Framework for developing an exposure science curriculum as part of the European Exposure Science Strategy 2020-2030.

BACKGROUND: Evaluating and managing exposures to chemical, physical and biological stressors, which frequently interplay with psychological stressors as well as social and behavioural aspects, is crucial for protecting human and environmental health and transitioning towards a sustainable future. Advances in our understanding of exposure rely on input from well-trained exposure scientists. However, no education programmes in Europe are currently explicitly dedicated to cover the broader range of exposure science approaches, applications, stressors and receptors. OBJECTIVE: To address this challenge, a curriculum is needed that yields credible, well-defined career pathways in exposure science. METHODS: Needs and conditions for advancing exposure science education in Europe were identified. As a starting point for a way forward, harmonised learning outcomes for exposure science were defined at each level of the European Qualifications Framework. The course programme coordinators were recruited for three varying courses, with respect to the course level and the proportion of the curriculum dedicated to exposure science. These courses were assessed via our systematic course review procedure. Finally, strategic objectives and actions are proposed to build exposure science education programmes. RESULTS: The ISES Europe 'Education, Training and Communication' expert working group developed a framework for creating a viable exposure science curriculum. Harmonised learning outcomes were structured under eight learning levels, categorised by knowledge, skills and competence. Illustrative case studies demonstrated how education providers integrated these learning outcomes for their educational context and aligned the overall exposure science curriculum. CONCLUSIONS: The international recognition and adoption of exposure science education will enable advances in addressing global exposure science challenges for various stressors, from behavioural aspects from individual to population scale, and effective communication between exposure scientists and relevant stakeholders and policy makers, as part of the European Exposure Science Strategy 2020-2030.

Building a European exposure science strategy.

Exposure information is a critical element in various regulatory and non-regulatory frameworks in Europe and elsewhere. Exposure science supports to ensure safe environments, reduce human health risks, and foster a sustainable future. However, increasing diversity in regulations and the lack of a professional identity as exposure scientists currently hamper developing the field and uptake into European policy. In response, we discuss trends, and identify three key needs for advancing and harmonizing exposure science and its application in Europe. We provide overarching building blocks and define six long-term activities to address the identified key needs, and to iteratively improve guidelines, tools, data, and education. More specifically, we propose creating European networks to maximize synergies with adjacent fields and identify funding opportunities, building common exposure assessment approaches across regulations, providing tiered education and training programmes, developing an aligned and integrated exposure assessment framework, offering best practices guidance, and launching an exposure information exchange platform. Dedicated working groups will further specify these activities in a consistent action plan. Together, these elements form the foundation for establishing goals and an action roadmap for successfully developing and implementing a 'European Exposure Science Strategy' 2020-2030, which is aligned with advances in science and technology.

Lead content in wild game shot with lead or non-lead ammunition - Does "state of the art consumer health protection" require non-lead ammunition?

The toxicity of lead has been known for a long time, and no safe uptake level can be derived for humans. Consumers' intake via food should therefore be kept as low as possible. Game meat can contain elevated levels of lead due to the use of lead ammunition for hunting. A risk assessment conducted in 2010 by the German Federal Institute for Risk Assessment including various consumption scenarios revealed a possible health risk for extreme consumers of game meat hunted with lead ammunition (i.e. hunters and members of hunters' households). Babies, infants, children and women of childbearing age were identified as vulnerable group with regards to the developmental neurotoxicity of lead. It was noted, that a sound data base was required in order to refine the assessment. Therefore, the research project "Safety of game meat obtained through hunting" (LEMISI) has been conducted in Germany, with the aims of determining the concentrations of lead (as well as of copper and zinc) brought into the edible parts of game meat (roe deer (Capreolus capreolus) and wild boar (Sus scrofa)) due to using either lead or non-lead hunting ammunition, whilst concurrently taking geogenic (i.e. "background") levels of lead into account. Compared to non-lead ammunition, lead ammunition significantly increased lead concentrations in the game meat. The use of both lead and non-lead ammunition deposited copper and zinc in the edible parts of game meat, and the concentrations were in the range of those detected regularly in meat of farm animals. For the average consumer of game meat in Germany the additional uptake of lead only makes a minor contribution to the average alimentary lead exposure. However, for consumers from hunters' households the resulting uptake of lead-due to lead ammunition-can be several times higher than the average alimentary lead exposure. Non-lead bullets in combination with suitable game meat hygienic measures are therefore recommended in order to ensure "state of the art consumer health protection".

