Научное обоснование на основе критериев риска здоровью допустимой суточной дозы кадмия при алиментарном поступлении

Dinitroanisole (DNAN), 3-nitro-1,2,4-triazol-5-one (NTO), and nitroguanidine (NQ) are constituents of insensitive munitions being developed to minimize the acute hazards associated with non-intentional detonation of warheads. Although a reference dose (RfD) has been established for NQ and occupational exposure levels have been developed for all three compounds, current state-of-the science methods were not used. Here we present the latest toxicity data and interpretations for NTO, DNAN, and NQ and use Bayesian Benchmark Dose modeling and a Bayesian approach to applying uncertainty factors to derive tolerable daily intake (TDI) values. A TDI of 0.02 mg/kg-d was calculated for DNAN based on extramedullary hematopoiesis in female rats. A TDI of 2.4 mg/kg-d was derived for NTO based on testicular toxicity in male rats. A TDI of 4.0 mg/kg-d was derived for NQ based on increased fetal resorptions in rabbits. These TDIs are generally an order of magnitude higher than previously developed reference values. These values can be used to inform public health, occupational safety, and product acquisition and stewardship decisions. Drinking water, soil, and tap water screening levels were derived for residential and worker exposure scenarios to help inform risk assessment decisions.

Cinnamon bark is commonly used in traditional Japanese herbal medicines (Kampo medicines). The coumarin contained in cinnamon is known to be hepatotoxic, and a tolerable daily intake (TDI) of 0.1 mg/kg/day, has been quantified and used in Europe to insure safety. Risk assessments for hepatotoxicity by the cinnamon contained in foods have been reported. However, no such assessment of cinnamon bark has been reported and the coumarin content of Kampo medicines derived from cinnamon bark is not yet known. To assess the risk for hepatotoxicity by Kampo medicines, we evaluated the daily coumarin intake of patients who were prescribed Kampo medicines and investigated the relation between hepatotoxicity and the coumarin intake. The clinical data of 129 outpatients (18 male and 111 female, median age 58 years) who had been prescribed keishibukuryogankayokuinin (TJ-125) between April 2008 and March 2013 was retrospectively investigated. Concurrent Kampo medicines and liver function were also surveyed. In addition to TJ-125, the patients took some of the other 32 Kampo preparations and 22 decoctions that include cinnamon bark. The coumarin content of these Kampo medicines was determined by high performance liquid chromatography (HPLC). TJ-125 had the highest daily content of coumarin (5.63 mg/day), calculated from the daily cinnamon bark dosage reported in the information leaflet inserted in each package of Kampo medicine. The coumarin content in 1g cinnamon bark decoction was 3.0 mg. The daily coumarin intake of the patients was 0.113 (0.049–0.541) mg/kg/day, with 98 patients (76.0%) exceeding the TDI. Twenty-three patients had an abnormal change in liver function test value, but no significant difference was found in the incidence of abnormal change between the group consuming less than the TDI value (6/31, 19.4%) and the group consuming equal to or greater than the TDI value (17/98, 17.3%). In addition, no abnormal change related to cinnamon bark was found for individual patients. This paper was done to assess the risk of hepatotoxicity by the coumarin contained in Kampo medicines and to clarify whether or not the Kampo preparations in general use that contain cinnamon bark may be safely used in clinical practice.

The European Commission mandated EFSA to assess the toxicity of bromide, the existing maximum residue levels (MRLs), and possible transfer from feed into food of animal origin. The critical effects of bromide in experimental animals are on the thyroid and central nervous system. Changes in thyroid hormone homeostasis could result in neurodevelopmental toxicity, among other adverse effects. Changes in thyroid hormone concentrations and neurophysiological parameters have also been observed in experimental human studies, but the evidence was limited. Dose-response modelling of decreased blood thyroxine concentrations in rats resulted in a reference point of 40 mg/kg body weight (bw) per day. The Scientific Committee established a tolerable daily intake (TDI) of 0.4 mg/kg bw per day and an acute reference dose (ARfD) of 0.4 mg/kg bw per day to protect against adverse neurodevelopmental effects. The TDI value is supported by the results of experimental human studies with a NOAEL of 4 mg/kg bw per day and 10-fold interindividual variability. The TDI and ARfD are considered as conservative with 90% certainty. Insufficient evidence related to the toxicological effects of bromide was available for animals, with the exception of dogs. Therefore, the reference point of 40 mg/kg bw per day was extrapolated to maximum safe concentrations of bromide in complete feed for other animal species. Bromide can transfer from feed to food of animal origin, but, from the limited data, it was not possible to quantify the transfer rate. Monitoring data exceeded the current MRLs for some food commodities, generally with a low frequency. A conservative safety screening of the MRLs indicated that the TDI and ARfD are exceeded for some EU diets. Dietary exposure assessment for animals was not feasible due to insufficient data. The Scientific Committee recommends data be generated to allow robust dietary exposure assessments in the future, and data that support the risk assessment.

