Chronic Dietary Exposure Research Articles

Toxaphene-induced mouse liver tumorigenesis is mediated by the constitutive androstane receptor.

Toxaphene was shown to increase liver tumor incidence in B6C3F1 mice following chronic dietary exposure. Preliminary evidence supported a role for the constitutive androstane receptor (CAR) in the mode of action of toxaphene-induced mouse liver tumors. However, these results could not rule out a role for the pregnane X receptor (PXR) in liver tumor formation. To define further the nuclear receptors involved in this study, we utilized CAR, PXR and PXR/CAR knockout mice (CAR-/- , PXR-/- and PXR-/- /CAR-/- ) along with the wild-type C57BL/6. In this study CAR-responsive genes Cyp3a11 and Cyp2b10 were induced in the liver of C57BL/6 (wild-type) mice by toxaphene (30-570-fold) (at the carcinogenic dose 320 ppm) and phenobarbital (positive control) (16-420-fold) following 14 days' dietary treatment. In contrast, in CAR-/- mice, no induction of these genes was seen following treatment with either chemical. Cyp3a11 and Cyp2b10 were also induced in PXR-/- mice with toxaphene and phenobarbital but were not changed in treated PXR-/- /CAR-/- mice. Similarly, induction of liver pentoxyresorufin-O-deethylase (CAR activation) activity by toxaphene and phenobarbital was absent in CAR-/- and PXR-/- /CAR-/- mice treated with phenobarbital or toxaphene. Ethoxyresorufin-O-deethylase (EROD, represents aryl hydrocarbon receptor activation) activity in CAR-/- mice treated with toxaphene or phenobarbital was increased compared with untreated control, but lower overall in activity in comparison to the wild-type mouse. Liver EROD activity was also induced by both phenobarbital and toxaphene in the PXR-/- mice but not in the PXR-/- /CAR-/- mice. Toxaphene treatment increased 7-benzyloxyquinoline activity (a marker for PXR activation) in a similar pattern to that seen with pentoxyresorufin-O-deethylase. These observations indicate that EROD and PXR activation are evidence, as expected, of secondary overlap to primary CAR receptor activation. Together, these results definitively show that activation of the CAR nuclear receptor is the mode of action of toxaphene-induced mouse liver tumors. Copyright © 2017 John Wiley & Sons, Ltd.

Chronic dietary exposure to branched chain amino acids impairs glucose disposal in vegans but not in omnivores.

Branched chain amino acids (BCAA) are among nutrients strongly linked with insulin sensitivity (IS) measures. We investigated the effects of a chronic increase of BCAA intake on IS in two groups of healthy subjects differing in their basal consumption of BCAA, that is, vegans and omnivores. Eight vegans and eight matched omnivores (five men and three women in each group) received 15 g (women) or 20 g (men) of BCAA daily for 3 months. Anthropometry, blood analyses, glucose clamp, arginine test, subcutaneous abdominal adipose tissue (AT) and skeletal muscle (SM) biopsies (mRNA levels of selected metabolic markers, respiratory chain (RC) activity) were performed at baseline, after the intervention and after a 6 month wash-out period. Compared with omnivores, vegans had higher IS at baseline (GIR, glucose infusion rate: 9.6±2.4 vs 7.1±2.4 mg/kg/min, 95% CI for difference: 0.55 to 5.82) that declined after the intervention and returned to baseline values after the wash-out period (changes in GIR with 95% CI, 3-0 months: -1.64 [-2.5; -0.75] and 9-3 months: 1.65 [0.75; 2.54] mg/kg/min). No such change was observed in omnivores. In omnivores the intervention led to an increased expression of lipogenic genes (DGAT2, FASN, PPARγ, SCD1) in AT. SM RC activity increased in both groups. Negative impact of increased BCAA intake on IS was only detected in vegans, that is, subjects with low basal amino acids/BCAA intake, which appear to be unable to induce sufficient compensatory changes within AT and SM on a BCAA challenge.

