Cancer risk assessment for crotonaldehyde and 2-hexenal: an approach.
Crotonaldehyde and 2-hexenal are bifunctional compounds that form 1,N2-propanodeoxyguanosine adducts and are mutagenic and genotoxic; crotonaldehyde is carcinogenic. Analysis of the mutations resulting from crotonaldehyde-induced DNA damage revealed the importance of deoxyguanosine adducts. Humans are exposed ubiquitously to these compounds by various routes. The highest daily intake of crotonaldehyde is assumed to be derived from cigarette smoke (31-169 micrograms/kg body weight), and the highest intake of 2-hexenal is probably from fruit and vegetables (31-165 micrograms/kg body weight per day). Because these compounds are suspected to play on important role in carcinogenicity, we developed sensitive 32P-postlabelling techniques for DNA adducts of crotonaldehyde and hexenal, in order to improve estimates of cancer risk. The respective standards were also synthesized and characterized spectroscopically. We report here the results of the 32P-postlabelling, e.g. the stability of the adducts in respect of nuclease P1 treatment, their labelling efficiencies, thin-layer chromatography of adduct spots and the recoveries and detection limits. In untreated male Fischer 344 rats, neither crotonaldehyde nor 2-hexenal adducts were detected, but crotonaldehyde adducts were found in the tissues of rats given single doses of 200 or 300 mg/kg body weight and in the livers of rats after repeated doses of 1 or 10 mg/kg body weight. The adduct levels were higher 20 h after gavage than after 12 h. The adducts persist to a certain extent. 2-Hexenal adducts were detected in tissues of male Fischer 344 rats after gavage with single doses of 50, 200 or 500 mg/kg body weight. The highest adduct levels were measured 48 h after gavage, but no adducts were found 8 h after gavage. Two approaches for cancer risk estimation are discussed. One is based on the correlation between the covalent binding index, calculated from adduct levels, and the median toxic dose (TD50) (Lutz, 1986) and showed a cancer risk of 1 per 10(7) lives for hexenal, assuming dietary intakes of 31-165 micrograms/kg body weight per day. The other is based on a cancer incidence of 0.07 at a dose of crotonaldehyde of 4.2 mg/kg body weight per day assessed from the study of Chung et al. (1986), which can be interpreted as a risk of 5.8-18 new cases per 10(4) smokers, assuming a consumption of 30 cigarettes per day. The latter approach may, however, lead to an overestimate of the cancer risk associated with exposure to crotonaldehyde; the estimate based on our binding studies resulted in a 20-fold lower estimate of the carcinogenic risk of crotonaldehyde.
Eder
E
E
Schuler
D
D
Budiawan
D000255:Adenosine Triphosphate / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D002855:Chromatography, Thin Layer; D018736:DNA Adducts / Q000378:metabolism; D004249:DNA Damage; D003849:Deoxyguanosine / Q000378:metabolism; D004032:Diet / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008099:Liver / Q000187:drug effects; D008297:Male; D008956:Models, Chemical; D009153:Mutagens / Q000633:toxicity; D009369:Neoplasms / Q000139:chemically induced*; D011116:Polynucleotide 5'-Hydroxyl-Kinase / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D018570:Risk Assessment; D014018:Tissue Distribution
D000447:Aldehydes; D002273:Carcinogens; D018736:DNA Adducts; D009153:Mutagens; C051750:2-hexenal; D000255:Adenosine Triphosphate; C012796:2-butenal; D011116:Polynucleotide 5'-Hydroxyl-Kinase; D003849:Deoxyguanosine