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Arsenic is a human carcinogen that occurs ubiquitously in soil and water. Based on epidemiological studies, a benchmark dose (lower/higher bound estimate) between 0.3 and 8 μg/kg bw/day was estimated to cause a 1 % increased risk of lung, skin and bladder cancer. A recently published study by EFSA on dietary exposure to inorganic arsenic in the European population reported 95th percentiles (lower bound min to upper bound max) for different age groups in the same range as the benchmark dose. For toddlers, a highly exposed group, the highest values ranged between 0.61 and 2.09 µg arsenic/kg bw/day. For all other age classes, the margin of exposure is also small. This scenario calls for regulatory action to reduce arsenic exposure. One priority measure should be to reduce arsenic in food categories that contribute most to exposure. In the EFSA study the food categories 'milk and dairy products,' 'drinking water' and 'food for infants' represent major sources of inorganic arsenic for infants and also rice is an important source. Long-term strategies are required to reduce inorganic arsenic in these food groups. The reduced consumption of rice and rice products which has been recommended may be helpful for a minority of individuals consuming unusually high amounts of rice. However, it is only of limited value for the general European population, because the food categories 'grain-based processed products (non rice-based)' or 'milk and dairy products' contribute more to the exposure with inorganic arsenic than the food category 'rice.' A balanced regulatory activity focusing on the most relevant food categories is required. In conclusion, exposure to inorganic arsenic represents a risk to the health of the European population, particularly to young children. Regulatory measures to reduce exposure are urgently required. [ABSTRACT FROM AUTHOR]

Abstract: In an age when vector-borne diseases are emerging worldwide, personal protective measures are essential for shielding soldiers and other exposed persons from arthropod attack. The development of permethrin-impregnated clothing has been one recent advance in protecting persons at-risk. However, to date risk assessment has not been performed related to wearing permethrin-impregnated clothing over longer time periods. Therefore, this paper describes relevant toxicological aspects of permethrin and estimates the extent of dermal permethrin uptake by soldiers wearing impregnated uniforms by determining urine metabolites of permethrin. The exposure monitoring conducted in wearers of untreated uniforms did not show any signs of increased permethrin uptake and was similar to that of the general population in Germany. By contrast, studies involving the soldiers wearing permethrin-impregnated uniforms identified far higher internal exposure, the amounts of urine metabolites clearly above the reference value for the background exposure of the German population at large. Comparing the median excretion values, an approximately 200 times higher exposure can be assumed. The excretion levels of the subject with the maximum amount of metabolites correspond to an internal exposure of around 5–6μg/kg body weight and day thereby considering that biomonitoring could not take all urine metabolites and other elimination routes into account. Based on an oral absorption rate of 50%, the internal dose of 5–6μg/kg body weight and day would correspond to an oral uptake of permethrin which is around 20% of the ADI value of 50μg/kg body weight and day. In addition, based on these data and using a dermal absorption rate of 2% the permethrin dose reaching the skin was estimated to be 250μg/kg body weight and day. Considering a standard body weight and the area covered by the uniform, an exposure level of about 1.25μgpermethrin/cm2 skin and day can be calculated. Clinical subjective symptoms were recorded by means of a self-reporting questionnaire which has been developed and used for this specific purpose in environmental outpatient departments in both groups (wearers of impregnated versus non-impregnated uniforms). Only minor sensory impairments were identified in one of the studies (Kabul/Afghanistan) which may represent skin paraesthesiae. Based on these results, it can be assumed that the normal use of permethrin-treated uniforms does not affect human health to a clinical relevant extent. We recommend that the release rate of permethrin from the textile material should be strictly monitored by means of a quality assurance method. It should comply with standards to which the results of this study may contribute. [Copyright &y& Elsevier]

Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10-100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration-time profile in human blood. Maximum concentrations ( C) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 μg/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why C and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest C value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA. [ABSTRACT FROM AUTHOR]