Acute and chronic dietary exposure to domoic acid in recreational harvesters: A survey of shellfish consumption behavior

Domoic acid (DA) is a neurotoxin that is naturally produced by phytoplankton and accumulates in seafood during harmful algal blooms. As the prevalence of DA increases in the marine environment, there is a critical need to identify seafood consumers at risk of DA poisoning. DA exposure was estimated in recreational razor clam (Siliqua patula) harvesters to determine if exposures above current regulatory guidelines occur and/or if harvesters are chronically exposed to low levels of DA. Human consumption rates of razor clams were determined by distributing 1523 surveys to recreational razor clam harvesters in spring 2015 and winter 2016, in Washington, USA. These consumption rate data were combined with DA measurements in razor clams, collected by a state monitoring program, to estimate human DA exposure. Approximately 7% of total acute exposures calculated (including the same individuals at different times) exceeded the current regulatory reference dose (0.075mgDA·kgbodyweight−1·d−1) due to higher than previously reported consumption rates, lower bodyweights, and/or by consumption of clams at the upper range of legal DA levels (maximum 20mg·kg−1 wet weight for whole tissue). Three percent of survey respondents were potentially at risk of chronic DA exposure by consuming a minimum of 15 clams per month for at 12 consecutive months. These insights into DA consumption will provide an additional tool for razor clam fishery management.

Scientific Opinion of Flavouring Group Evaluation 407 (FGE.407): 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylic acid.

The EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF) was requested to deliver a scientific opinion on the implications for human health of the flavouring substance 4‐amino‐5‐(3‐(isopropylamino)‐2,2‐dimethyl‐3‐oxopropoxy)‐2‐methylquinoline‐3‐carboxylic acid [FL‐no: 16.130], in the Flavouring Group Evaluation 407 (FGE.407), according to Regulation (EC) No 1331/2008 of the European Parliament and of the Council. The substance has not been reported to occur in natural source materials of botanical or animal origin. It is intended to be used as both the parent compound and its hemisulfate monohydrate salt as a flavouring substance with modifying properties in specific categories of food. The chronic dietary exposure to the substance estimated using the added portions exposure technique (APET), is calculated to be 882 μg/person per day for a 60‐kg adult and 547 μg/person per day for a 15‐kg 3‐year‐old child. There is no concern with respect to genotoxicity. A 90‐day dietary administration study in rats showed no adverse effects for doses up to 100 mg/kg body weight (bw) per day, providing an adequate margin of safety. Developmental toxicity was not observed in a study with rats at the dose levels up to 1,000 mg/kg bw per day. The Panel concluded that [FL‐no: 16.130] and its hemisulfate monohydrate salt are not expected to be of safety concern at the estimated levels of dietary exposure calculated using the APET approach. This conclusion applies only to the use of the substance as a flavour modifier as requested and when used at the levels as specified for foods from different food categories.

Dietary exposure assessment to Alternaria toxins in the European population

Alternaria toxins are secondary metabolites produced by fungi that can contaminate cereals, oilseeds, fruits and vegetables. The chronic dietary exposure to four individual Alternaria toxins was estimated using 15,563 analytical results/4,249 samples (3,648 on alternariol (AOH), 3,654 on alternariol monomethyl ether (AME), 4,168 on tenuazonic acid (TeA) and 4,093 on tentoxin (TEN)). Most of the analytical results were left-censored data (92%), with only 1,290 quantified results (mainly on ‘Oilseeds’ and ‘Grain milling products’). The highest exposure to AOH was estimated in ‘Toddlers’, with the mean exposure between 3.8 and 71.6 ng/kg body weight (bw) per day (minimum lower bound–maximum upper bound, (LB–UB)) and the 95th percentile exposure between 11.4 and 270.5 ng/kg bw per day (LB–UB). Overall, ‘Fruit and fruit products’ were the most important contributors to the dietary exposure to AOH. The highest exposure to AME was estimated in ‘Toddlers’, with mean exposure between 3.4 and 38.8 ng/kg bw per day (LB–UB) and 95th percentile exposure between 10.3 and 97.3 ng/kg bw per day (LB–UB). Overall, the main contributors to the dietary exposure to AME were ‘Vegetable oil’ and ‘Pome fruits’ (pears). The highest exposure to TeA was estimated in ‘Toddlers’ with mean exposure between 100 and 1,614 ng/kg bw per day (LB–UB), and in ‘Infants’ for the 95th percentile exposure estimations (98–3,603 ng/kg bw per day, LB–UB). ‘Cereal-based food for infants and young children’ was the main contributor in ‘Infants’ and ‘Toddlers’, and tomatoes and tomato-based products in other age classes. The highest exposure to TEN was estimated in ‘Toddlers’, with the mean exposure between 1.6 and 33.4 ng/kg bw per day (LB–UB), and the 95th percentile exposure around 55 ng/kg bw per day (UB) in different age classes. ‘Fruiting vegetables’ (tomatoes) were the major contributor to the dietary exposure to TEN. Although based on limited data, vegetarians seem to have higher dietary exposure to Alternaria toxins than the general population.