An estimation of the daily intake of di(2-ethylhexyl)phthalate (DEHP) and other phthalates in the general population

ABSTRACTRisk assessment and hormone evaluation were carried out for di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DBP), endocrine disrupting chemicals (EDCs), in 302 Korean children (n = 223) and adolescents (n = 79) (< age 19). Urinary and serum concentrations of DEHP, MEHP (mono(2-ethylhexyl) phthalate), DBP, MBP (monobutyl phthalate), and PA (phthalic acid, a common final metabolite of phthalates) were detected in children and adolescents. Daily exposure levels were estimated to be 16.45 ± 36.50 μg/kg b.w./day for DEHP, which is one-third of the tolerable daily intake (TDI) value (50 μg/kg b.w./day), but 14 out of 302 participants had a hazard index (HI = intake/TDI) value >1. The mean daily exposure level of DBP was 1.23 ± 1.45 μg/kg b.w./day, which is one-eighth of the TDI value (10 μg/kg b.w./day), but 1 out of 302 participants had a HI value > 1. Positive correlations were observed between serum DBP or MEHP, and serum estradiol (E2) and/or luteinizing hormone (LH) in prepubescent children. In addition, serum MBP levels were found to be negatively correlated with serum triiodothyronine (T3) or thyroxine (T4) in male participants, and serum DEHP levels with serum thyroid stimulating hormone (TSH) in female adolescents. Low-density lipoprotein (LDL) levels were positively correlated with serum PA levels in children and adolescents. DEHP, DBP or its metabolites may be associated with altered hormone levels in children and adolescents. Data suggest that exposure levels of DEHP and DBP in Korean children need to be reduced to levels below TDI to protect them from EDC-mediated toxicities.Abbreviations: DBP: dibutyl phthalate; DEHP: di(2-ethylhexyl) phthalate; E2: estradiol; EDC: endocrine disrupting chemical; EFSA: European Food Safety Authority; FSH: follicle stimulating hormone; HDL: high density lipoprotein; HI: hazard index; LDL: low density lipoprotein; LH: luteinizing hormone; MEHP: mono(2-ethylhexyl) phthalate; MBP: monobutyl phthalate; PA: phthalic acid; PPAR: peroxisome proliferator-activated receptor gamma; PVC: polyvinyl chloride; T3: triiodothyronine; T4: thyroxine; TDI: tolerable daily intake; TG: triglyceride; TSH: thyroid stimulating hormone; UPLC/MS/MS: Ultra Performance Liquid Chromatography/Tandem Mass Spectrometry; WWF: World Wildlife Fund.

Toxicological analysis points to a lower tolerable daily intake of melamine in food

The potential health effects of incineration of municipal solid waste (MSW) have been studied by the Swedish National Institute of Environmental Medicine. The greatest concern for health effects relates to the emission of PCDDs and PCDFs ("dioxins"). MSW incineration is presently estimated to be a large source for the emission of these compounds into ambient air. Based upon animal experiments, and by applying safety factors in the range 200-1000, a highest tolerable daily intake (TDI) has been estimated to be 1-5 pg kg-1 of TCDD for humans. This TDI-value has been extended to cover all the congeners of PCDDs and PCDFs by the application of the concept of "TCDD-equivalents" (Eadon et al., 1983). The high concentrations found in human breast milk and fish indicate that the TDI value may be exceeded, especially among breast-milk fed babies. If the emission can be reduced to the proposed Swedish limit value of 0.1 ng m-3n TCDD-equivalents, or less, the contribution from this source will be lowered. MSW incineration can be considered acceptable when the following aspects are taken into account: the risk estimation for TDI is conservative; there is no indication that man belongs to the most sensitive species although infants may be particularly sensitive; available studies indicate that the concept of TCDD-equivalents used overestimates the effect of mixtures of PCDDs and PCDFs; present levels in fish and human milk reflect the cumulative effect of many years of emission. Besides PCDDs and PCDFs, MSW incineration also gives rise to relatively high emissions of PAH, chlorinated PAH, phenols, benzenes and mutagenic substances under less well controlled combustion conditions. The emission of organic compounds is generally dependent on the combustion efficiency. If the combustion process is optimized and advanced flue-gas cleaning is applied so that the emission of TCDD-equivalents does not exceed 0.1 ng m-3, the emission of other organics probably will not cause significant health hazards.

