An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

Kiwamoto, R.; Spenkelink, A.; Rietjens, Ivonne M.C.M.; Punt, Ans

doi:10.1016/j.taap.2014.10.014

Cited by 12 publications

(7 citation statements)

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“…Continuous endogenous background exposure likely is not confined just to AA and AC but may comprise further electrophiles, arising from intermediary energy metabolism and/or from the human gut microbiome, including, for instance, several Michael reactive alkenals (Kiwamoto et al 2015 ). Future epidemiological studies should take note of the consequences regarding the dosimetry of total human exposure.…”

Section: Introductionmentioning

confidence: 99%

Revisiting the evidence for genotoxicity of acrylamide (AA), key to risk assessment of dietary AA exposure

Eisenbrand

2020

Arch Toxicol

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The weight of evidence pro/contra classifying the process-related food contaminant (PRC) acrylamide (AA) as a genotoxic carcinogen is reviewed. Current dietary AA exposure estimates reflect margins of exposure (MOEs) < 500. Several arguments support the view that AA may not act as a genotoxic carcinogen, especially not at consumer-relevant exposure levels: Biotransformation of AA into genotoxic glycidamide (GA) in primary rat hepatocytes is markedly slower than detoxifying coupling to glutathione (GS). Repeated feeding of rats with AA containing foods, bringing about uptake of 100 µg/kg/day of AA, resulted in dose x time-related buildup of AA-hemoglobin (Hb) adducts, whereas GA-Hb adducts remained within the background. Since hepatic oxidative biotransformation of AA into GA was proven by simultaneous urinary mercapturic acid monitoring it can be concluded that at this nutritional intake level any GA formed in the liver from AA is quantitatively coupled to GS to be excreted as mercapturic acid in urine. In an oral single dose–response study in rats, AA induced DNA N7-GA-Gua adducts dose-dependently in the high dose range (> 100 µg/kg b w). At variance, in the dose range below 100 µg/kg b.w. down to levels of average consumers exposure, DNA N7 -Gua lesions were found only sporadically, without dose dependence, and at levels close to the lower bound of similar human background DNA N7-Gua lesions. No DNA damage was detected by the comet assay within this low dose range. GA is a very weak mutagen, known to predominantly induce DNA N7-GA-Gua adducts, especially in the lower dose range. There is consensus that DNA N7-GA-Gua adducts exhibit rather low mutagenic potency. The low mutagenic potential of GA has further been evidenced by comparison to preactivated forms of other process-related contaminants, such as N-Nitroso compounds or polycyclic aromatic hydrocarbons, potent food borne mutagens/carcinogens. Toxicogenomic studies provide no evidence supporting a genotoxic mode of action (MOA), rather indicate effects on calcium signalling and cytoskeletal functions in rodent target organs. Rodent carcinogenicity studies show induction of strain- and species-specific neoplasms, with MOAs not considered likely predictive for human cancer risk. In summary, the overall evidence clearly argues for a nongenotoxic/nonmutagenic MOA underlying the neoplastic effects of AA in rodents. In consequence, a tolerable intake level (TDI) may be defined, guided by mechanistic elucidation of key adverse effects and supported by biomarker-based dosimetry in experimental systems and humans.

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Section: Introductionmentioning

confidence: 99%

Revisiting the evidence for genotoxicity of acrylamide (AA), key to risk assessment of dietary AA exposure

