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Marco J. Zeilmaker
National Institute for Public Health and the Environment, Department of Food Safety, NL-3721 Bilthoven, The Netherlands

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Journal article
Published: 08 August 2019 in Toxins
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Biomarkers for the determination of the dietary exposure to deoxynivalenol (DON) have been proposed in the past but so far no quantification of their use in humans has been carried out. Following a human intervention study with two mycotoxins, namely DON and deoxynivalenol-3-glucoside (DON3G), the renal excretion of these compounds, including their phase II metabolites, was analysed. The purpose was to develop biokinetic models that can be used to determine: (1) the preferred (set of) urinary biomarker(s), (2) the preferred urinary collection period, and (3) a method to estimate the dietary exposure to these mycotoxins. Twenty adult volunteers were restricted in consuming cereals and cereal-based foods for 4 days. At day 3, a single dose of 1 µg/kg body weight of DON or DON3G was orally administered to 16 volunteers; 4 volunteers served as control. All individual urine discharges were collected during 24 h after administration. The metabolism and renal excretion could be described by a biokinetic model using three physiological compartments (gastrointestinal tract, liver, and kidneys). Kinetic analysis revealed a complete recovery of the renal excretion of total DON (mainly DON and its glucuronides) within 24 h after administration of DON or DON3G. The so-called ‘reverse dosimetry’ factor was used to determine the preferred (set of) biomarker(s) and to estimate the dietary intake of the parent compounds in the future. The fact that DON3G was absorbed and mainly excreted as DON and its glucuronides confirms that DON3G (as well as other modified forms) should be taken into account in the exposure and risk assessment of this group of mycotoxins.

ACS Style

Marcel Mengelers; Marco Zeilmaker; Arnau Vidal; Marthe De Boevre; Sarah De Saeger; Rudolf Hoogenveen. Biomonitoring of Deoxynivalenol and Deoxynivalenol-3-glucoside in Human Volunteers: Renal Excretion Profiles. Toxins 2019, 11, 466 .

AMA Style

Marcel Mengelers, Marco Zeilmaker, Arnau Vidal, Marthe De Boevre, Sarah De Saeger, Rudolf Hoogenveen. Biomonitoring of Deoxynivalenol and Deoxynivalenol-3-glucoside in Human Volunteers: Renal Excretion Profiles. Toxins. 2019; 11 (8):466.

Chicago/Turabian Style

Marcel Mengelers; Marco Zeilmaker; Arnau Vidal; Marthe De Boevre; Sarah De Saeger; Rudolf Hoogenveen. 2019. "Biomonitoring of Deoxynivalenol and Deoxynivalenol-3-glucoside in Human Volunteers: Renal Excretion Profiles." Toxins 11, no. 8: 466.

Review
Published: 01 January 2018 in Toxicology Letters
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Human health risk assessment of inhalation exposures generally includes a high-to-low concentration extrapolation. Although this is a common step in human risk assessment, it introduces various uncertainties. One of these uncertainties is related to the toxicokinetics. Many kinetic processes such as absorption, metabolism or excretion can be subject to saturation at high concentration levels. In the presence of saturable kinetic processes of the parent compound or metabolites, disproportionate increases in internal blood or tissue concentration relative to the external concentration administered may occur resulting in nonlinear kinetics. The present paper critically reviews human health risk assessment of inhalation exposure. More specific, it emphasizes the importance of kinetic information for the determination of a safe exposure in human risk assessment of inhalation exposures assessed by conversion from a high animal exposure to a low exposure in humans. For two selected chemicals, i.e. methyl tert-butyl ether and 1,2-dichloroethane, PBTK-modelling was used, for illustrative purposes, to follow the extrapolation and conversion steps as performed in existing risk assessments for these chemicals. Human health-based limit values based on an external dose metric without sufficient knowledge on kinetics might be too high to be sufficiently protective. Insight in the actual internal exposure, the toxic agent, the appropriate dose metric, and whether an effect is related to internal concentration or dose is important. Without this, application of assessment factors on an external dose metric and the conversion to continuous exposure results in an uncertain human health risk assessment of inhalation exposures.

ACS Style

Liesbeth Geraets; Marco J. Zeilmaker; Peter M.J. Bos. The importance of inclusion of kinetic information in the extrapolation of high-to-low concentrations for human limit setting. Toxicology Letters 2018, 282, 81 -92.