The Norwegian Scientific Committee for Food Safety (Vitenskapskomiteen for mattrygghet, VKM) has at the request of the Norwegian Food Safety Authority (Mattilsynet) conducted a risk assessment of the coumarin intake in the Norwegian population. VKM was asked to assess if any part of the population has a total intake of coumarin that will exceed the tolerable daily intake (TDI). It should further be considered whether an intake of coumarin exceeding TDI 1-2 times a week for several years would represent a risk to the health of the consumer.&#x0D; The assessment has been performed by the VKM Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics (Panel 4).&#x0D; Coumarin is a naturally flavouring substance in cinnamon and occurs in many plants. The substance can be found in different types of cinnamon to a varying degree. The two main types are Ceylon (Cinnamomum zeylandicum) and Cassia cinnamon (Cinnamomum aromaticum). Cassia cinnamon, which currently is most frequently used in food products on the Norwegian market, contains more coumarin than the lesser used Ceylon cinnamon.&#x0D; Oral intake of coumarin is mostly related to consumption of cinnamon-containing foods or cinnamon as a spice. This includes both direct addition of cinnamon to foods as well as the use of cinnamon oils and other cinnamon extracts by the food industry. Other important sources of exposure could be food supplements based on cinnamon or the use of cosmetic products through dermal exposure, as synthetic coumarin is added as a fragrance ingredient to perfumes, skin gels, lotions and deodorants.&#x0D; It is known from animal experiments that coumarin can cause liver toxicity. It is considered as a non-genotoxic carcinogen in mice and rats. In 2004, the European Food Safety Authority (EFSA) established a TDI of 0.1 mg coumarin/kg body weight (bw), based on a no observed adverse effect level (NOAEL) for liver toxicity in a 2-year dog study. This TDI was maintained when the substance was re-evaluated in 2008. EFSA further concluded that exposure to coumarin resulting in an intake 3 times higher than the TDI for 1-2 weeks was not of safety concern.&#x0D; In order to answer the second question as stated in the terms of reference, the VKM Panel on Food Additives, Flavourings, Processing Aids, Materials in Contact with Food and Cosmetics found it necessary to further examine the data on toxicity of coumarin, which were the basis for the TDI established by EFSA. The most significant hazards of coumarin appears to be liver toxicity, which is well documented, and demonstrated in mice, rats, dogs, baboons and humans, and kidney adenomas in male rats. In a review of human case reports, a small subgroup of the human population appears for unknown reasons to be more susceptible to medical treatment with coumarin. The lowest reported dose of coumarin associated with liver toxicity in humans is around 0.4 mg/kg bw/day. It should be noted that the liver toxicity of coumarin in humans usually is reversible. Since there were no dose-response data for humans, animal data were used in the hazard characterisation.&#x0D; The VKM Panel decided to use the benchmark dose (BMD) approach to determine a point of departure for adverse effects of coumarin. The 2-year chronic toxicity/carcinogenicity study in rats by the US National Toxicology Program (NTP) was chosen for model simulation and BMD/BMDL (benchmark dose lower confidence limit) calculations. The best model fit of the dose-response data combined with the lowest BMDL05 (dose where the response is likely to be smaller than 5%) was seen for increased relative liver weight in female rats, which gave a BMDL05 of 7 mg/kg bw/day (converted from 10 mg/kg bw, 5 times per week).&#x0D; The VKM Panel used the BMDL05 for relative increase in liver weight in female rats to establish a TDI of 0.07 mg/kg bw/day using an uncertainty factor of 100 to account for interand intraspecies variation.&#x0D; The intake calculations for coumarin from food and drinks in this opinion are based on both data from the nationally representative food consumption surveys Norkost, Ungkost, Småbarnskost and Spedkost, as well as on assumed worst intake scenarios of different cinnamon-containing food products. The average coumarin levels found in cinnamoncontaining food categories such as ginger bread, cinnamon buns and similar bakery products, cinnamon-containing cakes, thin pastry with cinnamon and cinnamon-based tea sold on the Norwegian market, were used to calculate the total coumarin intake in different age groups in the population. For the calculation of the coumarin intake from cinnamon powder sprinkled on oatmeal porridge and rice porridge, a coumarin level of 3000 mg/kg in cinnamon powder was used. The frequency of consumption and the amount of cinnamon powder (from ¼ - 1 teaspoon) sprinkled on the porridge were taken into account in the calculations.&#x0D; To assess if any part of the Norwegian population has an intake of coumarin that will exceed the TDI, the different intake scenarios presented in the opinion have been compared with the TDI of 0.07 mg/kg bw/day established by VKM. The main conclusions from the VKM Panel were:&#x0D; The total estimated intake of coumarin for mean and high consumers of cinnamon-containing foods are below the TDI for all age groups when consumption of cinnamon-based tea and porridge with cinnamon was excluded.&#x0D; Children and adults who regularly consume oatmeal porridge sprinkled with cinnamon may exceed the TDI by several folds depending on the frequency of consumption and the amount of cinnamon used.&#x0D; Small children (1- and 2-years old) who have a mean or high consumption of oatmeal porridge may exceed the TDI even if they use moderate amounts of cinnamon powder on the porridge. In a worst case scenario with high consumption of porridge and use of high amounts of cinnamon powder, the estimated coumarin intake could exceed the TDI by about 20-fold.&#x0D; This intake is similar to dose levels of coumarin used in medical treatment of adults and where cases of liver toxicity have been reported.&#x0D; Drinking of cinnamon-based tea, which may have a high content of coumarin, can also result in a total intake of coumarin that exceeds the TDI both for children and adults.&#x0D; Other relevant sources of coumarin are cosmetics and food supplements with cinnamon. The recommended dose of two cinnamon supplements sold on the Norwegian market can lead to an exceedance of TDI in adults. It is not anticipated that children will consume supplements with cinnamon. Cosmetic products (shower gels, body lotions, deodorants and oils) are important sources of coumarin exposure both for children and adults, but quantification of the coumarin exposure from cosmetics was not possible due to lack of data.&#x0D; The VKM Panel concludes that based on the available data, the possibility of an adverse health effect by exceeding the TDI 3-fold for 1-2 times per week for several years cannot be assessed. Generally, a minor or an occasional exceedance of TDI is not considered to increase the risk of adverse health effects.&#x0D; The coumarin intake could exceed the TDI by 7-20 fold in some instances. Liver toxicity may occur shortly after the start of coumarin exposure. Such large daily exceedances of TDI, even for a limited time period of 1-2 weeks, cause concern of adverse health effects.

