Cancer risk assessment for the environmental mutagen and carcinogen crotonaldehyde on the basis of TD₅₀ and comparison with 1,N₂-propanodeoxyguanosine adduct levels

Humans are ubiquitously exposed to crotonaldehyde to a strongly varying extent, in particular, via food and alcoholic beverages. Like other α,β-unsaturated carbonyl compounds, crotonaldehyde forms 1,N²propanodeoxyguanosine adducts and is genotoxic, mutagenic, and carcinogenic. This study was designed to perform a cancer risk assessment on the basis of TD⁵⁰, which 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 via food and beverages. A relatively high cancer risk of 0.1-1 cancer incidence/10³ 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. To compare the 1,N²-propanodeoxyguanosine DNA adduct levels of crotonaldehyde with the assessed cancer risk, we synthesized adduct standards and developed a ³²P-postlabeling method for DNA adducts of crotonaldehyde providing a detection limit of 3 adducts/10⁹ nucleotides. Repeated gavages of 10 and 1 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 crotonaldehyde intakes were in the range of 3 adducts/10⁹ nucleotides. The adducts persisted to a certain extent. The persistence is important for considering the steady-state situation after permanent intakes of crotonaldehyde via food. However, the adducts are repaired to some extent; 2 weeks after the last of repeated gavages, only 19% of the initial amount measured directly after the last gavage is left. According to our results, a steady-state concentration in the range of 3 adducts/10⁹ 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,N²-propanodeoxyguanosine adducts considered here. No propanodeoxyguanosine adducts of crotonaldehyde were found in the DNA of untreated animals in our studies.