EVALUATION OF POSSIBLE GENOTOXIC MECHANISMS FOR ACRYLONITRILE TUMORIGENICITY

Citation
J. Whysner et al., EVALUATION OF POSSIBLE GENOTOXIC MECHANISMS FOR ACRYLONITRILE TUMORIGENICITY, Regulatory toxicology and pharmacology, 27(3), 1998, pp. 217-239
Citations number
130
Categorie Soggetti
Medicine, Legal","Pharmacology & Pharmacy",Toxicology
ISSN journal
02732300
Volume
27
Issue
3
Year of publication
1998
Pages
217 - 239
Database
ISI
SICI code
0273-2300(1998)27:3<217:EOPGMF>2.0.ZU;2-F
Abstract
Acrylonitrile (ACN) exposure is associated with tumors in rat brain, Z ymbal gland, and mammary gland. Adducts affecting base pairing were fo rmed in isolated DNA exposed in vitro to the ACN metabolite cyano-ethy lene oxide (CNEO). DNA from liver, which is not a cancer target organ in ACN-exposed rats, contained low levels of 7-(2-oxoethyl)guanine, an adduct believed not to interfere with base pairing. No adducts have b een detected in brain DNA from ACN-exposed rats, suggesting that brain tumors may have arisen by mechanisms other than ACN-DNA reactivity. G enotoxicity assays of ACN have indicated no particular carcinogenic me chanism. Positive reverse mutagenesis in Salmonella typhimurium HisG46 base substitution tester strains by ACN is attributable to CNEO. Othe r in vitro genotoxicity test assays of ACN have yielded mixed results, without consistent effect of metabolic activation. Some positive geno toxicity data for ACN appear to result from artifacts or from non-DNA- reactive mechanisms. lit vivo micronucleus, chromosome aberration, and autoradiographic unscheduled DNA synthesis assays were negative for A CN. The comparative genotoxicity of vinyl chloride and ACN indicates t hat despite other similarities, they cause rodent tumors by different mechanisms. Also, the absence of ACN-DNA adduct formation in the rat b rain suggests the operation of epigenetic mechanisms. (C) 1998 Academi c Press.