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  • 1.
    Aasa, Jenny
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Cancer Risk Assessment of Glycidol: Evaluation of a Multiplicative Risk Model for Genotoxic Compounds2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Humans are exposed to chemical compounds in everyday life, both from the environment and from endogenous processes. Some compounds constitute a risk for cancer development. One such compound is glycidol, which is genotoxic and an animal carcinogen. It is the model compound of this work, partly due to its presence in food. Glycidol, often together with 3-monochloropropane-1,2-diol (3-MCPD), occurs in the form of esters particularly in refined cooking oils, which are used in a variety of food products. The esters are hydrolyzed in the gastrointestinal tract to form glycidol (and 3-MCPD).

    The aim of the thesis has been to evaluate an approach for cancer risk estimation of genotoxic carcinogens based on a multiplicative (relative) risk model and genotoxic potency. Further, the aim was to estimate the cancer risk for exposure to glycidol via food. Measurement of the internal doses (concentration × time) of glycidol in the studied biological systems, including humans, has been crucial. Glycidol is electrophilic and forms adducts with nucleophilic sites in proteins and DNA. The doses of glycidol were quantified by mass spectrometry: in vivo from adduct levels to hemoglobin (Hb); in vitro from adducts to cob(I)alamin.

    The first part of the thesis concerns the genotoxic potency (genotoxic response per internal dose) of glycidol, measured in vitro by mutation studies and in vivo by micronuclei as a biomarker for genotoxicity (short-term studies in mice). The results were compared to that of ionizing radiation, used as a standard, to estimate the relative genotoxic potency of glycidol: 10 and 15 rad-equ./mMh from mutations and micronuclei, respectively. No induction of micronuclei was observed for the related compound 3-MCPD.

    Tumor incidence from published carcinogenicity studies of glycidol in mice and rats, together with the measured in vivo doses, was evaluated with the relative cancer risk model. A good agreement between predicted and observed tumor incidence was shown, and no significant difference of the obtained cancer risk coefficients (risk per dose) between mice (5.1 % per mMh) and rats (5.4 % per mMh) was observed. The overall results support that the relative risk coefficient (β) is independent of sex, tumor site, and species, and indicated that it can be transferred also to humans. The doubling dose, expressed as 1/β, is the dose that is required to double the background tumor incidence. The mean of the doubling doses from mice and rats (19 mMh) was assumed valid for risk estimation for humans. Transfer of β of glycidol to rad-equ. via its relative genotoxic potency showed a risk coefficient in agreement with the relative cancer risk coefficient of ionizing radiation.

    In the final work, the lifetime (70 years) in vivo doses of glycidol were calculated from measured Hb adduct levels in blood from 50 children and 12 adults, and compared to the doubling dose. A fivefold variation was observed in the in vivo doses. The estimated lifetime excess cancer risk from glycidol exceeds 1/1000. This is much higher than what is considered as an acceptable risk.

    To conclude, the multiplicative (relative) risk model together with relative genotoxic potency is promising to use in an approach for cancer risk estimation and in line with 3R (reduce-refine-replace) initiatives.

  • 2.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Carlsson, Henrik
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    The genotoxic potency of glycidol established from micronucleus frequency and hemoglobin adduct levels in mice2017In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 100, p. 168-174Article in journal (Refereed)
    Abstract [en]

    Glycidol is a genotoxic animal carcinogen that has raised concern due to its presence in food, as glycidyl fatty acid esters. Here we investigated the genotoxicity of glycidol in BalbC mice (0-120 mg/kg) by monitoring the induction of micronuclei in peripheral blood as a marker of chromosomal damage. The scoring of the micronuclei was assessed by flow cytometry. In the treated mice, the internal dose of glycidol, expressed as area under the concentration-time curve, AUC (mol x L-1 x h; Mh), was measured by dihydroxypropyl adducts to hemoglobin (Hb). The study showed that glycidol induced linear dose dependent increases of Hb adducts (20 pmol/g Hb per mg/kg) and of micronuclei frequencies (12 parts per thousand per mMh). Compared to calculations based on administered dose, an improved dose-response relationship was observed when considering internal dose, achieved through the applied combination of sensitive techniques used for the scoring of micronuclei and AUC estimation of glycidol in the same mice. By comparing with earlier studies on micronuclei induction in mice exposed to ionizing radiation we estimated the radiation dose equivalent (rad-eq.) of glycidol to be ca 15 rad-eq./mMh.