In the absence of toxicological data, as it is the case for, e.g. naturally occurring substances and chemicals underlying the new European chemicals legislation, distinct tools to derive quantitative toxicological data are of particular interest with regard to risk assessment of substances humans are repeatedly exposed. The software package TOPKAT 6.2 version 3.1 (Accelrys Inc., San Diego, USA) is a commercially available tool containing a (sub)chronic oral low observed adverse level (LOAEL) prediction model constructed by using structures and LOAELs of 393 chemicals contained in publicly accessible data banks. Applying this tool, we tested the prediction of (sub)chronic LOAELS for 807 industrial chemicals (purity ≥ 95%) by comparing the predicted values with their experimental LOAELs derived from repeated dose animal experiments performed according to standard guidelines. For 460 chemicals, a prediction could not be performed because of exclusion criteria defined in the system. They had either a lower LD50 as the predicted LOAEL ( n = 214) were outside the optimum prediction space which defines the domain of applicability ( n = 175), were used in the training data set ( n = 155), were not known to the system ( n = 50) or fulfilled other criteria for data exclusion ( n = 21). Of the remaining 347 substances, 34 to 62% LOAELs were predicted within a range of 1/5 and fivefold of the experimental LOAEL (factor 5), whereas 84 and 99% of the predicted LOAELs were within a range of 1/100 and 100-fold indicating high uncertainty of the prediction. Hence, a refined prediction tool is highly warranted. However, the uncertainty of the prediction could be accounted for if an additional factor of 100 is applied in addition to standard default adjustment factor of 100 which would result in an adjustment factor of 10,000 to be able to use a predicted NOAEL for risk assessment.. [ABSTRACT FROM AUTHOR]

Abstract: Technologies that generate information about the genome are being used to explore changes in gene expression and related proteins following exposure to chemicals. Conceptually, this information allows a greater understanding of genomic level mRNA expression (transcriptomics), cell and tissue protein expression (proteomics) and information about metabolite profiles (metabonomics). Having a greater understanding of this information alongside, empirical toxicological reference data provide for the continued evolution in our ability to understand toxicological modes of action, thereby providing a more scientific basis for extrapolation of toxicological information from animals to humans. Toxicogenomics also provides specific opportunities for improvements at different stages of the risk assessment process such as the development of new predictive models for identifying human health hazards and the identification of more precise molecular biomarkers of exposure. One possibility is that molecular fingerprinting in vivo or in vitro can be used to categorize chemicals and mixtures of chemicals into different mode of action groups. As there is indication that molecular signals differ at dose levels, it is hoped that toxicogenomic information can also contribute to the understanding and interpretation of effects seen with low dose exposure. Several gene polymorphisms have already been identified which play a role in the differing intra-species response to chemicals thus providing explanation for the observed differences in effects. It is therefore likely that a better understanding of genomic expression will enable a greater insight into the factors behind the observed variability in susceptibility to chemical exposure that can be seen in human populations. [Copyright &y& Elsevier]

During the past 20 years the EU legislation for the notification of chemicals has focussed on new chemicals and at the same time failed to cover the evaluation of existing chemicals in Europe. Therefore, in a new EU chemicals policy (REACH, Registration, Evaluation and Authorisation of Chemicals) the European Commission proposes to evaluate 30,000 chemicals within a period of 15 years. We are providing estimates of the testing requirements based on our personal experiences during the past 20 years. A realistic scenario based on an in-depth discussion of potential toxicological developments and an optimised “tailor-made” testing strategy shows that to meet the goals of the REACH policy, animal numbers may be significantly reduced below 10 million if industry would use in-house data from toxicity testing, which are confidential, if non-animal tests would be used, and if information from quantitative structure activity relationships (QSARs) would be applied in substance-tailored testing schemes. The procedures for evaluating the reproductive toxicity of chemicals have the strongest impact on the total number of animals bred for testing under REACH. We are assuming both an active collaboration with our colleagues in industry and substantial funding of the development and validation of advanced non-animal methods by the EU Commission, specifically in reproductive and developmental toxicity. [ABSTRACT FROM AUTHOR]