Effects of chronic dietary exposure of zinc oxide nanoparticles on the serum protein profile of juvenile common carp (Cyprinus carpio L.).

Zinc oxide (ZnO) nanoparticles (NPs) have been dramatically used in industry, biology, and medicine. Despite their interesting physico-chemical properties for application in various industrial, medical, and consumer products, safe use of ZnO NPs are under challenges due to the inadequate information related to their toxicological endpoints. Proteomics was applied to evaluate the sub-lethal effects of dietary exposure to ZnO NPs on serum proteome profile of juvenile common carp, (Cyprinus carpio). Therefore, ZnO NPs solution (500mgkg-1 of feed) was added to a commercial carp feed for six weeks. We compared the serum proteome profile from 7 controls and 7 treated fish. In addition, zinc accumulation were measured in intestine, liver, gill and brain. In total, we were able to identify 326 proteins from 6845 distinct peptides. As a result of the data analysis, the abundance levels of four proteins were significantly altered (fold change (fc) ≥2 and p<0.05) after dietary exposure to ZnO NPs. The protein levels of the complement component C4-2 (fc 2.5) and the uncharacterised protein encoded by kng1 (fc 5.8) were increased and major histocompatibility class I (fc 4.9) and the uncharacterised protein encoded by lum (fc 3.5) were decreased (fc 2.5). Molecular pathway analysis revealed four canonical pathways including acute-phase response signalling, liver and retinoid X receptors activation, and intrinsic and extrinsic prothrombin activation pathways as significantly regulated in the treated fish. No significant difference was observed for zinc accumulation in exposed fish compared to controls. In summary, despite no apparent accumulation, ZnO NPs exposure to common carp probably disturbs the fish homeostasis by affecting proteins of the haematological and the immune systems.

Effects of chronic dietary petroleum exposure on reproductive development in polar cod (Boreogadus saida)

Increasing human activities in the Arctic raise the risk of petroleum pollution, thus posing an elevated risk for Arctic organisms to be chronically exposed to petroleum compounds. The endocrine disrupting properties of some of these compounds (i.e. polycyclic aromatic hydrocarbons [PAHs]) present in crude oil may have negative effects on the long and energy intensive reproductive development of polar cod (Boreogadus saida), an Arctic keystone species. In the present study, selected reproductive parameters were examined in feral polar cod exposed to crude oil via a natural diet (0.11, 0.57 and 1.14μg crude oil/g fish/day [corresponding to low, medium and high treatments, respectively]) for 31 weeks prior to spawning. Fish maturing in the current reproductive period made up 92% of the experimental population while 5% were immature and 3% were identified as resting fish. Phase I metabolism of PAHs, indicated by ethoxyresorufin-O-deethylase (EROD) activity, showed a dose-dependent increase in high and medium crude oil treatments at week 6 and 22, respectively. Decreasing EROD activity and increasing PAH bile metabolite concentrations over the experimental period may be explained by reproductive maturity stage. Significant alterations in sperm motility were observed in crude oil exposed males compared to the controls. The investigated somatic indices (gonad and hepatic), germ cell development and plasma steroid levels (estradiol-17β [females], testosterone [males and females] and 11-ketotestosterone [males]) were not significantly altered by chronic dietary exposure to crude oil. The environmentally realistic doses polar cod were chronically exposed to in this study were likely not high enough to induce adverse effects in this ecologically important fish species. This study elucidated many baseline aspects of polar cod reproductive physiology and emphasized the influence of maturation state on biomarkers of PAH biotransformation (EROD and PAH bile metabolites).

Relationship of Metabolism and Cell Proliferation to the Mode of Action of Fluensulfone-Induced Mouse Lung Tumors. II: Additional Mechanistic Studies.