  • 3.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Granath, Fredrik
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Cancer risk estimation of glycidol based on rodent carcinogenicity studies, a multiplicative risk model and in vivo dosimetry2019In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 128, p. 54-60Article in journal (Refereed)
    Abstract [en]

    Here we evaluate a multiplicative (relative) risk model for improved cancer risk estimation of genotoxic compounds. 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 considered 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 hemoglobin 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 considering internal dose, and background cancer incidence.

  • 4.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry. National Food Agency, Sweden.
    Measurement of micronuclei and internal dose in mice demonstrates that 3-monochloropropane-1,2-diol (3-MCPD) has no genotoxic potency in vivo2017In: Food and Chemical Toxicology, ISSN 0278-6915, E-ISSN 1873-6351, Vol. 109, p. 414-420Article in journal (Refereed)
    Abstract [en]

    In this study 3-monochloropropane-1,2-diol (3-MCPD), a compound that appears as contaminant in refined cooking oils, has been studied with regard to genotoxicity in vivo (mice) with simultaneous measurement of internal dose using state-of-the-art methodologies. Genotoxicity (chromosomal aberrations) was measured by flow cytometry with dual lasers as the frequency of micronuclei in erythrocytes in peripheral blood from BalbC mice intraperitoneally exposed to 3-MCPD (0, 50, 75, 100, 125 mg/kg). The internal doses of 3-MCPD in the mice were calculated from N-(2,3-dihydroxypropyl)-valine adducts to hemoglobin (Hb), quantified at very low levels by high-resolution mass spectrometry.

    Convincing evidence for absence of genotoxic potency in correlation to measured internal doses in the mice was demonstrated, despite relatively high administered doses of 3-MCPD. The results are discussed in relation to another food contaminant that is formed as ester in parallel to 3-MCPD esters in oil processing, i.e. glycidol, which has been studied previously by us in a similar experimental setup. Glycidol has been shown to be genotoxic, and in addition to have ca. 1000 times higher rate of adduct formation compared to that observed for 3-MCPD. The conclusion is that at simultaneous exposure to 3-MCPD and glycidol the concern about genotoxicity would be glycidol.

  • 5.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Granath, Fredrik
    Cancer risk estimation of glycidol based on rodent carcinogenicity studies, a multiplicative risk model and in vivo dosimetryManuscript (preprint) (Other academic)
    Abstract [en]

    Here we evaluate a multiplicative (relative) risk model for more reliable cancer risk estimations of genotoxic compounds. According to this model, cancer risk is proportional to background tumor incidence and to internal dose of the genotoxic compound. A relative risk coefficient is considered to be common across species, sex, and tumor sites. The model has previously been shown to be successfully applied to rodent carcinogenicity data for a few genotoxic compounds. The aim of the present study was to evaluate this risk model for glycidol, a common food contaminant. Tumor data from published glycidol carcinogenicity studies in mice and rats were evaluated with the model, using internal doses estimated from hemoglobin adduct measurements in blood of B6C3F1 mice and Sprague Dawley rats treated with glycidol in short-term exposure studies.

    The evaluation demonstrated that the relative risk model is valid for glycidol. A good agreement between predicted and observed tumor incidence was demonstrated in the animals, supporting a relative risk coefficient that is independent of species, sex, and tumor site. There was no significant difference of the risk coefficients between mice (5.1 % per mMh) and rats (7.1 % per mMh) when the internal doses of glycidol were considered. Altogether, this mechanism-based risk model gives a common and more reliable risk coefficient which could be extrapolated to humans via internal dose measurements, and by considering the background cancer incidence.