The Panel on Food Additives and Flavourings added to food (FAF) provided a scientific opinion re‐evaluating the safety of hydrogenated poly‐1‐decene (E 907) when used as a food additive. Hydrogenated poly‐1‐decene (E 907) is authorised as a food additive in the EU in accordance with Annex II to Regulation (EC) No 1333/2008. Hydrogenated poly‐1‐decene is of low acute toxicity and does not raise concern for genotoxicity. Toxicity and carcinogenicity, as well as reproductive and developmental toxicological studies, were not available; therefore, the Panel based the derivation of the acceptable daily intake (ADI) on the no observed adverse effect level (NOAEL) identified in the subchronic study in rats and established an ADI of 20 mg/kg bw per day. Dietary exposure to hydrogenated poly‐1‐decene (E 907) from its use as a food additive was calculated based on regulatory maximum level exposure assessment scenario. Mean exposure to hydrogenated poly‐1‐decene (E 907) from its use as a food additive ranged from no exposure in infants to 2.35 mg/kg bw per day in toddlers. The high exposure to hydrogenated poly‐1‐decene (E 907) ranged from 0 mg/kg bw per day in infants and adults to 6.69 mg/kg bw per day in toddlers. The exposure estimates in the regulatory maximum level exposure assessment scenario did not exceed the ADI of 20 mg/kg bw per day for all population groups. The Panel concluded that the exposure to hydrogenated poly‐1‐decene (E 907) does not raise a safety concern when used at the maximum permitted levels. [ABSTRACT FROM AUTHOR]

Abstract: Whenever new substances are proposed for use as sources of nutrients in food supplements, foods for the general population or foods for specific groups, EFSA is requested by the European Commission to perform an assessment of their safety and of the bioavailability of the nutrient from the proposed source. This guidance describes the scientific data required to allow an evaluation of the safety of the source within the established framework for risk assessment of food additives and novel food ingredients and the bioavailability of the nutrient from this source. This document is arranged in five main sections: one on technical data aimed at characterising the proposed source and at identifying potential hazards resulting from its manufacture and stability in food; one on existing authorisations and evaluation, providing an overview of previous assessments on the proposed source and their conclusions; one on proposed uses and exposure assessment section, allowing an estimate of the dietary exposure to the source and the nutrient based on the proposed uses and use levels; one on toxicological data, describing approaches which can be used to identify (in conjunction with data on manufacture and composition) and to characterise hazards of the source and any relevant breakdown products; the final section on bioavailability focuses on determining the extent to which the nutrient from the proposed source is available for use by the body in comparison with one or more forms of the same nutrient that are already permitted for use on the positive lists. This guidance document should replace the previous guidance issued by the Scientific Committee for Food and published in 2001. [ABSTRACT FROM AUTHOR]

The Panel on Food Additives and Nutrient Sources added to Food (ANS) provides a scientific opinion re-evaluating the safety of tragacanth (E 413) as a food additive. In the EU, tragacanth (E 413) has been evaluated by the Scientific Committee for Food (SCF, 1989) and by the Joint FAO/WHO Expert Committee on Food Additives (JECFA, 1987), who both allocated an acceptable daily intake (ADI) 'not specified' for this gum. Following the conceptual framework for the risk assessment of certain food additives, re-evaluated under Commission Regulation (EU) No 257/2010, the Panel considered that adequate exposure and toxicity data were available. Tragacanth (E 413) is unlikely to be absorbed intact and is partially fermented by intestinal microbiota. No adverse effects were reported in carcinogenicity studies at the highest dose tested and there is no concern with respect to the genotoxicity. Oral daily intake of a large amount of tragacanth up to 9,900 mg tragacanth/person per day (approximately equivalent 141 mg tragacanth/kg body weight (bw) per day) for up to 21 days was well tolerated in humans. The Panel concluded that there is no need for a numerical ADI for tragacanth (E 413) and that there is no safety concern for the general population at the refined exposure assessment of tragacanth (E 413) as a food additive at the reported uses and use levels. [ABSTRACT FROM AUTHOR]

