Prenatal dietary exposure to mixtures of chemicals is associated with allergy or respiratory diseases in children in the ELFE nationwide cohort.

INTRODUCTION: Prenatal exposure to environmental chemicals may be associated with allergies later in life. We aimed to examine the association between prenatal dietary exposure to mixtures of chemicals and allergic or respiratory diseases up to age 5.5 y. METHODS: We included 11,638 mother-child pairs from the French "Étude Longitudinale Française depuis l'Enfance" (ELFE) cohort. Maternal dietary exposure during pregnancy to eight mixtures of chemicals was previously assessed. Allergic and respiratory diseases (eczema, food allergy, wheezing and asthma) were reported by parents between birth and age 5.5 years. Associations were evaluated with adjusted logistic regressions. Results are expressed as odds ratio (OR[95%CI]) for a variation of one SD increase in mixture pattern. RESULTS: Maternal dietary exposure to a mixture composed mainly of trace elements, furans and polycyclic aromatic hydrocarbons (PAHs) was positively associated with the risk of eczema (1.10 [1.05; 1.15]), this association was consistent across sensitivity analyses. Dietary exposure to one mixture of pesticides was positively associated with the risk of food allergy (1.10 [1.02; 1.18]), whereas the exposure to another mixture of pesticides was positively but slightly related to the risk of wheezing (1.05 [1.01; 1.08]). This last association was not found in all sensitivity analyses. Dietary exposure to a mixture composed by perfluoroalkyl acids, PAHs and trace elements was negatively associated with the risk of asthma (0.89 [0.80; 0.99]), this association was consistent across sensitivity analyses, except the complete-case analysis. CONCLUSION: Whereas few individual chemicals were related to the risk of allergic and respiratory diseases, some consistent associations were found between prenatal dietary exposure to some mixtures of chemicals and the risk of allergic or respiratory diseases. The positive association between trace elements, furans and PAHs and the risk of eczema, and that between pesticides mixtures and food allergy need to be confirmed in other studies. Conversely, the negative association between perfluoroalkyl acids, PAHs and trace elements and the risk of asthma need to be further explored.

Dose addition in mixtures of compounds with dissimilar endocrine modes of action in in vitro receptor activation assays and the zebrafish sexual development test.

BACKGROUND: Human exposure to pesticides is being associated with feminisation for which a decrease of the anogenital distance (AGD) is a sensitive endpoint. Dose addition for the cumulative risk assessment of pesticides in food is considered sufficiently conservative for combinations of compounds with both similar and dissimilar modes of action (MoA). OBJECTIVE: The present study was designed to test the dose addition hypothesis in a binary mixture of endocrine active compounds with a dissimilar mode of action for the endpoint feminisation. METHODS: Compounds were selected from a list of chemicals of which exposure is related to a decrease of the AGD in rats and completed with reference compounds. These chemicals were characterised using specific in vitro transcriptional activation (TA) assays for estrogenic and androgenic properties, leading to a final selection of dienestrol as an ER-agonist and flutamide, linuron, and deltamethrin as AR-antagonists. These compounds were then tested in an in vivo model, i.e. in zebrafish (Danio rerio), using sex ratio in the population as an endpoint in order to confirm their feminising effect and MoA. Ultimately, the fish model was used to test a binary mixture of flutamide and dienestrol. RESULTS: Statistical analysis of the binary mixture of flutamide and dienestrol in the fish sexual development tests (FSDT) with zebrafish supported dose addition.

Combined chronic dietary exposure to four nephrotoxic metals exceeds tolerable intake levels in the adult population of 10 European countries.

A mixture risk assessment (MRA) for four metals relevant to chronic kidney disease (CKD) was performed. Dietary exposure to cadmium or lead alone exceeded the respective reference values in the majority of the 10 European countries included in our study. When the dietary exposure to those metals and inorganic mercury and inorganic arsenic was combined following a classical or personalised modified reference point index (mRPI) approach, not only high exposure (95th percentile) estimates but also the mean exceeded the tolerable intake of the mixture in all countries studied. Cadmium and lead contributed most to the combined exposure, followed by inorganic arsenic and inorganic mercury. The use of conversion factors for inorganic arsenic and inorganic mercury from total arsenic and total mercury concentration data was a source of uncertainty. Other uncertainties were related to the use of different principles to derive reference points. Yet, MRA at the target organ level, as performed in our study, could be used as a way to efficiently prioritise assessment groups for higher-tier MRA. Since the combined exposure to the four metals exceeded the tolerable intake, we recommend a refined MRA based on a common, specific nephrotoxic effect and relative potency factors (RPFs) based on a similar effect size.

