title: Dose-dependent DNA adduct formation by cinnamaldehyde and other food-borne α,β-unsaturated aldehydes predicted by physiologically based in silico modelling.
abstract: Genotoxicity of α,β-unsaturated aldehydes shown in vitro raises a concern for the use of the aldehydes as food flavourings, while at low dose exposures the formation of DNA adducts may be prevented by detoxification. Unlike many α,β-unsaturated aldehydes for which in vivo data are absent, cinnamaldehyde was shown to be not genotoxic or carcinogenic in vivo. The present study aimed at comparing dose-dependent DNA adduct formation by cinnamaldehyde and 18 acyclic food-borne α,β-unsaturated aldehydes using physiologically based kinetic/dynamic (PBK/D) modelling. In rats, cinnamaldehyde was predicted to induce higher DNA adducts levels than 6 out of the 18 α,β-unsaturated aldehydes, indicating that these 6 aldehydes may also test negative in vivo. At the highest cinnamaldehyde dose that tested negative in vivo, cinnamaldehyde was predicted to form at least three orders of magnitude higher levels of DNA adducts than the 18 aldehydes at their respective estimated daily intake. These results suggest that for all the 18 α,β-unsaturated aldehydes DNA adduct formation at doses relevant for human dietary exposure may not raise a concern. The present study illustrates a possible use of physiologically based in silico modelling to facilitate a science-based comparison and read-across on the possible risks posed by DNA reactive agents.
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands. Electronic address: reikokiwamoto@hotmail.co.jp.
authors.forename: R
authors.initials: R
authors.lastname: Kiwamoto
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: Ploeg
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors.forename: I M C M
authors.initials: IM
authors.lastname: Rietjens
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE Wageningen, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Punt
mesh_terms: D000426:Alcohol Dehydrogenase / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000378:metabolism; D000449:Aldehyde Reductase / Q000378:metabolism; D000447:Aldehydes / Q000633:toxicity*; D000818:Animals; D003198:Computer Simulation; D018736:DNA Adducts; D004032:Diet; D005260:Female; D005421:Flavoring Agents / Q000633:toxicity*; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D007421:Intestine, Small / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008954:Models, Biological; D009153:Mutagens / Q000633:toxicity*; D017207:Rats, Sprague-Dawley
chemical_list: D000447:Aldehydes; D018736:DNA Adducts; D005421:Flavoring Agents; D009153:Mutagens; D000426:Alcohol Dehydrogenase; D000449:Aldehyde Reductase; D000444:Aldehyde Dehydrogenase; D005982:Glutathione Transferase; D005978:Glutathione
keywords: Cinnamaldehyde; DNA adducts; Genotoxicity; Physiologically based kinetic/dynamic modelling; Read-across; α,β-Unsaturated aldehydes