The Scientific Committee ( SC) reconfirms that the benchmark dose ( BMD) approach is a scientifically more advanced method compared to the NOAEL approach for deriving a Reference Point ( RP). Most of the modifications made to the SC guidance of 2009 concern the section providing guidance on how to apply the BMD approach. Model averaging is recommended as the preferred method for calculating the BMD confidence interval, while acknowledging that the respective tools are still under development and may not be easily accessible to all. Therefore, selecting or rejecting models is still considered as a suboptimal alternative. The set of default models to be used for BMD analysis has been reviewed, and the Akaike information criterion ( AIC) has been introduced instead of the log-likelihood to characterise the goodness of fit of different mathematical models to a dose-response data set. A flowchart has also been inserted in this update to guide the reader step-by-step when performing a BMD analysis, as well as a chapter on the distributional part of dose-response models and a template for reporting a BMD analysis in a complete and transparent manner. Finally, it is recommended to always report the BMD confidence interval rather than the value of the BMD. The lower bound ( BMDL) is needed as a potential RP, and the upper bound ( BMDU) is needed for establishing the BMDU/ BMDL per ratio reflecting the uncertainty in the BMD estimate. This updated guidance does not call for a general re-evaluation of previous assessments where the NOAEL approach or the BMD approach as described in the 2009 SC guidance was used, in particular when the exposure is clearly smaller (e.g. more than one order of magnitude) than the health-based guidance value. Finally, the SC firmly reiterates to reconsider test guidelines given the expected wide application of the BMD approach. [ABSTRACT FROM AUTHOR]

Purpose: In 1986, the risk of agranulocytosis prompted German authorities to restrict the indications for metamizole use. After an initial decline, prescriptions increased from <20 million defined daily doses in 1990 to >140 million in 2012. Concurrently, spontaneous reports of agranulocytosis increased from about 10 in 1990 to >50 in 2012. In this study, reports were analyzed to identify targets for risk minimization measures. Methods: Reports of suspected metamizole-induced agranulocytosis (neutrophils <0.5 × 10 cells/l) between 1990 and 2012 were identified in the German spontaneous reporting database. Cases for which original reporting documents were available were eligible for analysis. Patient characteristics, indication, clinical course, and outcome were assessed. Results: One hundred sixty-one reports were analyzed. The mean age of the patients was 56.8 years (11-93) and 64.6 % were female. Off-label use was identified in about 25 % of cases. Neutrophils fell below 100/μl in 63 and intercurrent infections developed in 109 cases. Thirty-eight patients (23.6 %) died. In two thirds of the cases, agranulocytosis occurred within 6 weeks of permanent or intermittent metamizole treatment, in 30.5 % within 7 days, including 18 cases of immediate onset after the first or second administration. Conclusion: The reported cases show severe clinical courses and are, to some extent, a result of off-label use. Due to the absence of individual risk factors and presence of variable onset patterns, risk minimization measures should focus on restricting use to defined clinical situations and providing concise risk information for patients and healthcare professionals. [ABSTRACT FROM AUTHOR]

Highlights: [•] Animal-free risk assessment must increasingly use human toxicokinetics predictions. [•] Only human physiologically-based toxicokinetic (PBTK) modelling can serve this need. [•] Freely-available open source PBTK modelling platforms are lacking largely. [•] In vitro and in silico (QSAR) tools to meaure and predict needed parameters are rather scarce. [•] Presented are a state of the art overview and five high priority recommendations. [Copyright &y& Elsevier]

