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Background: In human biomonitoring, blood is often used as a matrix to measure exposure to per- and polyfluoroalkyl substances (PFAS). Because the toxicokinetics of a substance (determining the steady-state blood concentration) may affect the toxic potency, the difference in toxicokinetics among PFAS has to be accounted for when blood concentrations are used in mixture risk assessment. Objectives: This research focuses on deriving relative potency factors (RPFs) at the blood serum level. These RPFs can be applied to PFAS concentrations in human blood, thereby facilitating mixture risk assessment with primary input from human biomonitoring studies. Methods: Toxicokinetic models are generated for 10 PFAS to estimate the internal exposure in the male rat at the blood serum level over time. By applying dose-response modeling, these internal exposures are used to derive quantitative internal RPFs based on liver effects. Results: Internal RPFs were successfully obtained for nine PFAS. Perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoDA), perfluorooctane sulfonic acid (PFOS), and hexafluoropropylene oxide- dimer acid (HFPODA, or GenX) were found to be more potent than perfluorooctanoic acid (PFOA) at the blood serum level in terms of relative liver weight increase, whereas perfluorobutane sulfonic acid (PFBS) and perfluorohexane sulfonic acid (PFHxS) were found to be less potent. The practical implementation of these internal RPFs is illustrated using the National Health and Nutrition Examination Survey (NHANES) biomonitoring data of 2017-2018. Discussion: It is recommended to assess the health risk resulting from exposure to PFAS as combined, aggregate exposure to the extent feasible.

Background: In human biomonitoring, blood is often used as a matrix to measure exposure to per- and polyfluoroalkyl substances (PFAS). Because the toxicokinetics of a substance (determining the steady-state blood concentration) may affect the toxic potency, the difference in toxicokinetics among PFAS has to be accounted for when blood concentrations are used in mixture risk assessment. Objectives: This research focuses on deriving relative potency factors (RPFs) at the blood serum level. These RPFs can be applied to PFAS concentrations in human blood, thereby facilitating mixture risk assessment with primary input from human biomonitoring studies. Methods: Toxicokinetic models are generated for 10 PFAS to estimate the internal exposure in the male rat at the blood serum level over time. By applying dose-response modeling, these internal exposures are used to derive quantitative internal RPFs based on liver effects. Results: Internal RPFs were successfully obtained for nine PFAS. Perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluorononanoic acid (PFNA), perfluorododecanoic acid (PFDoDA), perfluorooctane sulfonic acid (PFOS), and hexafluoropropylene oxide- dimer acid (HFPODA, or GenX) were found to be more potent than perfluorooctanoic acid (PFOA) at the blood serum level in terms of relative liver weight increase, whereas perfluorobutane sulfonic acid (PFBS) and perfluorohexane sulfonic acid (PFHxS) were found to be less potent. The practical implementation of these internal RPFs is illustrated using the National Health and Nutrition Examination Survey (NHANES) biomonitoring data of 2017-2018. Discussion: It is recommended to assess the health risk resulting from exposure to PFAS as combined, aggregate exposure to the extent feasible.

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.

Per- and polyfluoroalkyl substances (PFASs) are omnipresent and have been shown to induce a wide range of adverse health effects, including hepatotoxicity, developmental toxicity, and immunotoxicity. The aim of the present work was to assess whether human HepaRG liver cells can be used to obtain insight into differences in hepatotoxic potencies of a series of PFASs. Therefore, the effects of 18 PFASs on cellular triglyceride accumulation (AdipoRed assay) and gene expression (DNA microarray for PFOS and RT-qPCR for all 18 PFASs) were studied in HepaRG cells. BMDExpress analysis of the PFOS microarray data indicated that various cellular processes were affected at the gene expression level. From these data, ten genes were selected to assess the concentration–effect relationship of all 18 PFASs using RT-qPCR analysis. The AdipoRed data and the RT-qPCR data were used for the derivation of in vitro relative potencies using PROAST analysis. In vitro relative potency factors (RPFs) could be obtained for 8 PFASs (including index chemical PFOA) based on the AdipoRed data, whereas for the selected genes, in vitro RPFs could be obtained for 11–18 PFASs (including index chemical PFOA). For the readout OAT5 expression, in vitro RPFs were obtained for all PFASs. In vitro RPFs were found to correlate in general well with each other (Spearman correlation) except for the PPAR target genes ANGPTL4 and PDK4 . Comparison of in vitro RPFs with RPFs obtained from in vivo studies in rats indicate that best correlations (Spearman correlation) were obtained for in vitro RPFs based on OAT5 and CXCL10 expression changes and external in vivo RPFs. HFPO-TA was found to be the most potent PFAS tested, being around tenfold more potent than PFOA. Altogether, it may be concluded that the HepaRG model may provide relevant data to provide insight into which PFASs are relevant regarding their hepatotoxic effects and that it can be applied as a screening tool to prioritize other PFASs for further hazard and risk assessment.