  • 6.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Vare, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Motwani, Hitesh V.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Jenssen, Dag
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Quantification of the mutagenic potency and repair of glycidol-induced DNA lesions2016In: Mutation research. Genetic toxicology and environmental mutagenesis, ISSN 1383-5718, E-ISSN 1879-3592, Vol. 805, p. 38-45Article in journal (Refereed)
    Abstract [en]

    Glycidol (Gly) is an electrophilic low-molecular weight epoxide that is classified by IARC as probably carcinogenic to humans. Humans might be exposed to Gly from food, e.g. refined vegetable oils, where Gly has been found as a food process contaminant. It is therefore important to investigate and quantify the genotoxicity of Gly as a primary step towards cancer risk assessment of the human exposure. Here, quantification of the mutagenic potency expressed per dose (AUC: area under the concentration time curve) of Gly has been performed in Chinese hamster ovary (CHO) cells, using the HPRT assay. The dose of Gly was estimated in the cell exposure medium by trapping Gly with a strong nucleophile, cob(I)alamin, to form stable cobalamin adducts for analysis by LC-MS/MS. Gly was stable in the exposure medium during the time for cell treatment, and thus the dose in vitro is the initial concentration x cell treatment time. Gly induced mutations in the hprt-gene at ante of 0.08 +/- 0:01 mutations/10(5) cells/mMh. Through comparison with the effect of ionizing radiation in the same system a relative mutagenic potency of 9.5 rad-eq./mMh was obtained, which could be used for comparison of genotoxicity of chemicals and between test systems and also in procedures for quantitative cancer risk assessment. Gly was shown to induce strand breaks, that were repaired by base excision repair. Furthermore, Gly-induced lesions, present during replication, were found to delay the replication fork elongation. From experiments with repair deficient cells, homologous recombination repair and the ERCC1-XPF complex were indicated to be recruited to support in the repair of the damage related to the stalled replication elongation. The type of DNA damage responsible for the mutagenic effect of Gly could not be concluded from the present study.

  • 7.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Vryonidis, Efstathios
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Internal dose of glycidol in children and estimation of associated cancer riskManuscript (preprint) (Other academic)
    Abstract [en]

    Children are more susceptible to exposures to harmful compounds compared to adults. Monitoring of the actual exposures in vivo is important to enable risk mitigation actions. The general population, including children, is exposed to the carcinogen glycidol through food. A possible exposure source to glycidol is food containing refined cooking oils where it is present as a process-induced contaminant in the form of fatty acid esters.

    In the present study internal (in vivo) doses of the genotoxic and carcinogenic compound glycidol have been determined in a cohort of 50 children and in a reference group of 12 adults (non-smokers and smokers). The lifetime in vivo doses of glycidol have been calculated from the levels of the hemoglobin (Hb) adduct N-(2,3-dihydroxypropyl)-valine in blood samples from the subjects, demonstrating about a 5-fold variation between the children (71–322 µMh). This variation is likely due to different dietary habits and/or different genotypes/phenotypes of the enzymes involved in the detoxification of glycidol. Data from the adults indicate that the non-smoking subjects are exposed to about the same level as the children, whereas the smoking subjects have about double levels, likely due to the presence of glycidol in tobacco smoke. The estimated exposure to glycidol in the children is higher than those estimated by European Food Safety Authority.

    The calculated relative cancer risk increment due to glycidol exposure demonstrated an unacceptable risk for all subjects. The excess lifetime risk based on the estimated lifetime in vivo doses of glycidol exceeded 1/1000, which should be compared to a generally applied acceptable lifetime risk level of 1/100 000. A small contribution to the internal dose of glycidol from other precursors to the measured Hb adduct, and corresponding contribution to estimated risks from intake of glycidol from food cannot though be excluded.