Abstract: Coumarin (1,2-benzopyrone) is occurring in food, and is also used in cosmetics. In order to perform a risk assessment for both oral and dermal exposure, we applied a physiologically based approach to model kinetics in humans by simulating both routes of exposure. The concentration–time profile in liver revealed a higher peak concentration (C max-hep) for the oral when compared to the dermal route. The area under the concentration–time curve in the liver (AUChep) was found the same for both routes if the same extent of absorption is assumed. Dose response information from published rat studies were used to identify the metric relevant for liver toxicity. Liver exposure levels resulting from doses and durations as outlined in the studies were simulated in a rat model. We obtained 31 data pairs of C max-hep and AUChep. Liver toxicity was observed at doses which resulted in simulated C max-hep values exceeding a certain liver concentration whereas we could not identify a clear cut off value of AUChep. Our findings support the notion that liver toxicity of coumarin in rats is related to C max-hep rather than to AUChep. If these findings can be transferred to the situation in humans, the result demonstrates that route specific differences in organ peak concentrations have to be considered when performing route-to-route extrapolation. [Copyright &y& Elsevier]

Regarding the cancer risk assessment of acrylamide (AA) it is of basic interest to know, as to what amount of the absorbed AA is metabolized to glycidamide (GA) in humans, compared to what has been observed in laboratory animals. GA is suspected of being the ultimate carcinogenic metabolite of AA. From experiments with CYP2E1-deficient mice it can be concluded that AA is metabolized to GA primarily by CYP2E1. We therefore examined whether CYP2E1 is involved in GA formation in non-rodent species with the focus on humans by using human CYP2E1 supersomes™, marmoset and human liver microsomes and in addition, genetically engineered V79 cells expressing human CYP2E1 (V79h2E1 cells). Special emphasis was placed on the analytical detection of GA, which was performed by gas chromatography/mass spectrometry. The results show that AA is metabolized to GA in human CYP2E1 supersomes™, in marmoset and human liver microsomes as well as in V79h2E1 cells. The activity of GA formation is highest in supersomes™; in human liver it is somewhat higher than in marmoset liver. A monoclonal CYP2E1 human selective antibody (MAB-2E1) and diethyldithiocarbamate (DDC) were used as specific inhibitors of CYP2E1. The generation of GA could be inhibited by MAB-2E1 to about 80% in V79h2E1 cells and to about 90% in human and marmoset liver microsomes. Also DDC led to an inhibition of about 95%. In conclusion, AA is metabolized to GA by human CYP2E1. Overall, the present work describes (1) the application and refinement of a sensitive methodology in order to determine low amounts of GA, (2) the applicability of genetically modified V79 cell lines in order to investigate specific questions concerning metabolism and (3) the involvement, for the first time, of human CYP2E1 in the formation of GA from AA. Further studies will compare the activities of GA formation in genetically engineered V79 cells expressing CYP2E1 from different species. [ABSTRACT FROM AUTHOR]

Abstract: The increasing use of tissue dosimetry estimated using pharmacokinetic models in chemical risk assessments in various jurisdictions necessitates the development of internationally recognized good modelling practice (GMP). These practices would facilitate sharing of models and model evaluations and consistent applications in risk assessments. Clear descriptions of good practices for (1) model development i.e., research and analysis activities, (2) model characterization i.e., methods to describe how consistent the model is with biology and the strengths and limitations of available models and data, such as sensitivity analyses, (3) model documentation, and (4) model evaluation i.e., independent review that will assist risk assessors in their decisions of whether and how to use the models, and also model developers to understand expectations for various purposes e.g., research versus application in risk assessment. Next steps in the development of guidance for GMP and research to improve the scientific basis of the models are described based on a review of the current status of the application of physiologically based pharmacokinetic (PBPK) models in risk assessments in Europe, Canada, and the United States at the International Workshop on the Development of GMP for PBPK Models in Greece on April 27–29, 2007. [Copyright &y& Elsevier]