Fluensulfone is a nematicide for agricultural use. Chronic dietary exposure led to bronchiolo-alveolar hyperplasia and bronchiolo-alveolar adenomas in CD-1 mice but not in rats. Genotoxicity could be excluded as a mode of action (MOA). An earlier publication (Strupp, C., Banas, D. A., Cohen, S. M., Gordon, E. B., Jaeger, M., and Weber, K. (2012). Relationship of metabolism and cell proliferation to the mode of action of fluensulfone-induced mouse lung tumors: analysis of their human relevance using the IPCS framework. Toxicol. Sci. 128, 284-294.) reported MOA studies identifying the following key events: increased metabolism of fluensulfone by CYP2f2 in mouse lung Club cells, followed by local proliferation, finally leading to adenoma formation. Human lung microsomes were found not to metabolize fluensulfone. The Joint FAO/WHO Meeting on Pesticide Residues has reviewed the previous data and concluded that the MOA is plausible however some areas of uncertainty were identified. This publication provides additional data to address these. New cell proliferation studies in mice showed that the MOA is functionally independent of sex. A threshold of cell proliferation in Club cells correlating with the dose response for adenoma formation was shown. CYP2f2 knockout mice did not react to fluensulfone exposure with cell proliferation like wild-type mice, confirming the key role of this enzyme. The collective data for fluensulfone were evaluated according to the International Programme on Chemical Safety (IPCS) Mode of Action Framework which leads to the conclusion that the mouse-specific lung tumors after fluensulfone are not relevant to humans.

Balkan endemic nephropathy: an update on its aetiology.

Balkan endemic nephropathy (BEN) is a unique, chronic renal disease frequently associated with upper urothelial cancer (UUC). It only affects residents of specific farming villages located along tributaries of the Danube River in Bosnia-Herzegovina, Croatia, Macedonia, Serbia, Bulgaria, and Romania where it is estimated that ~100,000 individuals are at risk of BEN, while ~25,000 have the disease. This review summarises current findings on the aetiology of BEN. Over the last 50 years, several hypotheses on the cause of BEN have been formulated, including mycotoxins, heavy metals, viruses, and trace-element insufficiencies. However, recent molecular epidemiological studies provide a strong case that chronic dietary exposure to aristolochic acid (AA) a principal component of Aristolochia clematitis which grows as a weed in the wheat fields of the endemic regions is the cause of BEN and associated UUC. One of the still enigmatic features of BEN that need to be resolved is why the prevalence of BEN is only 3–7 %. This suggests that individual genetic susceptibilities to AA exist in humans. In fact dietary ingestion of AA along with individual genetic susceptibility provides a scenario that plausibly can explain all the peculiarities of BEN such as geographical distribution and high risk of urothelial cancer. For the countries harbouring BEN implementing public health measures to avoid AA exposure is of the utmost importance because this seems to be the best way to eradicate this once mysterious disease to which the residents of BEN villages have been completely and utterly at mercy for so long.

Dietary exposure assessment to pyrrolizidine alkaloids in the European population

Chronic and acute dietary exposure to pyrrolizidine alkaloids (PAs) was estimated in the European population via the consumption of plant-derived foods. This resulted in highest estimates of mean chronic dietary exposure of 34.5–48.4 ng/kg body weight (bw) per day in ‘Toddlers’ (LB–UB) and 154–214 ng/kg bw per day in the highly exposed population (LB–UB, also in ‘Toddlers’). Following a rather conservative scenario, the highest estimates of acute mean exposure and 95th percentile exposure were calculated for ‘Toddlers’, with mean exposure up to 311 ng/kg bw per day and 95th percentile exposure up to 821 ng/kg bw per day. Tea and herbal infusions were by far the main average contributors to the total exposure to PAs. Among consumers only, in the adult population, the mean chronic exposure via the consumption of honey ranged between 0.1 and 7.4 ng/kg bw per day (minimum LB–maximum UB), while for high consumers, it was between 0.4 and 18 ng/kg bw per day (minimum LB–maximum UB). In the young population, for the average consumers of honey, estimates were between 0.3 and 27 ng/kg bw per day (minimum LB–maximum UB), and between 0.7 and 31 ng/kg bw per day (minimum LB–maximum UB) among the high consumers. Ad hoc exposure scenarios for food supplements via consumption of pollen-based supplements showed chronic exposure to PAs that ranged between 0.7 and 12 ng/kg bw per day (minimum LB–maximum UB), while acute exposure was between 2.8 and 44 ng/kg bw per day (minimum LB–maximum UB), in both cases among consumers only. Likewise, the consumption of 150 mL infusion of 2 g of selected plant extracts can lead to exposures to PAs up to 890 ng/kg bw per day (e.g. infusion of Borage).