Prenatal dietary exposure to chemicals and allergy or respiratory diseases in children in the EDEN mother-child cohort.

INTRODUCTION: Maternal exposure to food chemicals may increase the risk of allergy and respiratory disorders in offspring. We aimed to assess the association of prenatal dietary exposure to single chemicals and chemical mixtures with allergy or respiratory events reported before age 8 y in children. METHODS: We included 1428 mother-child pairs enrolled in the EDEN mother-child cohort. Maternal dietary exposure to 209 chemicals and eight associated mixtures was investigated. Allergic and respiratory diseases (wheezing, asthma, allergic rhinitis, eczema and food allergy) were reported by parents between birth and age 8 y. Associations with the studied outcomes were evaluated with three approaches based on adjusted logistic regression, estimating odds ratios (ORs) and 95 % confidence intervals (CIs). First, food chemicals were considered individually, with correction for multiple testing. Second, chemicals selected by elastic net regression were considered simultaneously in a multiple exposure model. Third, predefined mixtures were introduced in the same adjusted logistic regression. Results are expressed as odds ratio (OR[95 % CI]). RESULTS: Prenatal single exposure to 74 food chemicals was associated with higher risk of allergic rhinitis. Prenatal single exposure to 11 chemicals was associated with higher risk of wheezing. In the multi-exposure approach, risk of wheezing was associated with the pesticides diazinon and triadimenol, and polycyclic aromatic hydrocarbon 5-methylchrysene. Phytoestrogen resveratrol was negatively associated with lower risk of both wheezing and allergic rhinitis, and mycotoxin monoacetoxyscirpenol was negatively associated with risk of eczema. Finally, a chemical mixture composed mainly of trace elements, furans and polycyclic aromatic hydrocarbons, was associated with higher risk of allergic rhinitis (1.33 [1.02;1.73]). CONCLUSION: Prenatal dietary exposure to chemicals was associated with risk of allergic rhinitis or wheezing up to age 8 y. A few chemicals were associated with other allergic and respiratory diseases. Larger prospective studies are needed to confirm these findings.

A case study of neurodevelopmental risks from combined exposures to lead, methyl-mercury, inorganic arsenic, polychlorinated biphenyls, polybrominated diphenyl ethers and fluoride.

We performed a mixture risk assessment (MRA) case study of dietary exposure to the food contaminants lead, methylmercury, inorganic arsenic (iAs), fluoride, non-dioxin-like polychlorinated biphenyls (NDL-PCBs) and polybrominated diphenyl ethers (PBDEs), all substances associated with declines in cognitive abilities measured as IQ loss. Most of these chemicals are frequently measured in human biomonitoring studies. A component-based, personalised modified reference point index (mRPI) approach, in which we expressed the exposures and potencies of our chosen substances as lead equivalent values, was applied to perform a MRA for dietary exposures. We conducted the assessment for four different age groups (toddlers, children, adolescents, and women aged 18-45 years) in nine European countries. Populations in all countries considered exceeded combined tolerable levels at median exposure levels. NDL-PCBs in fish, other seafood and dairy, lead in grains and fruits, methylmercury in fish and other seafoods, and fluoride in water contributed most to the combined exposure. We identified uncertainties for the likelihood of co-exposure, assessment group membership, endpoint-specific reference values (ESRVs) based on epidemiological (lead, methylmercury, iAs, fluoride and NDL-PCBs) and animal data (PBDE), and exposure data. Those uncertainties lead to a complex pattern of under- and overestimations, which would require probabilistic modelling based on expert knowledge elicitation for integration of the identified uncertainties into an overall uncertainty estimate. In addition, the identified uncertainties could be used to refine future MRA for cognitive decline.

Challenges of studying the dietary exposure to chemical mixtures: Example of the association with mortality risk in the E3N French prospective cohort.

Food is contaminated by many chemicals which interact with each other, resulting in additive, synergistic or antagonistic effects. It is thus necessary to study the health effects of dietary exposure to chemical mixtures rather than single contaminants. We aimed to investigate the association between dietary exposure to chemical mixtures and mortality risk in the E3N French prospective cohort. We included 72,585 women from the E3N cohort who completed a food frequency questionnaire in 1993. From 197 chemicals, and using sparse non-negative matrix under-approximation (SNMU), we identified six main chemical mixtures to which these women were chronically exposed through the diet. We estimated the associations between dietary exposure to these mixtures and all-cause or cause-specific mortality using Cox proportional hazard models. During the follow-up (1993-2014), 6441 deaths occurred. We observed no association between dietary exposure to three mixtures and all-cause mortality, and a non-monotonic inverse association for the three other mixtures. These results could be explained by the fact that, despite the different dietary adjustment strategies tested, we did not fully succeed in excluding the residual confounding from the overall effect of the diet. We also questioned the number of chemicals to include in mixtures' studies, as a balance needs to be reached between including a large number of chemicals and the interpretability of the results. Integrating a priori knowledge, such as toxicological data, could lead to the identification of more parsimonious mixtures, thus to more interpretable results. Moreover, as the SNMU is a non-supervised method, which identifies the mixtures only on the basis of the correlations between the exposure variables, and not in relation to the outcome, it would be interesting to test supervised methods. Finally, further studies are needed to identify the most adequate approach to investigate the health effects of dietary exposure to chemical mixtures in observational studies.