Mycotoxins belong to substances harmful to human health. They are found mainly in cereal products and their preparations. In particular, infants and young children who consume cereal products, including porridge and gruel, are exposed to these substances. The aim of the study is to assess the exposure of infants and young children in Poland to micotoxins (ochratoxin A. deoxynivalenol, nivalenol, fumonisins B1 and B1, T-2 and HT-2 toxins) derived from cereal products intended for infants and children. Samples of products (302) were taken from all over the country in the following three years (2011, 2012 and 2013). HPLC-MS / MS method was used to determine the test compounds. Using the HPLC-MS / MS method, the assessment of population exposure in Poland to mikototoxins (ochratoxin A, deoxynivalenol, nivalenol, fumonisins B1 and B1, T-2 and HT-2 toxins) derived from cereal products (porridge, gruel) intended for infants and small children. Samples (302) were taken from across the country over the next three years. The exposure values obtained in the average exposure scenario range from 0.2 to 3% compared to the reference toxicological parameters. Considering that in the case of infants and young children, the tested products constitute a quantitatively significant part of the balanced diet of these consumers, and the remaining groups of foodstuffs, including vegetable products. fruit and meat and dairy products do not contribute significant amounts of mycotoxins to the diet can be accepted. that the level of contamination of cereal products does not pose a significant risk to the health of consumers. In the case of high exposure, it did not exceed 10% of the reference values for deoxynivalenol and the sum of fumonisins B1 and B2. These values were assessed as not relevant for the exposure of infants and young children. In contrast, in the case of zearalenone, the high level of exposure corresponded to 36% of the value of tolerable daily intake (TDI), and for the sum of T-2 and HT-2 toxins, the value of 48% of tolerable daily intake. In both cases, the contribution of pollutants to the diet was significant, but still remained 2-3 times less than the tolerable daily intake. Given, that cereal products are the main source of these contaminants, it can be estimated that exceeding the TDI value in relation to the total diet of infants and young children is unlikely. The exposure values obtained in the average exposure scenario range from 0.2 to 3% compared to the reference toxicological parameters. In the case of zearalenone, the high level of exposure corresponded to 36% of the TDI value. and for the sum of T-2 and HT-2 toxins, 48% TDI. The contribution of pollutants to the diet in both cases was significant. however, it still remained 2-3 times less than the tolerable daily intake. Considering, that cereal products are the main source of these pollutants can be assessed. that exceeding the TDI value for the total diet of infants and young children is unlikely.