Regulatory toxicology in the twenty-first century: challenges, perspectives and possible solutions.

The advent of new testing systems and "omics"-technologies has left regulatory toxicology facing one of the biggest challenges for decades. That is the question whether and how these methods can be used for regulatory purposes. The new methods undoubtedly enable regulators to address important open questions of toxicology such as species-specific toxicity, mixture toxicity, low-dose effects, endocrine effects or nanotoxicology, while promising faster and more efficient toxicity testing with the use of less animals. Consequently, the respective assays, methods and testing strategies are subject of several research programs worldwide. On the other hand, the practical application of such tests for regulatory purposes is a matter of ongoing debate. This document summarizes key aspects of this debate in the light of the European "regulatory status quo", while elucidating new perspectives for regulatory toxicity testing.

Lead exposure from food: the German LExUKon project.

Lead is a highly toxic contaminant with food being the major source of exposure for the general public. The second German food consumption survey (Nationale Verzehrsstudie II - NVS II) with about 20 000 participants (15 371 for dietary history interviews used for this study) allowed for an updated exposure assessment for the German population. Based on these comprehensive data, information on consumption of 545 individual food items by the German population was generated. Lead concentrations in food were compiled from the German food monitoring programme, European countries' authority programmes and the published literature, covering the years from 2000 to 2009, and were multiplied with consumption data to obtain estimates of lead intake from food. Average lead concentrations per main food group were highest for meat (including offal), followed by fish (including seafood), vegetables and cereals. Due to high consumption, beverages contributed most to the intake of the general public, followed by main groups vegetables, fruits & nuts and cereals. Lead intake from food was estimated to be 0.53 and 0.72 µg kg(-1) bw and day for average and high-end consumers, respectively. This is close to (average consumers) respectively above (high-end consumers) a reference value derived from a recent health risk evaluation performed by EFSA, using the benchmark approach. Uncertainties in these estimates pertain to the influence of values below the limit of quantification and some foods not considered due to lacking occurrence data. In conclusion, the estimated lead intake of the German population from food is still close to health-based reference values. Further efforts to reduce lead intake are required.

Cadmium exposure from food: the German LExUKon project.

Cadmium is a very toxic contaminant with food being the major source of exposure for the general public. The second German food consumption survey (Nationale Verzehrsstudie II - NVS II) with about 20 000 participants (15 371 for dietary history interviews used for this study) allowed for an updated exposure assessment for the German population. Based on these comprehensive data, information on the consumption of 545 individual food items by the German population was generated. Cadmium concentrations in food were compiled from the German food monitoring programme, European countries' authority programmes and the published literature, covering the years from 1993 to 2008, and were multiplied with consumption data to obtain estimates of cadmium intake from food. Consumption-weighted mean cadmium concentrations per main food group were highest for cereals, followed by oily seeds & fruits, and vegetables. Due to both high consumption and considerable occurrence of cadmium, cereals and vegetables contributed most to the intake of the general public, followed by the main groups beverages, fruits & nuts, and dairy products (including milk). Cadmium intake from food was estimated to be 1.46 and 2.35 µg kg(-1) bw week(-1) for average and high-end consumers, respectively. This corresponds to 58% for average and 95% for high-end consumers, respectively, of a reference value derived from a recent health risk evaluation performed by EFSA, using the benchmark approach. Uncertainties in these estimates pertain to the influence of values below the limit of quantification and some foods not considered due to lacking occurrence data. In conclusion, the estimated cadmium intake of the German population from food is still close to health-based reference values. Further efforts to reduce cadmium intake are required.

Dioxin and dl-PCB exposure from food: the German LExUKon project.