Abstract: A number of zero tolerance provisions are contained in both food and animal feed law, e.g. for chemical substances whose occurrence is not permitted or is directly prohibited in food or animal feed. In the European Union, bans of this kind were introduced to give consumers and animals the greatest possible protection from substances with a possible hazard potential within the intendment of the hazard prevention principles and current precautionary measures. This also applies to substances for which an acceptable daily intake cannot be derived and a maximum residue limit cannot, therefore, be established, e.g. due to missing or inadequate toxicological data. Zero tolerances are also under discussion as trade barriers because their use has triggered numerous legal disputes. This paper draws together the results of an evaluation of alternative risk assessment methods to be used for the risk assessment of substances to which currently only zero tolerances apply. It will demonstrate that, depending on the available toxicological data, a scientifically sound risk assessment may still be possible. In this context, the two concepts – margin of exposure and threshold of toxicological concern – are very promising approaches. Until the scientific and sociopolitical discussions have been completed, it is essential that the principle of zero tolerances be upheld, especially for those substances which may be genotoxic carcinogens. In microbiology, there is no legal room for manoeuvre with regard to food safety criteria established for reasons of consumer health protection on the basis of scientific assessments. [Copyright &y& Elsevier]

Abstract: Risk assessment for acute airborne exposure to volatile organic compounds (VOCs), including exposure to chemical warfare agents, requires consideration of local and systemic effects at high concentrations. The operating procedure developed by the US Acute Exposure Guideline Level (AEGL) committee has gained special attention, in part because of the international collaboration in the project. The procedure defines three levels (AEGL-1: discomfort; AEGL-2: irreversible or other serious, long-lasting adverse effects; AEGL-3: life-threatening effects or death) for different exposure times (10 and 30min, and 1, 4 and 8h). In this article, the methodology for deriving AEGL values is reported. Extending the areas covered by the existing AEGL methodology, sensitive subpopulations are dealt with in more detail. Sensitive persons are expected to suffer from stronger effects when exposed to a given external concentration. Using a kinetic model with the sample substance dichloromethane (DCM), the higher internal exposure of children is quantified and compared to a healthy, young adult. The difference is shown to depend on age, on dose, and on duration of exposure. Furthermore, several ways are presented to derive AEGL values for exposure times which differ from the exposure duration in animal studies (‘time scaling’). In comparison to the conventional procedure, the alternative approaches are based on mechanistic models of the toxicodynamic effect. Use of these models results in AEGL values which are biologically justified. [Copyright &y& Elsevier]

Describing the toxicological profile of a substance is the first step required for risk assessment. Although a wide range ofin vitromethods are widely used to characterise toxicological properties including toxicokinetics, regulatory acceptance is mainly confined toin vitrotests which investigate genotoxic end-points.In vitrotests have been proposed for the endpoints acute toxicity, repeated dose toxicity and toxicity to reproduction which encompass the minimum requirements in the OECD SIDS programme. However, until now, limitations of the proposed tests preclude their application in a regulatory framework. Presently,in vitrotests play a major role in obtaining information on mechanism of toxicity with the perspective to be able to identify pathways of toxic responses by applying toxicogenomics techniques. Physiologically based toxicokinetic modelling is using data fromin vitrostudies to build up the model for a specific compound. Information from both areas is incorporated into the risk assessment to derive compound-specific safety factors, which account for species differences and for the variability among the human population, including possible sensitive subpopulations. Future developments to further enhance the use ofin vitromethods in regulatory toxicology include the development of (Q)SAR approaches supplemented by mechanisms of toxicity, which can be addressed by developing methods of molecular toxicology. [ABSTRACT FROM AUTHOR]

When deriving health-based exposure limits in recent years, increasing attention has been drawn to susceptible subpopulations, in particular to children. We investigated the differences in kinetics between children and adults during inhalation of styrene as a typical category-3 volatile organic compound (VOC), i.e., a gas with a low reactivity and low water solubility allowing a high rate of alveolar absorption. Internal exposure was simulated using a physiologically based kinetic model over a broad range of airborne concentrations (1-1000 ppm) and for an exposure time of up to 8 h according to the scenario in the acute exposure guideline level (AEGL) program. Age-specific anatomical and physiological parameters and compound-specific data was derived from the literature. The calculated concentrations in arterial blood are higher in children than in adults, and are highest in the newborn. For an 8-h exposure to low concentrations, the calculated arterial concentration in the newborn is higher by a factor of 2.3 than in the adult. This is due mainly to the relatively high ventilation rate and the immature metabolism. With increasing airborne concentration, the ratio of arterial concentrations (newborn/adult) increases to a maximum of 3.8 at 130 ppm in ambient air, and declines with further increments of concentration to a value of 1.7. This is because the metabolism of the newborn becomes non-linear at lower concentrations than in adults. At high concentrations, metabolism is saturated in both age groups. For shorter exposures, the dose dependency of the concentration ratios (newborn/adult) is less pronounced. This is the first article to show that the intraspecies assessment factor may vary with concentration and duration of exposure. [ABSTRACT FROM AUTHOR]