Toxicokinetic modelling provides a powerful tool in relating internal human exposure (i.e., assessed through urinary biomarker levels) to external exposure. Chemical specific toxicokinetic models are available; however, this specificity prevents their application to similar contaminants or to other routes of exposure. For this reason, we investigated whether a generic physiological-based kinetic (PBK) model might be a suitable alternative for a biokinetic model of deoxynivalenol (DON). IndusChemFate (ICF) was selected as a generic PBK model, which could be fit for purpose. Being suited for simulating multiple routes of exposure, ICF has particularly been used to relate the inhalation and dermal exposure of industrial chemicals to their urinary excretion. For the first time, the ICF model was adapted as a generic model for the human biomonitoring of mycotoxins, thereby extending its applicability domain. For this purpose, chemical-specific data for DON and its metabolites were collected directly from the literature (distribution and metabolism) or indirectly (absorption and excretion) by fitting the ICF model to previously described urinary excretion data. The obtained results indicate that this generic model can be used to model the urinary excretion of DON and its glucuronidated metabolites following dietary exposure to DON. Additionally, the present study establishes the basis for further development of the model to include an inhalation exposure route alongside the oral exposure route.

Background Chemical exposures have been associated with a variety of health effects; however, little is known about the global disease burden from foodborne chemicals. Food can be a major pathway for the general population's exposure to chemicals, and for some chemicals, it accounts for almost 100% of exposure.  Methods and Findings Groups of foodborne chemicals, both natural and anthropogenic, were evaluated for their ability to contribute to the burden of disease.  The results of the analyses on four chemicals are presented here - cyanide in cassava, peanut allergen, aflatoxin, and dioxin.  Systematic reviews of the literature were conducted to develop age- and sex-specific disease incidence and mortality estimates due to these chemicals.  From these estimates, the numbers of cases, deaths and disability adjusted life years (DALYs) were calculated.  For these four chemicals combined, the total number of illnesses, deaths, and DALYs in 2010 is estimated to be 339,000 (95% uncertainty interval [UI]: 186,000-1,239,000); 20,000 (95% UI: 8,000-52,000); and 1,012,000 (95% UI: 562,000-2,822,000), respectively.  Both cyanide in cassava and aflatoxin are associated with diseases with high case-fatality ratios.  Virtually all human exposure to these four chemicals is through the food supply.  Conclusion Chemicals in the food supply, as evidenced by the results for only four chemicals, can have a significant impact on the global burden of disease. The case-fatality rates for these four chemicals range from low (e.g., peanut allergen) to extremely high (aflatoxin and liver cancer).  The effects associated with these four chemicals are neurologic (cyanide in cassava), cancer (aflatoxin), allergic response (peanut allergen), endocrine (dioxin), and reproductive (dioxin).

The dietary exposure to the mycotoxin deoxynivalenol (DON) can be assessed by human biomonitoring (HBM). Here, we assessed the relation between dietary DON intake and the excretion of its major metabolite DON-15-glucuronide (DON15GlcA) through time, in an everyday situation. For 49 volunteers from the EuroMix biomonitoring study, the intake of DON from each meal was calculated and the excretion of DON and its metabolites was analyzed for each urine void collected separately throughout a 24-h period. The relation between DON and DON15GlcA was analyzed with a statistical model to assess the residence time and the excreted fraction of ingested DON as DON15GlcA (fabs_excr). Fabs_excr was treated as a random effect variable to address its heterogeneity in the population. The estimated time in which 97.5% of the ingested DON was excreted as DON15GlcA was 12.1 h, the elimination half-life was 4.0 h. Based on the estimated fabs_excr, the mean reversed dosimetry factor (RDF) of DON15GlcA was 2.28. This RDF can be used to calculate the amount of total DON intake in an everyday situation, based on the excreted amount of DON15GlcA. We show that urine samples collected over 24 h are the optimal design to study DON exposure by HBM.