Polychlorinated dibenzo-p-dioxin and -furan (PCDD/F) and dioxin-like polychlorinated biphenyl (dl-PCB) exposure from food were estimated using new food consumption data from the recent German food consumption survey (Nationale Verzehrsstudie II - NVS II). Based on these comprehensive data, information on the consumption of 545 individual food items by the German population was derived. Concentrations of dioxin-like compounds in food were compiled from the German Food Monitoring Programme (GFMP), the German Dioxin Database, other German authority programmes, European countries' authority programmes and the published literature covering the years 2000-2010. By multiplication with consumption data, estimates of intake from food were determined. The main food groups contributing most to the intake of the general public are dairy products (including milk), meat and fish (including seafood), followed - due to high consumption - by the main group vegetables. The combined intake of PCDD/F and dl-PCB (as toxic equivalents - TEQ) from food was estimated to be 2.11/1.53 pg kg(-1) bw and day and 3.56/2.85 pg kg(-1) bw and day (upper/lower bound) for average and high-end consumers, respectively. The estimated intake of average consumers is close to a reference value derived by the Scientific Committee on Food in 2001. Uncertainties in these estimates pertain to the influence of values below the limit of quantification (upper/lower bound ratio) and some foods not considered due to the lack of contamination data.

German database on the occurrence of food additives: application for intake estimation of five food colours for toddlers and children.

To get a more realistic estimation of food additive intake for toddlers and children, a German database on the occurrence of food additives was created. It uses consumption data of two recent national nutrition surveys for toddlers and children in combination with qualitative information of food additive occurrence in the consumed food. The information on food additive occurrence is based on food labelling. A categorisation system was developed according to regulations to classify the foods consumed and to identify possible food additive use in the food groups. Two natural (E120, E160b) and three artificial food colours (E110, E124, E129) were chosen for an assessment of food additive intake. The percentage of food items containing one of the chosen food colours was calculated for every food group and the food groups with most items containing the additive were identified. Intake estimations were performed based on maximum permitted-use levels (MPLs). Firstly, additive use was assumed in all foods consumed (tier 2); and secondly, food additive use was assumed only for those items where labelling confirmed the use and for all foods with no labelling available (tier 2b). Intake estimations were then compared with the ADI. Most food items with at least one of the food colours were found in the food groups confectionary, desserts, fermented milk products, flavoured drinks and breakfast cereals. The tier 2b approach provided more realistic estimations, which were always below those of the tier 2 approach and below the ADI for mean exposure. Exposure for high-level consumers exceeded the ADI for two of the food additives in tier 2b. Keeping in mind that the database is only mirroring the current situation, it provides a good possibility to refine the estimation of food additive intake for toddlers and children in Germany.

Dietary exposure to selected perfluoroalkyl acids (PFAAs) in four European regions.

The dietary exposure to selected PFAAs was estimated in four selected European states (Belgium, the Czech Republic, Italy and Norway) representing Western, Southern, Eastern and Northern Europe. The harmonised sampling programme designed in the European Union project PERFOOD was targeted at identifying seven selected PFAAs, including perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA), in food items that are most important both in terms of consumption and based on known high contamination patterns. The estimated average dietary exposure for adults (18-64 years) and children (3-9 years) is generally below or close to 1 ng kg⁻¹ BW day⁻¹ for all seven PFAAs. Considering the high consumption of food groups that contribute most to the exposure does not result in estimates exceeding 4 ng kg⁻¹ BW day⁻¹. Thus, based on the TDIs proposed by EFSA for PFOS (150 ng kg⁻¹ BW day⁻¹) and PFOA (1500 ng kg⁻¹ BW day⁻¹), no concern can be identified. There are distinct dietary exposure patterns from region to region as a result of different food consumption and contamination patterns. Foods of plant origin (e.g. fruit and vegetables) are most important for the dietary exposure to PFHxA, PFOA and PFHxS, while the consumption of foods of animal origin (particularly fish and seafood) mostly contributes to the dietary exposure to PFDA and PFUnDA. For the dietary exposure to PFNA and PFOS, food of animal and plant origin contributes with equal importance. In conclusion, region-to-region differences as well as the relative importance of food of different origin for each PFAA should be paid more attention in further research.

Occurrence of selected perfluorinated alkyl acids in lunch meals served at school canteens in Italy and their relevance for children's intake.