Eisenbrand

2020

Arch Toxicol

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“…For example the data reviewed above on acrylamide DNA adduct formation revealed that upon single oral AA application in the dose range up to 100 µg/kg bw to rats the resulting tissue DNA adduct levels are considerably lower than reported for human background levels of structurally related N7-dG adducts (Wu et al 1999 ; Cheng et al 2010 ; Watzek et al 2012a ). Furthermore, a PBK study on acrolein revealed that at realistic dietary intake, the predicted formation of acrolein-DNA adducts in the liver is predicted to be orders of magnitude lower than endogenous background levels of structurally similar 1, N 2 -exocyclic deoxyguanosine adducts observed in disease free human liver (Kiwamoto et al 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…Being an α,β-unsaturated aldehyde, acrolein reacts with cellular nucleophiles including proteins and DNA and forms conjugates with glutathione. The reaction with glutathione presents an important pathway for its detoxification unless glutathione levels are depleted (Ohno et al 1985 ; Silva and O’Brien 1989 ; Kehrer and Biswal 2000 ; Kiwamoto et al 2015 ).…”

Section: State Of the Artmentioning

confidence: 99%

“…Kiwamoto et al ( 2015 ) developed physiologically based kinetic/dynamic models to examine dose-dependent detoxification and DNA adduct formation of a group of 18 food-borne acyclic α,β-unsaturated aldehydes, including acrolein. Acrolein was identified to induce the highest DNA adduct levels among the 18 aldehydes tested, primarily due to its relatively lower detoxification efficiency via oxidation or glutathione S -transferase-mediated mediated GSH conjugation.…”

Section: State Of the Artmentioning

confidence: 99%

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Exposure assessment of process-related contaminants in food by biomarker monitoring

et al. 2018

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Exposure assessment is a fundamental part of the risk assessment paradigm, but can often present a number of challenges and uncertainties. This is especially the case for process contaminants formed during the processing, e.g. heating of food, since they are in part highly reactive and/or volatile, thus making exposure assessment by analysing contents in food unreliable. New approaches are therefore required to accurately assess consumer exposure and thus better inform the risk assessment. Such novel approaches may include the use of biomarkers, physiologically based kinetic (PBK) modelling-facilitated reverse dosimetry, and/or duplicate diet studies. This review focuses on the state of the art with respect to the use of biomarkers of exposure for the process contaminants acrylamide, 3-MCPD esters, glycidyl esters, furan and acrolein. From the overview presented, it becomes clear that the field of assessing human exposure to process-related contaminants in food by biomarker monitoring is promising and strongly developing. The current state of the art as well as the existing data gaps and challenges for the future were defined. They include (1) using PBK modelling and duplicate diet studies to establish, preferably in humans, correlations between external exposure and biomarkers; (2) elucidation of the possible endogenous formation of the process-related contaminants and the resulting biomarker levels; (3) the influence of inter-individual variations and how to include that in the biomarker-based exposure predictions; (4) the correction for confounding factors; (5) the value of the different biomarkers in relation to exposure scenario’s and risk assessment, and (6) the possibilities of novel methodologies. In spite of these challenges it can be concluded that biomarker-based exposure assessment provides a unique opportunity to more accurately assess consumer exposure to process-related contaminants in food and thus to better inform risk assessment.

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“…(Q) SARs for kinetics aim at the use of chemical descriptors of a compound to predict kinetic parameters such as rate of absorption, metabolism or the type of metabolites that might be formed (Kiwamoto et al, 2015;Pirovano et al, 2014). PBPK models mathematically describe the absorption, distribution, metabolism, and excretion of a chemical in an organism based on a series of ordinary differential equations and are used to simulate the fate of chemicals in a body (Rietjens et al, 2010).…”

Section: Background On Available In Silico Methods For Kineticsmentioning

confidence: 99%

Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

Punt

2017

ALTEX

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An integrated QSAR-PBK/D modelling approach for predicting detoxification and DNA adduct formation of 18 acyclic food-borne α,β-unsaturated aldehydes

Cited by 12 publications

References 42 publications

Revisiting the evidence for genotoxicity of acrylamide (AA), key to risk assessment of dietary AA exposure

Revisiting the evidence for genotoxicity of acrylamide (AA), key to risk assessment of dietary AA exposure

Exposure assessment of process-related contaminants in food by biomarker monitoring

Non-animal approaches for toxicokinetics in risk evaluations of food chemicals

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