Cancer risk assessment for the environmental mutagen and carcinogen crotonaldehyde on the basis of TD50 and comparison with 1,N-2-propanodeoxyguanosine adduct levels

Humans are ubiquitously exposed to crotonaldehyde to a strongly varying ext ent, in particular, via food and alcoholic beverages. Like other alpha,beta -unsaturated carbonyl compounds, crotonaldehyde forms 1,N-2- propanodeoxyg uanosine adducts and is genotoxic, mutagenic, and carcinogenic. This study was designed to perform a cancer risk assessment on the basis of TD50, whic h was available from a long-term cancer study with F-344 rats (F. L. Chung et al., Cancer Res., 46: 1285-1289, 1986), and the estimated daily intake v ia food and beverages. A relatively high cancer risk of 0.1-1 cancer incide nce/10(3) humans was extrapolated on the basis of the TD50 from the cancer study of Chung et al. for the estimated dietary intake and drinking wine. T o compare the 1,N-2-propanodeoxyguanosine DNA adduct levels of crotonaldehy de with the assessed cancer risk, we synthesized adduct standards and devel oped a P-32-postlabeling method for DNA adducts of crotonaldehyde providing a detection limit of 3 adducts/10(9) nucleotides. Repeated gavages of 10 a nd I mg/kg were given to simulate the steady-state situation of the animal cancer study of Chung et al and to estimate the adduct levels after intake of crotonaldehyde via food. The estimated adduct levels at these crotonalde hyde intakes were in the range of 3 adducts/10(9) nucleotides. The adducts persisted to a certain extent. The persistence is important for considering the steady-state situation after permanent intakes of crotonaldehyde via f ood. However, the adducts are repaired to some extent; 2 weeks after the la st of repeated gavages, only 19% of the initial amount measured directly af ter the last gavage is left. According to our results, a steady-state conce ntration in the range of 3 adducts/10(9) nucleotides is responsible for the induction of cancer in the study of Chung et al., in the case that cancer from crotonaldehyde depends exclusively on the 1,N-2-propanodeoxyguanosine adducts considered here. No propanodeoxyguanosine adducts of crotonaldehyde were found in the DNA of untreated animals in our studies.