Ready-to-eat servings may be more contaminated with perfluorinated alkyl acids (PFAAs) than the corresponding unprocessed foods due to the presence of PFAAs in and transfer from food contact materials (FCM) and cookware. Therefore, the presence of selected PFAAs in meals served weekly at lunch time in six Italian school canteens was assessed. Five towns were selected representing different areas with local water and food supply. Daily lunch menus were sampled and pooled to form a composite. Analyses were carried out on the weekly composite from each canteen. UPLC-MS/MS quantification limits were in the 6.0-12 pg g⁻¹ range for the selected PFAAs (PFHxA, PFOA, PFNA, PFDA, PFUnDA, PFHxS, branched and non-branched PFOS). Non-branched PFOS was quantified in four out of six composites, with levels ranging from 14 to 25 pg g⁻¹, while PFOA and PFDA were determined in two out of six in the range 6.5-8.2 pg g⁻¹. Theoretical estimates and analytical results in the same order of magnitude indicate a negligible contribution from food processing and serving to meal contamination. When composite analytical data are transposed into dietary estimates, it is shown that Italian school-age children have intakes in the range of 0.3-1.1 and 0.5-1.4 ng kg⁻¹ bw day⁻¹ for PFOA and PFOS respectively, well below the corresponding tolerable daily intakes (TDIs).

Perfluorinated alkylated substances in vegetables collected in four European countries; occurrence and human exposure estimations.

The human diet is recognised as one possible major exposure route to the overall perfluorinated alkylated substances (PFAS) burden of the human population, resulting directly from contamination of dietary food items, as well as migration of PFAS from food packaging or cookware. Most European countries carry out national monitoring programs (food basket studies) to monitor contamination with pollutants. Usually, for PFASs, non-coordinated approaches are used in Europe, since food basket studies are mainly carried out by national authorities following national requirements and questions, making comparisons between different countries difficult. A harmonised sampling campaign collecting similar food items in a uniform procedure enabling direct comparison between different regions in Europe was designed. We selected four countries (Belgium, Czech Republic, Italy and Norway), representing the four regions of Europe: West, East, South and North. In spring 2010 and 2011, 20 different types of vegetables were sampled in Belgium, Czech Republic, Italy and Norway. Perfluorinated carboxylic acids (PFCAs) were the main group of detected PFASs, with perfluorinated octanoic acid (PFOA) as the most abundant PFCA (with exception of samples from Czech Republic), followed by perfluorinated hexanoic acid and perfluorinated nonanoic acid. Dietary intake estimates for PFOA show only low human exposure due to vegetable consumption for adults and children, mostly governed by high intake of potatoes.

Estimation of dietary intake of bis(2-ethylhexyl)phthalate (DEHP) by consumption of food in the German population.

In the study presented here, we evaluated the exposure of the German population aged 14-80 years to bis(2-ethylhexyl)phthalate (DEHP) from consumption of food by means of deterministic and probabilistic estimations. The study was performed on the basis of an extensive review of literature from around the world reporting measured data on DEHP in food, as well as official German food control data. Only data from individual measurements were considered and used for fitting of distributions. A wide range of concentrations in non-representative samples are reported in the literature. On the basis of the available DEHP concentration data, 37 food categories were characterized which covered all major food classes. Food consumption data were taken from the diet history interviews of the German National Nutrition Survey II (Nationale Verzehrsstudie II) which was performed in 2005/2006 in a representative study population of 15,371 and is the most recent data source of this kind in Germany. Average DEHP intake was estimated deterministically using data on measured concentrations in food (medians and means) and food consumption (means). A total dietary exposure to DEHP of 3.6 (median based) and 9.3µg/kg of BW per day (based on mean values) was estimated deterministically. In addition, distributions of both concentrations and consumption figures were fitted using the @RISK best fit tool for further probabilistic estimations. This approach resulted in estimates within the same range: the estimated median DEHP intake in the whole population (both non-consumers and consumers of the foods considered) was 10.2, the arithmetic mean 14.0 and the 95th percentile 28.6µg/kg of BW per day. The respective estimates for consumers only were 12.4, 18.7 and 36.5µg/kg of BW per day. These results demonstrate that the probabilistic approach is able to estimate broader ranges of exposure even when using data representing an average intake. Moreover, it reflects the uncertainties of the estimation due to insufficient analytical data on concentrations of DEHP in food.

