolation and increases in cell replication. Chloral, a metabolite of TCE that accumulates in Clara cells and has been shown to be the cause of the toxicity, also causes aneuploidy in some test systems. Cytotoxicity, increased cell division, and aneuploidy are known risk factors in the development of cancer and provide a plausible mode of action for TCE as a mouse lung carcinogen. All acute and chronic effects of TCE on the mouse lung are believed to be a direct consequence of high cytochrome P450 activity and impaired metabolism of chloral in Clara cells. Comparisons between species suggest that the ability of the human lung to metabolize TCE is approximately 600-fold less than that in the mouse. In addition, the human lung differs markedly from the mouse lung in the number and morphology of its Clara cells. Thus, the large quantitative differences between the metabolic capacity of the mouse lung and the human lung, together with the species differences in the number and morphology of lung Clara cells, suggest that the risks to humans are minimal and that other tumor sites should take precedent over the lung when assessing the potential risks to humans exposed to TCE.
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Zeneca Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, United Kingdom. trvor.green@ctl.zeneca.com
D000818:Animals; D002274:Carcinogens, Environmental / Q000009:adverse effects / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000139:chemically induced; D013045:Species Specificity; D014241:Trichloroethylene / Q000009:adverse effects / Q000378:metabolism / Q000633:toxicity*
D002274:Carcinogens, Environmental; D014241:Trichloroethylene