Chronic dietary exposure to pesticide residues and associated risk in the French ELFE cohort of pregnant women

Dietary exposure to pesticide residues may present a risk to public health, especially for sensitive populations such as pregnant women. To characterize this risk, this study assessed chronic dietary exposure to pesticide residues based on the French ELFE cohort. A self-administered food frequency questionnaire (FFQ) about the last three months of pregnancy filled in by pregnant women in 2011 was used in combination with occurrence data from French Total Diet Studies completed by the results of national monitoring programs on pesticide residues in food. The dietary intake of pesticides (μg/kg of body weight/day) was estimated for 14,099 pregnant women with a complete FFQ, for 317 substances under two occurrence scenarios to handle left-censored data: a lower-bound scenario (LB), where undetected results were set to zero, and an upper-bound scenario (UB), where undetected results were set to the detection limit if the substance was expected to be found in food and zero if it was not. The risk was assessed for 284 substances with a toxicological reference value (TRV) and a good coverage level of the diet potentially contributing to pesticide intake. The cumulative risk was also assessed for seven effects on nervous and thyroid systems using the hazard index and the Cumulative Assessment Groups defined by EFSA. Substances with the highest exposure levels under the LB scenario were, in decreasing order, imazalil, piperonyl butoxide, chlorpropham, thiabendazole, iprodione and propargite. Under the LB scenario, only for lindane did women have a statistically significant probability of exceeding the TRV (2.4%). Under the UB scenario, risk could not be excluded for nine other substances. A better management of left-censored data and more sensitive analyses of the main food contributors might help to refine the UB exposure and risk assessments. A statistically significant cumulative risk was found for neurochemical effects related to high intake levels of three organophosphate insecticides (chlorpyrifos, pirimiphos-methyl and dimethoate) mainly detected in fruits and cereals.

Hepatic and renal trace element concentrations in American alligators (Alligator mississippiensis) following chronic dietary exposure to coal fly ash contaminated prey

Little is known about the propensity of crocodilians to bioaccumulate trace elements as a result of chronic dietary exposure. We exposed 36 juvenile alligators (Alligator mississippiensis) to one of four dietary treatments that varied in the relative frequency of meals containing prey from coal combustion waste (CCW)-contaminated habitats vs. prey from uncontaminated sites, and evaluated tissue residues and growth rates after 12 mo and 25 mo of exposure. Hepatic and renal concentrations of arsenic (As), cadmium (Cd) and selenium (Se) varied significantly among dietary treatment groups in a dose-dependent manner and were higher in kidneys than in livers. Exposure period did not affect Se or As levels but Cd levels were significantly higher after 25 mo than 12 mo of exposure. Kidney As and Se levels were negatively correlated with body size but neither growth rates nor body condition varied significantly among dietary treatment groups. Our study is among the first to experimentally examine bioaccumulation of trace element contaminants in crocodilians as a result of chronic dietary exposure. A combination of field surveys and laboratory experiments will be required to understand the effects of different exposure scenarios on tissue residues, and ultimately link these concentrations with effects on individual health.

Do vervets and macaques respond differently to BMAA?

Vervets with chronic dietary exposure to BMAA develop neurofibrillary tangles (NFT) and sparse β-amyloid plaque-like deposits in the brain. Macaques dosed via oral gavage with BMAA developed marked neurological signs in the absence of cell death. These differences may result from increased vulnerability of macaques to BMAA, the higher effective dose they received via oral gavage, and the possibility of stable adducts due to the bicarbonate used to neutralize their BMAA dose. Confirmation of chromatolysis and cell death in macaque brains was visualized using toluidine staining. In contrast, immunological staining with AT8 and β-amyloid (1–42) antibodies and thioflavine-S stain in vervet brains suggests early stage labeling of neurites and NFT and plaque-like formation in the absence of neuronal loss. The lack of neurologic deficits reported in vervets is in keeping with early preclinical pathology observed with these immunohistochemical methods. BMAA toxicity in vervet brains causes the early events that occur in the genesis of neurofibrillary pathology. Taken together, these different studies of vervets and macaques demonstrate BMAA toxicity in the brain due to chronic exposures. The use of more sensitive immunohistochemical methods in the vervet study most likely explains the differences in neuropathology reported for vervets and macaques.

Dietary exposure to an environmental toxin triggers neurofibrillary tangles and amyloid deposits in the brain.