Risk assessment of combined exposure to multiple chemicals: A WHO/IPCS framework.

This paper describes a framework for the risk assessment of combined exposure to multiple chemicals based on and developed subsequent to the World Health Organization/International Programme on Chemical Safety Workshop on Aggregate/Cumulative Risk Assessment (Combined Exposures to Multiple Chemicals) held in 2007. The framework is designed to aid risk assessors in identifying priorities for risk management for a wide range of applications where co-exposures to multiple chemicals are expected. It is based on a hierarchical (phased) approach that involves integrated and iterative consideration of exposure and hazard at all phases, with each tier being more refined (i.e., less cautious and more certain) than the previous one, but more labor and data intensive. It includes reference to predictive and probabilistic methodology in various tiers in addition to tiered consideration of uncertainty. The paper also annexes two case studies that have been developed to test and refine the framework.

Toxicology and risk assessment of 5-Hydroxymethylfurfural in food.

5-Hydroxymethylfurfural (5-HMF) as a product of the Maillard reaction is found in many foods. Estimated intakes range between 4 and 30 mg per person and day, while an intake of up to 350 mg can result from, e.g., beverages made from dried plums. In vitro genotoxicity was positive when the metabolic preconditions for the formation of the reactive metabolite 5-sulphoxymethylfurfural were met. However, so far in vivo genotoxicity was negative. Results obtained in short-term model studies for 5-HMF on the induction of neoplastic changes in the intestinal tract were negative or cannot be reliably interpreted as "carcinogenic". In the only long-term carcinogenicity study in rats and mice no tumours or their precursory stages were induced by 5-HMF aside from liver adenomas in female mice, the relevance of which must be viewed as doubtful. Hence, no relevance for humans concerning carcinogenic and genotoxic effects can be derived. The remaining toxic potential is rather low. Various animal experiments reveal that no adverse effect levels are in the range of 80-100 mg/kg body weight and day. Safety margins are generally sufficient. However, 5-HMF exposure resulting from caramel colours used as food additives should be further evaluated.

Toxicology and risk assessment of coumarin: focus on human data.

Coumarin is a secondary phytochemical with hepatotoxic and carcinogenic properties. For the carcinogenic effect, a genotoxic mechanism was considered possible, but was discounted by the European Food Safety Authority in 2004 based on new evidence. This allowed the derivation of a tolerable daily intake (TDI) for the first time, and a value of 0.1 mg/kg body weight was arrived at based on animal hepatotoxicity data. However, clinical data on hepatotoxicity from patients treated with coumarin as medicinal drug is also available. This data revealed a subgroup of the human population being more susceptible for the hepatotoxic effect than the animal species investigated. The cause of the high susceptibility is currently unknown; possible mechanisms are discussed. Using the human data, a TDI of 0.1 mg/kg body weight was derived, confirming that of the European Food Safety Authority. Nutritional exposure may be considerably, and is mainly due to use of cassia cinnamon, which is a popular spice especially, used for cookies and sweet dishes. To estimate exposure to coumarin during the Christmas season in Germany, a telephone survey was performed with more than 1000 randomly selected persons. Heavy consumers of cassia cinnamon may reach a daily coumarin intake corresponding to the TDI.

Concepts of exposure analysis for consumer risk assessment.

Risk assessment of health hazards introduced by chemicals is based on two basic elements: (i) exposure assessment and (ii) hazard identification. Risk characterisation is performed by comparing the exposure level with the NOAEL to establish the margin of exposure. If this margin is too narrow, then a concern is assumed which requires additional analyses, e.g. by refining data, or by performing additional studies. Assessment of risks by inhalation normally takes into consideration the concentrations in air that lead to toxic effects which can be compared by concentrations revealed from model assessments of measurements of concentrations of substances in room air. The key issues for exposure assessment can be separated into three parts: (i) the characterisation of the exposure scenario, (ii) the derivation of an adequate exposure model and (iii) the selection of model parameters, i.e. the determinants of the exposure. Particularly, complex evaluations need high efforts to retrieve and provide information and data. Therefore, exposure analysis should follow a tiered approach, starting with simple assumptions for exposure scenarios and models, as well as default parameters. The refinement aims at narrowing the assessment closely to reality. Therefore, due to different regulations, this approach avoids unnecessary investigations of data. The consideration of variability and uncertainty is getting more and more important in exposure evaluations, and some concepts have been recently published. The main objective of an uncertainty analysis (UA) in exposure assessment is to identify the sources of uncertainty thus providing support for decision makers which parameter is, e.g. the most critical one in an exposure scenario. An UA gives the assessor the opportunity to re-evaluate the scenario, model approaches and parameters of the analysis, and to consider their influence in the overall analysis by means of a tiered approach.