AMA Style

Liesbeth Geraets, Marco J. Zeilmaker, Peter M.J. Bos. The importance of inclusion of kinetic information in the extrapolation of high-to-low concentrations for human limit setting. Toxicology Letters. 2018; 282 ():81-92.

Chicago/Turabian Style

Liesbeth Geraets; Marco J. Zeilmaker; Peter M.J. Bos. 2018. "The importance of inclusion of kinetic information in the extrapolation of high-to-low concentrations for human limit setting." Toxicology Letters 282, no. : 81-92.

Journal article
Published: 01 October 2015 in Chemosphere
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Fires and improper drying may result in contamination of feed with PCDD/Fs and PCBs. To predict the impact of elevated feed levels, it is important to understand the carry-over to edible products from food producing animals. Therefore, a carry-over study was performed with maize silage contaminated by a fire with PVC materials, and with sugar beet pulp contaminated by drying with coal, containing particles from a plastic roof. Levels of PCDD/Fs and dl-PCBs in the maize silage were 0.93 and 0.25 ng TEQ kg(-1), those in beet pulp 1.90 and 0.15 ng TEQ kg(-1) (both on 88% dry matter (DM)). Dairy cows (3 per treatment) received either 16.8 kg DM per day of maize silage or 5.6 kg DM per day of sugar beet pellets for a 33-d period, followed by clean feed for 33 days. This resulted in a rapid increase of PCDD/F levels in milk within the first 10 days with levels at day 33 of respectively 2.6 and 1.7 pg TEQ g(-1) fat for maize silage and beet pulp. Levels of dl-PCBs at day 33 were lower, 1.0 and 0.5 pg TEQ g(-1) fat. In the case of the maize silage, the carry-over rates (CORs) at the end of the exposure were calculated to be 25% and 32% for the PCDD/F- and dl-PCB-TEQ, respectively. For the dried beet pulp the CORs were 18% and 35%. This study shows that the carry-over of PCDD/Fs and dl-PCBs formed during drying processes or fires can be substantial.

ACS Style

Ron L.A.P. Hoogenboom; Arie Klop; Rik Herbes; Jan C.H. van Eijkeren; Marco J. Zeilmaker; Ad M. van Vuuren; Wim A. Traag. Carry-over of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) in dairy cows fed smoke contaminated maize silage or sugar beet pulp. Chemosphere 2015, 137, 214 -220.

AMA Style

Ron L.A.P. Hoogenboom, Arie Klop, Rik Herbes, Jan C.H. van Eijkeren, Marco J. Zeilmaker, Ad M. van Vuuren, Wim A. Traag. Carry-over of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) in dairy cows fed smoke contaminated maize silage or sugar beet pulp. Chemosphere. 2015; 137 ():214-220.

Chicago/Turabian Style

Ron L.A.P. Hoogenboom; Arie Klop; Rik Herbes; Jan C.H. van Eijkeren; Marco J. Zeilmaker; Ad M. van Vuuren; Wim A. Traag. 2015. "Carry-over of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) and polychlorinated biphenyls (PCBs) in dairy cows fed smoke contaminated maize silage or sugar beet pulp." Chemosphere 137, no. : 214-220.

Original articles
Published: 09 July 2015 in Food Additives & Contaminants: Part A
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Lidocaine is a topical anaesthetic drug used in dairy cows for laparotomy (caesarean section, abomasal displacement). Because there are no registered drugs for this indication, it can be applied under the so-called Cascade rules (off-label use), with the restriction that the off-label withdrawal periods of 7 days for milk and 28 days for meat are taken into account. In animals, lidocaine is rapidly metabolised into various metabolites, one being 2,6-dimethylaniline (DMA) which is reported to possess carcinogenic and mutagenic properties and detected also in milk. To investigate whether the off-label withdrawal periods are long enough to exclude the presence of lidocaine and DMA, and potential other metabolites, in edible products, a study was performed with eight dairy cows treated with lidocaine by injection in the abdominal muscles. At various time points blood samples, milk and urine were collected. Four animals were slaughtered 3.5 h after treatment, the other four after 48.5 h. The injection site, meat, liver and kidney were analysed for levels of lidocaine, DMA, monoethylglycinexylidide (MEGX) and 3-OH-lidocaine. It was shown that DMA is an important metabolite in dairy cows and can be detected in both meat and milk. In addition, also MEGX, 3-OH-lidocaine and three other metabolites were identified and to some extent quantified. These metabolites were 4-OH-lidocaine, lidocaine-N-oxide and 4-hydroxy-DMA. The latter compound was the most important metabolite in urine. However, levels in milk and meat decreased rapidly after the application. Overall, it can be concluded that the off-label withdrawal times of 7 and 28 days for milk and meat, respectively, guarantee the absence of detectable levels of lidocaine and metabolites.