Xenobiotic metabolizing Cytochrome P450 (P450) enzymes were investigated in leukapheresed samples from 50 human individuals. It was the aim of the study (a) to get insight into the extent of extrahepatic P450 variability, (b) to investigate whether and to which extent P450 expression and variability as it is seen in the liver corresponds to P450 expression at extrahepatic sites, and (c) to contribute to the replacement of traditionally used default factors (usually 10 for interindividual variability) by data-derived factors in the risk assessment process. P450 enzymes were determined by Western Blotting. Immunoquantification was performed for P450 1A, 1B1, 2C, 2D6, 2E1, and 3A which were—with the exception of the polymorphically expressed CYP2D6—detectable in all samples investigated. Amounts of P450 enzymes in leukapheresed samples were (except CYP1B1) lower compared to those reported for the liver. The P450 variabilities were expressed by the ratios between the 95th and the 5th percentiles. They displayed 7-(CYP1A), 4-(CYP1B1), 6-(CYP2C), 30-(CYP2D6), 3-(CYP2E1), and 4-(CYP3A) fold variability in specific protein content. The results show (a) qualitative and quantitative differences in the expression of P450 proteins in leukapheresed samples from 50 individuals compared to liver, (b) a different extent of variability depending on the P450 enzyme, and (c) in cases where polymorphically distributed P450 enzymes are involved, the traditionally used factor of 10 might be too low to account for interindividual variability in both toxicokinetics and toxicodynamics. [Copyright &y& Elsevier]

The Panel on Food Additives and Flavourings (FAF) provided a scientific opinion re‐evaluating the safety of benzyl alcohol (E 1519) when used as a food additive. The Panel considered that adequate exposure and toxicity data were available. Benzyl alcohol (E 1519) is authorised as a food additive in the EU in accordance with Annex III to Regulation (EC) No 1333/2008. The Panel considered benzyl alcohol of low acute toxicity with no concern with respect to genotoxicity and carcinogenicity and established an acceptable daily intake (ADI) of 4 mg/kg body weight (bw) per day based on a no observable adverse effect level (NOAEL) of 400 mg/kg bw per day from the carcinogenicity study in rats. The mean and high exposure estimates in the refined exposure scenarios were maximally 0.27 and 0.81 mg/kg bw per day in toddlers, respectively. The exposure estimates to benzyl alcohol (E 1519) were below the ADI of 4 mg/kg bw per day in all population groups. The Panel noted that also the exposure in the regulatory maximum level exposure assessment scenario is below the ADI in all population groups. The Panel concluded that the exposure to benzyl alcohol (E 1519) does not raise a safety concern at the reported uses and use levels. [ABSTRACT FROM AUTHOR]

