Evaluation of the developmental toxicity of trichloroethylene and detoxification metabolites using Xenopus.
Potential mechanisms of trichloroethylene-induced developmental toxicity were evaluated using FETAX (Frog Embryo Teratogenesis Assay--Xenopus). Early Xenopus laevis embryos were exposed to trichloroethylene for 96 h in two separate definitive concentration-response assays with and without an exogenous metabolic activation system (MAS) and inhibited MAS. The MAS was treated with either carbon monoxide or cyclohexene oxide to modulate mixed-function oxidase (MFO) or epoxide hydrolase activity, respectively. Trichloroethylene metabolites: dichloroacetic acid, trichloroacetic acid, trichloroethanol, and oxalic acid were also evaluated in two separate definitive, static renewal tests. Addition of the MAS decreased the 96 h LC50 and EC50 (malformation) of trichloroethylene 1.8-fold and 3.8-fold, respectively. Addition of the carbon monoxide inhibited MAS decreased the developmental toxicity of activated trichloroethylene to levels approximating that of the parent compound. Cyclohexene oxide-inhibited MAS substantially increased the developmental toxicity of trichloroethylene. In addition, each of the metabolites tested were significantly less developmental toxic than the parent compound, trichloroethylene. Results indicate that a highly embryotoxic epoxide intermediate, trichloroethylene oxide, formed as the results of MFO mediated metabolism may play a significant role in the developmental toxicity of trichloroethylene in vitro.
Fort
D J
DJ
Stover Biometric Laboratories, Inc., Oklahoma State University, Stillwater 74076.
Stover
E L
EL
Rayburn
J R
JR
Hull
M
M
Bantle
J A
JA
D000818:Animals; D002248:Carbon Monoxide; D003510:Cyclohexanes; D053138:Cyclohexenes; D003999:Dichloroacetic Acid; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives; D066298:In Vitro Techniques; D008658:Inactivation, Metabolic; D008297:Male; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors; D010070:Oxalates; D019815:Oxalic Acid; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*; D014238:Trichloroacetic Acid; D014241:Trichloroethylene / Q000633:toxicity*; D014982:Xenopus laevis
D003510:Cyclohexanes; D053138:Cyclohexenes; D010070:Oxalates; D013723:Teratogens; C044588:1,1,2-trichloroethanol; C007193:cyclohexene oxide; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D005023:Ethylene Chlorohydrin; D002248:Carbon Monoxide; D019815:Oxalic Acid; D003999:Dichloroacetic Acid; D006899:Mixed Function Oxygenases; D004851:Epoxide Hydrolases