ACS Style

Ron L.A.P. Hoogenboom; Tina Zuidema; Martien Essers; Ad M. Van Vuuren; Piet G. Van Wikselaar; Jan C.H. Van Eijkeren; Marcel J.B. Mengelers; Marco J. Zeilmaker; Astrid S. Bulder. Concentrations of dimethylaniline and other metabolites in milk and tissues of dairy cows treated with lidocaine. Food Additives & Contaminants: Part A 2015, 32, 1256 -1264.

AMA Style

Ron L.A.P. Hoogenboom, Tina Zuidema, Martien Essers, Ad M. Van Vuuren, Piet G. Van Wikselaar, Jan C.H. Van Eijkeren, Marcel J.B. Mengelers, Marco J. Zeilmaker, Astrid S. Bulder. Concentrations of dimethylaniline and other metabolites in milk and tissues of dairy cows treated with lidocaine. Food Additives & Contaminants: Part A. 2015; 32 (8):1256-1264.

Chicago/Turabian Style

Ron L.A.P. Hoogenboom; Tina Zuidema; Martien Essers; Ad M. Van Vuuren; Piet G. Van Wikselaar; Jan C.H. Van Eijkeren; Marcel J.B. Mengelers; Marco J. Zeilmaker; Astrid S. Bulder. 2015. "Concentrations of dimethylaniline and other metabolites in milk and tissues of dairy cows treated with lidocaine." Food Additives & Contaminants: Part A 32, no. 8: 1256-1264.

Original articles
Published: 23 December 2014 in Food Additives & Contaminants: Part A
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Growing male pigs were exposed to cadmium (Cd) at levels around 1 and 10 mg kg–1 feed for up to 12 weeks, administered as CdCl2 or Cd-cysteine (CdCys). Pigs exposed to 10 mg kg–1 showed decreased growth during the last 3 weeks. Liver and kidney concentrations of Cd continuously increased over the entire 12-week exposure, exceeding the European Union limits of 1.0 mg kg–1 (kidney) and 0.5 mg kg–1 (liver) within 3 weeks at the feed level of 10 mg kg–1. A switch to clean feed after 3 weeks for 5 or 9 weeks resulted in steadily decreased levels in kidney and liver, which could be completely attributed to organ growth. At the lower feed level, the level in kidney exceeded the limit almost twofold after 12 weeks, but not after 3 weeks. Liver levels remained below the limit. Metallothionein (MT) levels in livers showed a steady decrease in both untreated and treated animals over time. In kidney such a decrease was only observed in control animals, whereas in the highest-dosed animals the MT concentrations steadily increased. The observed carryover of Cd from feed to liver and kidney was modelled by means of a simple transfer model relating levels in feed via MT levels to accumulation of Cd. Using this model, it was shown that the exposure period of growing pigs to feed containing the European Union limit of 0.5 mg kg–1 feed should be less than 12 weeks in order to prevent Cd levels in the kidneys to exceed the European Union limit.

ACS Style

Ron L.A.P. Hoogenboom; Jasper Hattink; Ab Van Polanen; Sjaak Van Oostrom; John T. Verbunt; Wim A. Traag; Kees A. Kan; Jan C.H. Van Eijkeren; Gudrun De Boeck; Marco J. Zeilmaker. Carryover of cadmium from feed in growing pigs. Food Additives & Contaminants: Part A 2014, 32, 68 -79.

AMA Style

Ron L.A.P. Hoogenboom, Jasper Hattink, Ab Van Polanen, Sjaak Van Oostrom, John T. Verbunt, Wim A. Traag, Kees A. Kan, Jan C.H. Van Eijkeren, Gudrun De Boeck, Marco J. Zeilmaker. Carryover of cadmium from feed in growing pigs. Food Additives & Contaminants: Part A. 2014; 32 (1):68-79.