Integrating Selection and Risk Assessment of Chemical Mixtures: A Novel Approach Applied to a Breast Milk Survey.

BACKGROUND: One of the main challenges of modern risk assessment is to account for combined exposure to the multitude of various substances present in food and the environment. OBJECTIVE: The present work proposes a methodological approach to perform chemical risk assessment of contaminant mixtures across regulatory silos regarding an extensive range of substances and to do so when comprehensive relevant data concerning the specific effects and modes of action of the mixture components are not available. METHODS: We developed a complete step-by-step approach using statistical methods to prioritize substances involved in combined exposure, and we used a component-based approach to cumulate the risk using dose additivity. The most relevant toxicological end point and the associated reference point were selected from the literature to construct a toxicological threshold for each substance. DISCUSSION: By applying the proposed method to contaminants in breast milk, we observed that among the 19 substances comprising the selected mixture, ∑DDT, ∑PCBi, and arsenic were main joint contributors to the risk of neurodevelopmental and thyroid effects for infants. In addition, ∑PCCD/F contributed to the thyroid effect and ∑aldrin-dieldrin to the neurodevelopmental effect. Our case study on contaminants in breast milk demonstrated the importance of crossing regulatory silos when studying mixtures and the importance of identifying risk drivers to regulate the risk related to environmental contamination. Applying this method to another set of data, such as human biomonitoring or in ecotoxicology, will reinforce its relevance for risk assessment. https://doi.org/10.1289/EHP8262.

Advancing tools for human early lifecourse exposome research and translation (ATHLETE): Project overview.

Early life stages are vulnerable to environmental hazards and present important windows of opportunity for lifelong disease prevention. This makes early life a relevant starting point for exposome studies. The Advancing Tools for Human Early Lifecourse Exposome Research and Translation (ATHLETE) project aims to develop a toolbox of exposome tools and a Europe-wide exposome cohort that will be used to systematically quantify the effects of a wide range of community- and individual-level environmental risk factors on mental, cardiometabolic, and respiratory health outcomes and associated biological pathways, longitudinally from early pregnancy through to adolescence. Exposome tool and data development include as follows: (1) a findable, accessible, interoperable, reusable (FAIR) data infrastructure for early life exposome cohort data, including 16 prospective birth cohorts in 11 European countries; (2) targeted and nontargeted approaches to measure a wide range of environmental exposures (urban, chemical, physical, behavioral, social); (3) advanced statistical and toxicological strategies to analyze complex multidimensional exposome data; (4) estimation of associations between the exposome and early organ development, health trajectories, and biological (metagenomic, metabolomic, epigenetic, aging, and stress) pathways; (5) intervention strategies to improve early life urban and chemical exposomes, co-produced with local communities; and (6) child health impacts and associated costs related to the exposome. Data, tools, and results will be assembled in an openly accessible toolbox, which will provide great opportunities for researchers, policymakers, and other stakeholders, beyond the duration of the project. ATHLETE's results will help to better understand and prevent health damage from environmental exposures and their mixtures from the earliest parts of the life course onward.

Identification of chemical mixtures to which women are exposed through the diet: Results from the French E3N cohort.

Due to the large number of chemical food contaminants, consumers are exposed simultaneously to a wide range of chemicals which can interact and have a negative impact on health. Nevertheless, due to the multitude of possible chemical combinations it is unrealistic to test all combined toxicological effects. It is therefore essential to identify the most relevant mixtures to which the population is exposed through the diet and investigate their impact on heath. The present study aims to identify and describe the main chemical mixtures to which women enrolled in the E3N study, a large French prospective cohort, are chronically exposed through the diet. 74522 women who had answered a validated semi-quantitative food frequency questionnaire in 1993, were included in the present study. Dietary exposure to chemical contaminates was estimated based on the food contamination measured in 186 core food in France collected between 2007 and 2009 by the French agency for food, environment and occupational health, and safety (ANSES) in the framework of the second French total diet study (2TDS). The sparse non-negative matrix under-approximation (SNMU) was used to identify mixtures of chemical substances. A k-means clustering classification of the whole study population was then performed to define clusters with similar co-exposure profiles. Overall, 8 mixtures which explained 83% of the total variance, were retained. The first mixture, entitled "Minerals, inorganic contaminants, and furans", explained the highest proportion of the total variance (38%), and was correlated in particular with the consumption of "Offal" (rho = 0.22), "Vegetables except roots" (rho = 0.20), and "Eggs" (rho = 0.19). The other seven mixtures explained between 17% and 1% of the variance. Finally, 5 clusters were identified based on the adherence to the 8 mixtures. This study, being the largest ever conducted to identify dietary exposure to chemical mixtures, represents a concrete attempt to prioritize mixtures for which it is essential to investigate combined health effects based on exposure.

