Evaluation of possible genotoxic mechanisms for acrylonitrile tumorigenicity.
Acrylonitrile (ACN) exposure is associated with tumors in rat brain, Zymbal gland, and mammary gland. Adducts affecting base pairing were formed in isolated DNA exposed in vitro to the ACN metabolite cyanoethylene oxide (CNEO). DNA from liver, which is not a cancer target organ in ACN-exposed rats, contained low levels of 7-(2-oxoethyl)guanine, and adduct believed not to interfere with base pairing. No adducts have been detected in brain DNA from ACN-exposed rats, suggesting that brain tumors may have arisen by mechanisms other than ACN-DNA reactivity. Genotoxicity assays of ACN have indicated no particular carcinogenic mechanism. Positive reverse mutagenesis in Salmonella typhimurium HisG46 base substitution tester strains by ACN is attributable to CNEO. Other in vitro genotoxicity test assays of ACN have yielded mixed results, without consistent effect of metabolic activation. Some positive genotoxicity data for ACN appear to result from artifacts or from non-DNA-reactive mechanisms. In vivo micronucleus, chromosome aberration, and autoradiographic unscheduled DNA synthesis assays were negative for ACN. The comparative genotoxicity of vinyl chloride and ACN indicates that despite other similarities, they cause rodent tumors by different mechanisms. Also, they absence of ACN-DNA adduct formation in the rat brain suggests the operation of epigenetic mechanisms.
Toxicology and Risk Assessment Program, American Health Foundation, Valhalla, New York 10595, USA.
J
J
Whysner
P M
PM
Ross
C C
CC
Conaway
L K
LK
Verna
G M
GM
Williams
D000181:Acrylonitrile / Q000494:pharmacology / Q000633:toxicity*; D000818:Animals; D001345:Autoradiography; D001932:Brain Neoplasms / Q000139:chemically induced* / Q000503:physiopathology; D002869:Chromosome Aberrations; D004247:DNA / Q000096:biosynthesis; D018736:DNA Adducts; D009152:Mutagenicity Tests; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics
D018736:DNA Adducts; D004247:DNA; D000181:Acrylonitrile