Chicago/Turabian Style

Ron L.A.P. Hoogenboom; Jasper Hattink; Ab Van Polanen; Sjaak Van Oostrom; John T. Verbunt; Wim A. Traag; Kees A. Kan; Jan C.H. Van Eijkeren; Gudrun De Boeck; Marco J. Zeilmaker. 2014. "Carryover of cadmium from feed in growing pigs." Food Additives & Contaminants: Part A 32, no. 1: 68-79.

Journal article
Published: 01 April 2013 in Food and Chemical Toxicology
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The fish ingredient N3-docosahexaenoic acid 22:6 n-3 (DHA) stimulates brain development. On the other hand methylmercury (MeHg) in fish disturbs the developing central nervous system. In this Context the IQ score in children is considered as an aggregate measure of in utero brain development. To determine the effect of DHA exposure on prenatal neurodevelopment the maternal DHA intake during pregnancy was compared with its epidemiologically observed effect on the IQ score of children. For MeHg the maternal intake was converted into its accumulation in the maternal body. The maternal body burden then was compared with its epidemiologically observed relationship with the IQ score. Taking the MeHg and DHA content of 33 fish species the net effect of these compounds on the IQ score was quantified. For most fish species the adverse effect of MeHg on the IQ score exceeded the beneficial effect of DHA. In the case of long-living predators a negative effect up to 10 points on the IQ score was found. The results of this study indicate that food interventions aiming at the beneficial effects of fish consumption should focus on fish species with a high DHA content, while avoiding fish species with a high MeHg content.

ACS Style

Marco J. Zeilmaker; Jeljer Hoekstra; Jan C.H. van Eijkeren; Nynke de Jong; Andy Hart; Marc Kennedy; Helen Owen; Helga Gunnlaugsdottir. Fish consumption during child bearing age: A quantitative risk–benefit analysis on neurodevelopment. Food and Chemical Toxicology 2013, 54, 30 -34.

AMA Style

Marco J. Zeilmaker, Jeljer Hoekstra, Jan C.H. van Eijkeren, Nynke de Jong, Andy Hart, Marc Kennedy, Helen Owen, Helga Gunnlaugsdottir. Fish consumption during child bearing age: A quantitative risk–benefit analysis on neurodevelopment. Food and Chemical Toxicology. 2013; 54 ():30-34.

Chicago/Turabian Style

Marco J. Zeilmaker; Jeljer Hoekstra; Jan C.H. van Eijkeren; Nynke de Jong; Andy Hart; Marc Kennedy; Helen Owen; Helga Gunnlaugsdottir. 2013. "Fish consumption during child bearing age: A quantitative risk–benefit analysis on neurodevelopment." Food and Chemical Toxicology 54, no. : 30-34.

Journal article
Published: 01 April 2013 in Food and Chemical Toxicology
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The EU project BRAFO proposed a framework for risk-benefit assessment of foods, or changes in diet, that present both potential risks and potential benefits to consumers (Hoekstra et al., 2012a). In higher tiers of the BRAFO framework, risks and benefits are integrated quantitatively to estimate net health impact measured in DALYs or QALYs (disability- or quality-adjusted life years). This paper describes a general model that was developed by a second EU project, Qalibra, to assist users in conducting these assessments. Its flexible design makes it applicable to a wide range of dietary questions involving different nutrients, contaminants and health effects. Account can be taken of variation between consumers in their diets and also other characteristics relevant to the estimation of risk and benefit, such as body weight, gender and age. Uncertainty in any input parameter may be quantified probabilistically, using probability distributions, or deterministically by repeating the assessment with alternative assumptions. Uncertainties that are not quantified should be evaluated qualitatively. Outputs produced by the model are illustrated using results from a simple assessment of fish consumption. More detailed case studies on oily fish and phytosterols are presented in companion papers. The model can be accessed as web-based software at www.qalibra.eu.

ACS Style

Andy Hart; Jeljer Hoekstra; Helen Owen; Marc Kennedy; Marco J. Zeilmaker; Nynke De Jong; Helga Gunnlaugsdottir. Qalibra: A general model for food risk–benefit assessment that quantifies variability and uncertainty. Food and Chemical Toxicology 2013, 54, 4 -17.

AMA Style

Andy Hart, Jeljer Hoekstra, Helen Owen, Marc Kennedy, Marco J. Zeilmaker, Nynke De Jong, Helga Gunnlaugsdottir. Qalibra: A general model for food risk–benefit assessment that quantifies variability and uncertainty. Food and Chemical Toxicology. 2013; 54 ():4-17.