Human risk assessment of chemicals is traditionally presented as the ratio between the actual level of exposure and an acceptable level of exposure, with the acceptable level of exposure most often being estimated by appropriate authorities. This approach is generally sound when assessing the risk of individual chemicals. However, several chemicals may concurrently target the same receptor, work through the same mechanism or in other ways induce the same effect(s) in the body. In these cases, cumulative risk assessment should be applied. The present study uses biomonitoring data from 129 Danish children and adolescents and resulting estimated daily intakes of four different phthalates. These daily intake estimates are used for a cumulative risk assessment with anti-androgenic effects as the endpoint using Tolerable Daily Intake (TDI) values determined by the European Food Safety Authorities (EFSA) or Reference Doses for Anti-Androgenicity (RfD AA) determined by Kortenkamp and Faust [Int J Androl 33 (2010) 463] as acceptable levels of exposure. United States Environmental Protection Agency Reference Doses (US EPA RfD) could not be used as none of them identifies anti-androgenic effects as the most sensitive endpoint for the phthalates included in this article. Using the EFSA TDI values, 12 children exceeded the hazard quotient for the sum of di-n-butyl phthalate and di-iso-butyl phthalate (∑DBP((i+n))) and one child exceeded the hazard quotient for di-(2-ethylhexyl)phthalate (DEHP). Nineteen children exceeded the cumulated hazard index for three phthalates. Using the RfD AA values, one child exceeded the hazard quotient for DEHP and the same child exceeded the cumulated hazard index for four phthalates. The EFSA TDI approach thus is more restrictive and identifies ∑DBP((i+n)) as the compound(s) associated with the greatest risk, while DEHP is the compound associated with the greatest risk when using the RfD AA approach.

Bisphenol A (BPA) and its analogues (BPs) are suspected posing potential endocrine disrupting properties. They might migrate into foodstuffs through food packaging materials or contaminated water and soil. Dietary exposure is of paramount importance way for human health. European Food Safety Authority (EFSA) lowered the value of tolerable daily intake (TDI) from 50 μg/kg bw/day (d) to a temporary (t) TDI (t-TDI) of 4 μg/kg bw/d. In this study, the Chinese total dietary samples were analyzed for assessing the exposure risk of BPs by diets. BPA, bisphenol F (BPF), bisphenol S (BPS), and bisphenol AF (BPAF) were found in 12 kinds of food samples except for bisphenol B (BPB). A deterministic approach was used to calculate the dietary intakes of 4 kinds of compounds. For different age and gender groups, the exposure levels of BPA (178.440-403.672 ng/kg bw/d) was the highest, followed by BPS (21.372-52.112 ng/kg bw/d), BPF (20.641-50.507 ng/kg bw/d), and BPAF (0.434-1.210 ng/kg bw/d). Based on the t-TDI set by EFSA (4 μg/kg bw/d for BPA), the BPs through dietary intake pose low risks on the Chinese general population even summarization exposure levels of different BPs. However, human can be exposed to multiple endocrine disrupting chemicals rather than BPs alone; combined exposure risks should be further considered.

Preliminary data on citrinin kinetics in humans and their use to estimate citrinin exposure based on biomarkers

Risk Assessment of Contaminants in Sewage Sludge Applied on Norwegian Soils

The Use of an Additional Safety or Uncertainty Factor for Nature of Toxicity in the Estimation of Acceptable Daily Intake and Tolerable Daily Intake Values

Impact on health of chlorinated dioxins and other trace organic emissions