title: A physiologically based in silico model for trans-2-hexenal detoxification and DNA adduct formation in human including interindividual variation indicates efficient detoxification and a negligible genotoxicity risk.
abstract: A number of α,β-unsaturated aldehydes are present in food both as natural constituents and as flavouring agents. Their reaction with DNA due to their electrophilic α,β-unsaturated aldehyde moiety may result in genotoxicity as observed in some in vitro models, thereby raising a safety concern. A question that remains is whether in vivo detoxification would be efficient enough to prevent DNA adduct formation and genotoxicity. In this study, a human physiologically based kinetic/dynamic (PBK/D) model of trans-2-hexenal (2-hexenal), a selected model α,β-unsaturated aldehyde, was developed to examine dose-dependent detoxification and DNA adduct formation in humans upon dietary exposure. The kinetic model parameters for detoxification were quantified using relevant pooled human tissue fractions as well as tissue fractions from 11 different individual subjects. In addition, a Monte Carlo simulation was performed so that the impact of interindividual variation in 2-hexenal detoxification on the DNA adduct formation in the population as a whole could be examined. The PBK/D model revealed that DNA adduct formation due to 2-hexenal exposure was 0.039 adducts/10⁸ nucleotides (nt) at the estimated average 2-hexenal dietary intake (0.04 mg 2-hexenal/kg bw) and 0.18 adducts/10⁸ nt at the 95th percentile of the dietary intake (0.178 mg 2-hexenal/kg bw) in the most sensitive people. These levels are three orders of magnitude lower than natural background DNA adduct levels that have been reported in disease-free humans (6.8-110 adducts/10⁸ nt), suggesting that the genotoxicity risk for the human population at realistic dietary daily intakes of 2-hexenal may be negligible.
authors.affiliation: Division of Toxicology, Wageningen University, Tuinlaan 5, 6703 HE, Wageningen, The Netherlands. reiko.kiwamoto@wur.nl
authors.forename: R
authors.initials: R
authors.lastname: Kiwamoto
authors.forename: A
authors.initials: A
authors.lastname: Spenkelink
authors.forename: I M C M
authors.initials: IM
authors.lastname: Rietjens
authors.forename: A
authors.initials: A
authors.lastname: Punt
mesh_terms: D000447:Aldehydes / Q000009:adverse effects / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D000818:Animals; D019295:Computational Biology; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D018736:DNA Adducts / Q000378:metabolism; D004032:Diet / Q000009:adverse effects*; D005103:Expert Systems; D005421:Flavoring Agents / Q000009:adverse effects / Q000378:metabolism* / Q000493:pharmacokinetics; D006801:Humans; D008658:Inactivation, Metabolic; D007421:Intestine, Small / Q000201:enzymology* / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology* / Q000378:metabolism; D008861:Microsomes / Q000201:enzymology / Q000378:metabolism; D008954:Models, Biological; D009010:Monte Carlo Method; D009152:Mutagenicity Tests; D051381:Rats; D015203:Reproducibility of Results; D018570:Risk Assessment / Q000379:methods
chemical_list: D000447:Aldehydes; D018736:DNA Adducts; D005421:Flavoring Agents; C051750:2-hexenal