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    Food and Chemical Toxicology
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    Cancer risk estimation of glycidol based on rodent carcinogenicity studies, a T multiplicative risk model and in vivo dosimetry
    Jenny Aasaa,∗, Fredrik Granathb, Margareta Törnqvista,∗∗
    a Department of Environmental Science and Analytical Chemistry, Stockholm University, Sweden b Department of Medicine, Solna, Clinical Epidemiology Division, Karolinska Institute, Stockholm, Sweden
    Cancer risk estimation
    Multiplicative risk model
    Internal dose
    Hb adducts 
    Here we evaluate a multiplicative (relative) risk model for improved cancer risk estimation of genotoxic com-pounds. According to this model, cancer risk is proportional to the background tumor incidence and to the internal dose of the genotoxic compound. Furthermore, the relative risk coefficient per internal dose is con-sidered to be approximately the same across tumor sites, sex, and species.
    In the present study, we demonstrate that the relative risk model is valid for cancer risk estimation of glycidol, a common food contaminant. Published tumor data from glycidol carcinogenicity studies in mice and rats were evaluated in combination with internal dose estimates from Temozolomide adduct measurements in blood from mice and rats treated with glycidol in short-term studies. A good agreement between predicted and observed tumor incidence in responding sites was demonstrated in the animals, supporting a relative risk coefficient that is independent of tumor site, sex, and species. There was no significant difference between the risk coefficients for mice (5.1% per mMh) and rats (5.4% per mMh) when considering internal doses of glycidol. Altogether, this mechanism-based risk model gives a reliable risk coefficient, which then was extrapolated to humans con-sidering internal dose, and background cancer incidence.
    1. Introduction
    The risk for cancer is dependent on interactions between intrinsic factors and exposure to environmental risk factors, including diet, occupational exposures, smoking, and air pollution (NTP, 2016). Hereditary mutations, and particularly spontaneous mutations induced during DNA replication have been discussed lately as important intrinsic factors (Tomasetti et al., 2017; Tomasetti and Vogelstein, 2015). Electrophilic compounds produced endogenously during normal meta-bolism should also be considered as intrinsic cancer risk factors and are indeed included in the concept of the exposome - the sum of all exposures to an individual over a lifetime (Rappaport, 2016; Wild, 2005).
    Avoiding all cancer risk factors in everyday life is not possible, but a reduction of certain exposures would be beneficial to human health. The human diet contains many undesirable chemicals, including genotoxic compounds formed during food-processing (c.f. e.g. Jägerstad and Skog, 2005; Chaundhry et al., 2006). One well known example is acrylamide, formed during preparation of food at high temperatures (Tareke et al.,
    2002). Acrylamide is metabolized to the genotoxic and carcinogenic me-tabolite glycidamide (Beland et al., 2015; Vikström et al., 2011; Sumner et al., 1992). Another example of contaminants in food are glycidyl fatty acid esters, which are compounds that occur in, for example, heat-processed edible oils. The ester bonds are hydrolyzed in the gastrointestinal tract (Appel et al., 2013), resulting in the genotoxic and carcinogenic compound glycidol (IARC, 2000). In the present study, glycidol is used as a model compound for the evaluation of an approach for cancer risk estimation.
    Cancer risk estimates for a compound can be obtained by different approaches but are normally based on data from standardized rodent carcinogenicity studies, whereby at least 50 animals of each sex at each dose level (≥3 levels plus control) are used for the test species, mouse and rat (OECD, 2009). For genotoxic carcinogens in food, linear ex-trapolations from high dose-response data are used, e.g. as in an ad-ditive model used by the U.S. Environmental Protection Agency, EPA (2005a). In 2005, the European Food Safety Authority (EFSA) proposed a harmonized approach for genotoxic carcinogens. The recommenda-tion was to apply the Margin of Exposure (MOE) approach, where a
    Abbreviations: AUC, area under the concentration-time curve; b.w., body weight; diHOPrVal, N-(2,3-dihydroxypropyl)valine; FITC, fluorescein isothiocyanate; FTH, fluorescein thiohydantoin; Hb, hemoglobin; HRMS, high-resolution mass spectrometry ∗ Corresponding author. Stockholm University, SE-10691, Stockholm, Sweden. ∗∗ Corresponding author. Stockholm University, SE-10691, Stockholm, Sweden.