Neurofibrillary tangles (NFT) and β-amyloid plaques are the neurological hallmarks of both Alzheimer's disease and an unusual paralytic illness suffered by Chamorro villagers on the Pacific island of Guam. Many Chamorros with the disease suffer dementia, and in some villages one-quarter of the adults perished from the disease. Like Alzheimer's, the causal factors of Guamanian amyotrophic lateral sclerosis/parkinsonism dementia complex (ALS/PDC) are poorly understood. In replicated experiments, we found that chronic dietary exposure to a cyanobacterial toxin present in the traditional Chamorro diet, β-N-methylamino-l-alanine (BMAA), triggers the formation of both NFT and β-amyloid deposits similar in structure and density to those found in brain tissues of Chamorros who died with ALS/PDC. Vervets (Chlorocebus sabaeus) fed for 140 days with BMAA-dosed fruit developed NFT and sparse β-amyloid deposits in the brain. Co-administration of the dietary amino acid l-serine with l-BMAA significantly reduced the density of NFT. These findings indicate that while chronic exposure to the environmental toxin BMAA can trigger neurodegeneration in vulnerable individuals, increasing the amount of l-serine in the diet can reduce the risk.

Chronic cumulative risk assessment of the exposure to organophosphorus, carbamate and pyrethroid and pyrethrin pesticides through fruit and vegetables consumption in the region of Valencia (Spain)

In the present study, the chronic cumulative exposure to organophosphorus (OPs), carbamates (CBs) and pyrethroid and pyrethrin (PPs) pesticides in the region of Valencia through fruit and vegetables consumption is presented. A total of 752 samples and 84 pesticides were studied of which, 52 were OPs, 23 CBs and 9 PPs. Residue data were derived from the Valencia Region monitoring program 2007–2011 and food consumption levels from a questionnaire-based dietary survey conducted in 2010 in the same area. The relative potency factor (RPFs) approach was used to estimate chronic cumulative dietary exposure to OPs, CBs and PPs using acephate, oxamyl and deltamethrin as index compounds, respectively. The exposure was estimated using a deterministic approach and two scenarios were assumed for left-censored results: the lower-bound (LB) scenario, in which unquantified results (below the limit of quantification (LOQ)) were set to zero and the upper-bound (UB) scenario, in which unquantified results were set to the LOQ. Results demonstrate that the chronic exposure of the young (<16 years) and adult (≥16 years) population to pesticides through fruits and vegetables is under control (even at high or frequent consumption of fruits and vegetables), for the three groups of pesticides.

Risk assessment of chronic dietary exposure to the conjugated mycotoxin deoxynivalenol-3-β-glucoside in the Dutch population

In this study, a risk assessment of dietary exposure to the conjugated mycotoxin deoxynivalenol-3-β-glucoside (DON-3G) in the Dutch population was conducted. Data on DON-3G levels in food products available in the Netherlands are scarce. Therefore, data on co-occurring levels of DON-3G and deoxynivalenol (DON), its parent compound, were used to estimate the DON-3G/DON ratio for several food product categories. This resulted in a DON-3G/DON ratio of 0.2 (90% confidence interval (CI): 0.04-0.9) in grains &amp; grain-milling products, 0.3 (90% CI: 0.03-2.8) in grain-based products and 0.8 (90% CI: 0.4-1.8) in beer. These ratios were applied to the Dutch monitoring data of DON to estimate the DON-3G concentrations in food products available in the Netherlands. DON and DON-3G concentrations were combined with food consumption data of two Dutch National Food Consumption Surveys to assess chronic exposure in young children (2-6 years), children (7-16 years) and adults (17-69 years) using the Monte Carlo Risk Assessment program. The chronic exposure levels of DON, DON-3G and the sum of both compounds (DON+DON-3G) were compared to the tolerable daily intake (TDI) of 1 μg/kg body weight/day which is based on the most critical effect of DON, namely decreased body weight gain. The assumption was made that DON-3G is deconjugated and then fully absorbed as DON in the gastro-intestinal tract. Exposure (P97.5) of the population aged 7-16 years and 17-69 years to DON or DON-3G separately, did not exceed the TDI. However, exposure to upper bound levels of DON+DON-3G (i.e. worst-case scenario) in the same age categories (P97.5) exceeded the TDI with a maximum factor of 1.3. Exposure (P97.5) of the 2-6 year-olds to DON was close to the TDI. Within this group, exposure (P97.5) to upper bound levels of DON+DON-3G exceeded the TDI with not more than a factor 2.