Background: In human biomonitoring, blood is often used as a matrix to measure exposure to per- and polyfiuoroalkyl substances (PFAS). Because the toxicokinetics of a substance (determining the steady-state blood concentration) may affect the toxic potency, the difference in toxicokinetics among PFAS has to be accounted for when blood concentrations are used in mixture risk assessment. Objectives: This research focuses on deriving relative potency factors (RPFs) at the blood serum level. These RPFs can be applied to PFAS concentrations in human blood, thereby facilitating mixture risk assessment with primary input from human biomonitoring studies. Methods: Toxicokinetic models are generated for 10 PFAS to estimate the internal exposure in the male rat at the blood serum level over time. By applying dose-response modeling, these internal exposures are used to derive quantitative internal RPFs based on liver effects. Results: Internal RPFs were successfully obtained for nine PFAS. Perfluorobutanoic acid (PFBA), perfluorohexanoic acid (PFHxA), perfluoronona-noic acid (PFNA), perfluorododecanoic acid (PFDoDA), perfluorooctane sulfonic acid (PFOS), and hexafluoropropylene oxide-dimer acid (HFPO-DA, or GenX) were found to be more potent than perfluorooctanoic acid (PFOA) at the blood serum level in terms of relative liver weight increase, whereas perfluorobutane sulfonic acid (PFBS) and perfluorohexane sulfonic acid (PFHxS) were found to be less potent. The practical implementation of these internal RPFs is illustrated using the National Health and Nutrition Examination Survey (NHANES) biomonitoring data of 2017-2018. Discussion: It is recommended to assess the health risk resulting from exposure to PFAS as combined, aggregate exposure to the extent feasible.

The carry-over of contaminants from feed to animal food products is an important aspect of the animal production chain. For a proper containment, limits for feed as well food products are fixed for a series of chemicals, e.g. dioxins and dioxin-like PCBs, lead, cadmium, some chlorinated pesticides, and aflatoxin B1 (and its metabolite M1 in milk). The relationship between feed and food limits is an important issue. An ideal goal is to assure that compliance to a feed limits automatically results in compliance to food limits. In order to collect information about this relationship, several simulation models and a large database on transfer factors have been developed. An optimal choice between either a model or an application of data from the Transfer Database is based on both the knowledge level, and on the circumstances of the specific situation. To reach and validate such an optimal choice an Expert System Carry-Over is currently in development, containing four different modules: 1) the different calculation models and the Transfer Database, 2) a decision tree for choosing the optimal strategy, 3) data tables indicating knowledge levels of compound/animal/product parameters, and 4) supporting databases containing information on consumption and composition of daily diets, animal parameters, and amounts of (daily) production. Calculations indicate that for dioxins compliance to feed levels does not necessarily mean that food limits are complied as well. Besides an estimation of the compliance to limits, the expert system is a tool for feed related risk assessments, and for planning of future research.

Grapevine (Vitis vinifera) is a valuable crop in Europe for both economical and cultural reasons, but highly susceptible to Downy mildew (DM). The generation of resistant vines is of critical importance for a sustainable viticulture and can be achieved either by introgression of resistance genes in susceptible varieties or by mutation of Susceptibility (S) genes, e.g., by gene editing. This second approach offers several advantages: it maintains the genetic identity of cultivars otherwise disrupted by crossing and generally results in a broad-spectrum and durable resistance, but it is hindered by the poor knowledge about S genes in grapevines. Candidate S genes are Downy mildew Resistance 6 (DMR6) and DMR6-Like Oxygenases (DLOs), whose mutations confer resistance to DM in Arabidopsis. In this work, we show that grapevine VviDMR6-1 complements the Arabidopsis dmr6-1 resistant mutant. We studied the expression of grapevine VviDMR6 and VviDLO genes in different organs and in response to the DM causative agent Plasmopara viticola. Through an automated evaluation of causal relationships among genes, we show that VviDMR6-1, VviDMR6-2, and VviDLO1 group into different co-regulatory networks, suggesting distinct functions, and that mostly VviDMR6-1 is connected with pathogenesis-responsive genes. Therefore, VviDMR6-1 represents a good candidate to produce resistant cultivars with a gene-editing approach.