  • 8.
    Aasa, Jenny
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Vryonidis, Efstathios
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Internal Doses of Glycidol in Children and Estimation of Associated Cancer Risk2019In: toxics, ISSN 2305-6304, Vol. 7, no 1, article id 7Article in journal (Refereed)
    Abstract [en]

    The general population is exposed to the genotoxic carcinogen glycidol via food containing refined edible oils where glycidol is present in the form of fatty acid esters. In this study, internal (in vivo) doses of glycidol were determined in a cohort of 50 children and in a reference group of 12 adults (non-smokers and smokers). The lifetime in vivo doses and intakes of glycidol were calculated from the levels of the hemoglobin (Hb) adduct N-(2,3-dihydroxypropyl)valine in blood samples from the subjects, demonstrating a fivefold variation between the children. The estimated mean intake (1.4 mu g/kg/day) was about two times higher, compared to the estimated intake for children by the European Food Safety Authority. The data from adults indicate that the non-smoking and smoking subjects are exposed to about the same or higher levels compared to the children, respectively. The estimated lifetime cancer risk (200/10(5)) was calculated by a multiplicative risk model from the lifetime in vivo doses of glycidol in the children, and exceeds what is considered to be an acceptable cancer risk. The results emphasize the importance to further clarify exposure to glycidol and other possible precursors that could give a contribution to the observed adduct levels.

  • 9.
    Carlsson, Henrik
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Aasa, Jenny
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Abramsson-Zetterberg, Lilianne
    Vare, Daniel
    Stockholm University, Faculty of Science, Department of Molecular Biosciences, The Wenner-Gren Institute.
    Kotova, Natalia
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Adductomic Screening of N-terminal Hemoglobin Adducts and Measurement of Micronuclei in Blood Samples from Swedish School ChildrenArticle in journal (Refereed)
  • 10.
    Carlsson, Henrik
    et al.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Aasa, Jenny
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Kotova, Natalia
    National Food Agency.
    Vare, Daniel
    National Food Agency.
    Sousa, Pedro F. M.
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Rydberg, Per
    Department of Oncology-Pathology, Karolinska Institute.
    Abramsson-Zetterberg, Lilianne
    National Food Agency.
    Törnqvist, Margareta
    Stockholm University, Faculty of Science, Department of Environmental Science and Analytical Chemistry.
    Adductomic Screening of Hemoglobin Adducts and Monitoring of Micronuclei in School-Age Children2017In: Chemical Research in Toxicology, ISSN 0893-228X, E-ISSN 1520-5010, Vol. 30, no 5, p. 1157-1167Article in journal (Refereed)
    Abstract [en]

    Electrophilic compounds/metabolites present in humans, originating from endogenous processes or exogenous exposure, pose a risk to health effects through their reactions with nucleophilic sites in proteins and DNA, forming adducts. Adductomic approaches are developed to screen for adducts to biomacromolecules in vivo by mass spectrometry (MS), with the aim to detect adducts corresponding to unknown exposures from electrophiles. In the present study, adductomic screening was performed using blood samples from healthy children about 12 years old (n = 51). The frequencies of micronuclei (MN) in erythrocytes in peripheral blood were monitored as a measure of genotoxic effect/genotoxic exposure. The applied adductomic approach has been reported earlier by us and is based on analysis of N-terminal valine adducts in hemoglobin (Hb) by liquid chromatography tandem mass spectrometry (LC-MS/MS). High resolution MS was introduced for refined screening of previously unknown N-terminal Hb adducts. Measured adduct levels were compared with MN frequencies using multivariate data analysis. In the 51 individuals, a total of 24 adducts (whereof 12 were previously identified) were observed and their levels quantified. Relatively large interindividual variations in adduct levels were observed. The data analysis (with partial least-squares regression) showed that as much as 60% of the MN variation could be explained by the adduct levels. This study, for the first time, applies the combination of these sensitive methods to measure the internal dose of potentially genotoxic chemicals and genotoxic effects, respectively. The results indicate that this is a valuable approach for the characterization of exposure to chemical risk factors for the genotoxic effects present in individuals of the general population.

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