Estimation of toxic hazard – A revised Cramer–Ford–Hall decision tree

Aluminium is neurotoxic in humans and has been implicated in several neurological disorders. Chronic use of buffered aspirins, as aspegic, would likely constitute the major human aluminium uptake source. Low-dose aspirin is beneficial in secondary prevention of cardiovascular events, so it is widely used for long periods of time. We studied if oral administration of aspegic to rats modified the aluminium inhibitory effect on brain (Na+/K+)ATPase due to alteration in synaptosomal membrane aluminium content. Adult male Wistar rats were submitted to sub-acute (1.00 g/day during 10 days) and chronic (0.03 g/day during 4 months) dietary AlCl3 exposure and/or to aspegic (0.11 g/day). The exposure protocol increased the synaptosomal aluminium content especially after a long-term exposure to aluminium and aspegic. Although no alterations were observed in rat body weight gain and adenylate energy charge, the (Na+/K+)ATPase activity was significantly reduced when aluminium was orally administered to rats. The oral administration of aspegic increased the synaptosomal aluminium content and concomitantly enhanced the (Na+/K+)ATPase inhibition. In our exposure protocol the increase in synaptosomal aluminium content correlates with the reduction of the (Na+/K+)ATPase activity.

OR013: Chronic Dietary Exposure to Branched Chain AMINO ACIDS Causes Impaired Glucose Disposal and Higher Adipose Tissue Lipogenesis

OR013: Chronic Dietary Exposure to Branched Chain AMINO ACIDS Causes Impaired Glucose Disposal and Higher Adipose Tissue Lipogenesis

Effects of chronic dietary exposure to monosodium glutamate on feeding behavior, adiposity, gastrointestinal motility, and cardiovascular function in healthy adult rats.

Monosodium glutamate (MSG) is a flavor-enhancer widely used as a food additive. However, its safe dietary concentration and its toxicity, including its possible implication in the recent metabolic syndrome pandemia, is still a controversial issue. Therefore, a deep knowledge of its effects upon regular dietary use is needed. Our aim was to evaluate the effects of chronic exposure to MSG on feeding behavior, abdominal fat, gastrointestinal motility, and cardiovascular function in rats. Two groups of adult male Wistar rats were used: control and treated with MSG (4g/L in drinking water) for 6weeks. Different functional parameters were determined and the histological structure was analyzed in tissues of interest. Compared to control animals, chronic MSG increased water intake but did not modify food ingestion or body weight gain. Neither the abdominal fat volume nor the fat fraction, measured by magnetic resonance imaging, was modified by MSG. Monosodium glutamate did not alter general gastrointestinal motility, but significantly increased the colonic response to mechanical stimulation. It slightly reduced endothelium-dependent relaxation in aorta, without significantly modifying any other cardiovascular parameters. No significant histological alterations were detected in salivary glands, intestinal wall, aorta, heart, and kidney. Chronic treatment with MSG in the adult rat increased water intake. This supports its potential to improve acceptance of low-fat regimens and to increase hydration in the elderly and sportspeople, often at risk of dehydration. Changes in colonic contractility and cardiovascular function could have some long-term repercussions warranting further research.

Cumulative dietary exposure of the population of Denmark to pesticides

We used the Hazard Index (HI) method to carry out a cumulative risk assessment after chronic dietary exposure to all monitored pesticides in fruit, vegetables and cereals for various consumer groups in Denmark. Residue data for all the pesticides were obtained from the Danish monitoring programme during the period 2004–2011. Food consumption data were obtained from DANSDA (the DAnish National Survey of Diet and physical Activity) for the period 2005–2008. The calculations were made using three different models to cope with residues below the limit of reporting (LOR). We concluded that a model that included processing factors and set non-detects to ½ LOR, but limited the correction (Model 3), gave the most realistic exposure estimate. With Model 3 the HI was calculated to be 0.44 for children and 0.18 for adults, indicating that there is no risk of adverse health effects following chronic cumulative exposure to the pesticides found in fruit, vegetables and cereals on the Danish market. The HI was below 1 even for consumers who eat more than 550 g of fruit and vegetables per day, corresponding to 1/3 of the population. Choosing Danish-produced commodities whenever possible could reduce the HI by a factor of 2.