Chicago/Turabian Style

Andy Hart; Jeljer Hoekstra; Helen Owen; Marc Kennedy; Marco J. Zeilmaker; Nynke De Jong; Helga Gunnlaugsdottir. 2013. "Qalibra: A general model for food risk–benefit assessment that quantifies variability and uncertainty." Food and Chemical Toxicology 54, no. : 4-17.

Review article
Published: 22 August 2012 in Critical Reviews in Toxicology
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We developed a population physiology model, physB, which provides a statistical description of the physiological characteristics in the human population, in terms of the physiological parameters that are needed in physiologically based pharmacokinetic modelling. The model predicts individual organ weights, blood flows and some respiratory parameters from anthropometric properties (body height and weight, age and gender). It draws on two existing models, PK-Pop and P3M, but various changes and improvements were made. The conceptual differences among the three models are discussed and they are quantitatively compared by running all three models for various specific combinations of anthropometric properties.

ACS Style

Sieto Bosgra; Jan Van Eijkeren; Peter Bos; Marco Zeilmaker; Wout Slob. An improved model to predict physiologically based model parameters and their inter-individual variability from anthropometry. Critical Reviews in Toxicology 2012, 42, 751 -767.

AMA Style

Sieto Bosgra, Jan Van Eijkeren, Peter Bos, Marco Zeilmaker, Wout Slob. An improved model to predict physiologically based model parameters and their inter-individual variability from anthropometry. Critical Reviews in Toxicology. 2012; 42 (9):751-767.

Chicago/Turabian Style

Sieto Bosgra; Jan Van Eijkeren; Peter Bos; Marco Zeilmaker; Wout Slob. 2012. "An improved model to predict physiologically based model parameters and their inter-individual variability from anthropometry." Critical Reviews in Toxicology 42, no. 9: 751-767.

Journal article
Published: 29 March 2010 in Toxicological Sciences
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The consumption of fish and nitrate-rich vegetables may lead to the formation of the genotoxic carcinogen N-nitrosodimethylamine (NDMA) in the stomach. To assess human cancer risk associated with this formation, a dynamic in vitro gastrointestinal model was used to simulate NDMA formation in the stomach after a fish + vegetable meal. The experimental results were combined with statistical modeling of Dutch food consumption data resulting in predicted exposures to endogenously formed NDMA in the population. The 95th percentile of the long-term exposure distribution was around 4 ng/kg-bw in young children and 0.4 ng/kg-bw in adults. By comparing this exposure with the Benchmark Dose Lower bound (BMDL) 10 for liver cancer in a chronic carcinogenicity study, a chronic margin of exposure (MOE) was calculated of 7000 and 73,000 for young children and adults. Furthermore, the long-term exposure distribution was combined with a dose-response analysis of the liver cancer incidence data to obtain a cancer risk distribution for the human population. The 95th percentile of that distribution was 6 x 10(-6) extra risk for 5-year-old children and 8 x 10(-7) for adults. The liver cancer data allowed for the analysis of the relationship between tumor incidence and time to tumor. For an extra risk of 10(-6), the decrease in time to tumor was conservatively estimated at 3.8 min in the rat, equivalent to 0.1 days in humans. We also combined acute exposure estimates with the BMDL10 from an acute carcinogenicity study for NDMA, resulting in an acute MOE of 110,000. We conclude that the combined consumption of fish and nitrate-rich vegetables appears to lead to marginal increases of additional cancer risk.

ACS Style

Marco J. Zeilmaker; Martine I. Bakker; Ronald Schothorst; Wout Slob. Risk Assessment of N-nitrosodimethylamine Formed Endogenously after Fish-with-Vegetable Meals. Toxicological Sciences 2010, 116, 323 -335.

AMA Style

Marco J. Zeilmaker, Martine I. Bakker, Ronald Schothorst, Wout Slob. Risk Assessment of N-nitrosodimethylamine Formed Endogenously after Fish-with-Vegetable Meals. Toxicological Sciences. 2010; 116 (1):323-335.

Chicago/Turabian Style

Marco J. Zeilmaker; Martine I. Bakker; Ronald Schothorst; Wout Slob. 2010. "Risk Assessment of N-nitrosodimethylamine Formed Endogenously after Fish-with-Vegetable Meals." Toxicological Sciences 116, no. 1: 323-335.