The Panel on Food Additives and Flavourings (FAF) provided a scientific opinion re‐evaluating the safety of sulphuric acid (E 513) and its sodium (E 514), potassium (E 515), calcium (E 516) and ammonium (E 517) salts when used as a food additive. The Panel considered that adequate exposure and toxicity data were available. Sulphuric acid and its sodium, potassium, calcium and ammonium salts (E 513, E 514, E 515, E 516, E 517) are authorised food additives in the EU, in accordance with Annex II and Annex III to Regulation (EC) No 1333/2008. In the refined estimated exposure non brand‐loyal scenario, mean exposure ranged from 0.4 mg sulphate/kg body weight (bw) per day in infants to 35 mg sulphate/kg bw per day in toddlers. The high percentile of exposure ranged from 3 mg sulphate/kg bw per day in adolescents to 68 mg sulphate/kg bw per day in toddlers. The Panel considered sulphates of low acute toxicity and there is no concern with respect to genotoxicity and carcinogenicity. The Panel noted that the exposure to sulphates at mean and 95th percentile in the non brand‐loyal scenario as well as in the other scenarios, is far below the 300 mg/kg a dose that induced laxative effect in humans. Based on the toxicological database available, the Panel concluded that the exposure to sulphuric acid (E 513), sodium sulphate (E 514), potassium sulphates (E 515), calcium sulphate (E 516) and ammonium sulphate (E 517) does not raise a safety concern at the reported uses and use levels and there is no need for a numerical acceptable daily intake (ADI). [ABSTRACT FROM AUTHOR]

The Panel on Food Additives and Flavourings added to Food (FAF) provided a scientific opinion re‐evaluating the safety of chlorides (E 507–509, E 511) as food additives. Chlorides are authorised food additives in the EU in accordance with Annex II and III to Regulation (EC) No 1333/2008. In the non‐ brand‐loyal scenario, mean exposure to chlorides (E 507–509, E 511) as food additives ranged from 2 mg/kg body weight (bw) per day in the elderly to 42 mg/kg bw per day in toddlers. The 95th percentile of exposure ranged from 5 mg/kg bw per day in the elderly to 71 mg/kg bw per day in toddlers. Chloride is an essential nutrient and after absorption is distributed to organs and tissues. The Panel considered chlorides to be of low acute oral toxicity and there is no concern with respect to genotoxicity and carcinogenicity. No effects were reported in developmental toxicity studies in rats following administration of magnesium chloride hexahydrate at 800 mg/kg bw per day. Some animal studies suggested a role of chloride in increasing blood pressure but based on the toxicological database available the Panel considered human data more appropriate to identify a level of chloride intake which does not raise a safety concern. The Panel identified a human dose of 40 mg chloride/kg bw per day as a reference value for the assessment. Mean levels of exposure in all age groups were below or at this reference value, which indicates no safety concern. In some age groups (toddlers, children and adolescents), the 95th percentile exposure estimates were slightly above this reference value. The Panel concluded that the exposure to chloride from hydrochloric acid and its potassium, calcium and magnesium salts (E 507, E 508, E 509 and E 511) does not raise a safety concern at the reported use and use levels. [ABSTRACT FROM AUTHOR]

The Scientific Committee confirms that the Threshold of Toxicological Concern (TTC) is a pragmatic screening and prioritisation tool for use in food safety assessment. This Guidance provides clear step‐by‐step instructions for use of the TTC approach. The inclusion and exclusion criteria are defined and the use of the TTC decision tree is explained. The approach can be used when the chemical structure of the substance is known, there are limited chemical‐specific toxicity data and the exposure can be estimated. The TTC approach should not be used for substances for which EU food/feed legislation requires the submission of toxicity data or when sufficient data are available for a risk assessment or if the substance under consideration falls into one of the exclusion categories. For substances that have the potential to be DNA‐reactive mutagens and/or carcinogens based on the weight of evidence, the relevant TTC value is 0.0025 μg/kg body weight (bw) per day. For organophosphates or carbamates, the relevant TTC value is 0.3 μg/kg bw per day. All other substances are grouped according to the Cramer classification. The TTC values for Cramer Classes I, II and III are 30 μg/kg bw per day, 9 μg/kg bw per day and 1.5 μg/kg bw per day, respectively. For substances with exposures below the TTC values, the probability that they would cause adverse health effects is low. If the estimated exposure to a substance is higher than the relevant TTC value, a non‐TTC approach is required to reach a conclusion on potential adverse health effects. This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2019.EN-1661/full [ABSTRACT FROM AUTHOR]