Assessment of the genotoxicity of trichloroethylene and its metabolite, S-(1,2-dichlorovinyl)-L-cysteine (DCVC), in the comet assay in rat kidney.
Trichloroethylene (TCE) has been reported to give a small, but significant, increase in renal tumours in the rat. These tumours were always associated with nephrotoxicity which is most likely caused by the metabolism of TCE to S-(1,2-dichlorovinyl)-L-cysteine (DCVC) which accumulates in the proximal tubules. The genotoxicity of TCE and DCVC have been evaluated in vivo using the comet assay to assess DNA breakage in the proximal tubules of rat kidneys. Rats were exposed to TCE by inhalation or to DCVC by oral gavage at dose levels in excess of those which produced effects in long-term bioassays. Cell suspensions were produced from proximal tubules isolated from the kidneys of treated rats and the level of DNA damage assessed in these cells using the pH >13 comet assay. In vitro and in vivo positive controls were included and demonstrated the sensitivity of the assay. TCE gave a clearly negative response in the assay at all dose levels as did DCVC at the 16-h sampling time and at the 2-h sampling time with the lower dose level. At the 2-h sampling time following administration of DCVC at the higher dose level (10 mg/kg), there was limited evidence of DNA damage in a small number of animals, but this was considered insufficient to indicate a positive response in this assay. These data support an overall conclusion, based on these and other published data, that the renal tumours seen in bioassays are non-genotoxic in origin.
Clay
Philip
P
Syngenta Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, SK10 4TJ, UK. phil.clay@mac.com
D000818:Animals; D002478:Cells, Cultured; D020552:Comet Assay; D003545:Cysteine / Q000031:analogs & derivatives* / Q000633:toxicity; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D007687:Kidney Tubules, Proximal / Q000187:drug effects*; D008297:Male; D009153:Mutagens / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000633:toxicity*; D014241:Trichloroethylene / Q000633:toxicity*
D009153:Mutagens; D012997:Solvents; D014241:Trichloroethylene; C039961:S-(1,2-dichlorovinyl)cysteine; D004247:DNA; D003545:Cysteine