Exposure-triggered reproductive toxicity testing under the REACH legislation: a proposal to define significant/relevant exposure.

Under the new REACH legislation, toxicological testing is required in relation to annual tonnages produced or imported. Requirements for toxicological information increase when production volume increases. The respective information requirements are laid down in the REACH Annexes VII-X. Concerning human toxicology, certain toxicological tests may be waived under specific conditions. Aside from waiving criteria such as technical feasibility, exposure plays a decisive role in the waiving process with the consequence that toxicological testing will not be required in case of "no relevant exposure", "limited exposure", "no exposure" or "no significant exposure" (as expressed in the documents). However, up to now criteria are lacking which precisely define these terms. Attempts have been made to establish cut-off criteria between "non-relevant" and "relevant" (detrimental) exposure based on external exposure concentrations and the threshold of toxicological concern (TTC) principle. In this paper we make a proposal and describe a strategy how to define the currently insufficiently described terms "relevant/significant" exposure. We propose to define relevant/significant exposure based on an endpoint-specific TTC approach, starting from a comparison of the tentative external exposure to the specific TTC. This can be followed by a refinement of exposure estimates and may culminate in the experimental determination of internal and target tissue exposure. This strategy enables a well-founded assessment of what "no relevant exposure" is and safeguards an appropriate level of protection of the general population. The feasibility of the approach is demonstrated for reproductive toxicity endpoints.

Risk management measures for chemicals in consumer products: documentation, assessment, and communication across the supply chain.

This paper analyzes the way risk management measures (RMMs) for consumer products have been used to date in authority and industry risk assessments. A working concept for consumer product RMMs is developed, aimed at controlling, limiting or avoiding exposures, and helping to insure the safe use (or handling) of a substance as part of a consumer product. Particular focus is placed on new requirements introduced by REACH (registration, evaluation, and authorization of chemicals). A RMMs categorization approach is also developed, dividing consumer product RMMs into those that are product integrated and those that are communicated to consumers. For each of these categories, RMMs for normal use, accidental use or misuse need to be distinguished. The level of detail for documenting, assessing and communicating RMMs across supply chains can vary, depending on the type of the assessment (tiered approach). Information on RMMs was collected from published sources to demonstrate that a taxonomical approach using standard descriptors for RMMs libraries is needed for effective information exchange across supply chains.

Use of product databases for risk assessment purposes.

Product information databases are important prerequisites for providing data to poison centers (PC) to give adequate advice in cases of poisonings and for preparation of statistics as annual reports. For risk assessment measures, they can help for exposure assessments and for priority setting. A product database is a set of information of product and substance names, compositions, and uses of products. Data are provided due to national regulations as well as to national and international agreements between industry, international associations, e.g. the European Association of Poison Centres and Clinical Toxicologists (EAPCCT), and clinical toxicology institutions. They have different contents, i.e. complete formulations, frame formulations, and material safety data sheets. For definite identification of products, the product name should be readily taken from the labels and must be similar to the names provided by electronic media as databases. Products should be classified according to their use. The first system that has been prepared for that purpose is the ATC classification for pharmaceuticals. For chemicals, several systems e.g. the WHO-IPCS classification code, exist; the EU technical guidance document for risk assessment of chemicals is mentioning use categories, and they are used on national levels as well. For risk assessment purposes, statistics of poisonings and other health hazards are important as well as information about exposure. Linking cases of poisonings with product data enables risk assessors to perform statistical evaluations about health effects due to product use categories which can be compared to product compositions. If products are categorized by their use, information about use characteristics, such as frequencies and durations, can be derived. Hence, product categories can be taken to characterize scenarios and thus help for model estimations of exposure and respective doses.