Guidance Document on Scientific criteria for grouping chemicals into assessment groups for human risk assessment of combined exposure to multiple chemicals.

This guidance document provides harmonised and flexible methodologies to apply scientific criteria and prioritisation methods for grouping chemicals into assessment groups for human risk assessment of combined exposure to multiple chemicals. In the context of EFSA's risk assessments, the problem formulation step defines the chemicals to be assessed in the terms of reference usually through regulatory criteria often set by risk managers based on legislative requirements. Scientific criteria such as hazard-driven criteria can be used to group these chemicals into assessment groups. In this guidance document, a framework is proposed to apply hazard-driven criteria for grouping of chemicals into assessment groups using mechanistic information on toxicity as the gold standard where available (i.e. common mode of action or adverse outcome pathway) through a structured weight of evidence approach. However, when such mechanistic data are not available, grouping may be performed using a common adverse outcome. Toxicokinetic data can also be useful for grouping, particularly when metabolism information is available for a class of compounds and common toxicologically relevant metabolites are shared. In addition, prioritisation methods provide means to identify low-priority chemicals and reduce the number of chemicals in an assessment group. Prioritisation methods include combined risk-based approaches, risk-based approaches for single chemicals and exposure-driven approaches. Case studies have been provided to illustrate the practical application of hazard-driven criteria and the use of prioritisation methods for grouping of chemicals in assessment groups. Recommendations for future work are discussed.

Estimating human exposure to pyrethroids' mixtures from biomonitoring data using physiologically based pharmacokinetic modeling.

Human biomonitoring data provide evidence to exposure of environmental chemicals. Physiologically based pharmacokinetic (PBPK) modelling together with an adequate exposure scenario allows to transpose measured concentrations of chemicals or their metabolites into exposure levels, as daily intakes. In France, high levels of urinary pyrethroids metabolites have been measured in populations. Our work aims at estimating the exposure of the French ENNS cohort to mixtures of four pyrethroids (deltamethrin, permethrin, cypermethrin, and cyfluthrin) from the urinary concentrations of five pyrethroids' metabolites commonly measured in biomonitoring studies. We developed a modelling approach based on a global toxicokinetic model that accounts for the cumulative exposure to pyrethroids as some of the metabolites can be shared by several parent compounds and for human inter-individual variability in metabolism. The median of the individual daily intakes was estimated to 8.1 ng/kg bw/day for permethrin, 17.7 ng/kg bw/day for cypermethrin, 20.4 ng/kg bw/day for cyfluthrin and 34.3 ng/kg bw/day for deltamethrin leading to similar weights for the pair permethrin and cypermethrin (36%), cyfluthrin (31%) and deltamethrin (33%) to the cumulative exposure. Accounting for human variability enabled to explain some of the variations in the metabolites' levels within the cohort. The cumulative exposure was then weighted by their toxicities towards three neurotoxic effects to calculate margins of exposure (MOE). Low MOE values were always associated with high measured concentrations of metabolites in urine and the lowest MOEs were observed for the autonomic division. No risks associated with reconstructed mixtures of pyrethroids were expected for the ENNS cohort. Our approach is an asset to analyse the biomarkers of exposure to pyrethroids simultaneously and could be easily adapted to any local or national specificities in pyrethroids' exposure or populations.

Aggregate and cumulative chronic risk assessment for pyrethroids in the French adult population.

Pyrethroids are commonly used as insecticides in households, in agriculture or in veterinary and medicinal products. This study aimed to assess cumulative aggregate exposure to cyfluthrin, cypermethrin, deltamethrin and permethrin in adults in France and the associated health risk, and to identify major contributions of exposure sources and routes. External chronic exposures were estimated from dietary and several environmental sources for the oral, inhalation and dermal routes. Internal concentrations of five associated metabolites were simulated with a physiologically-based pharmacokinetic model. The predicted urinary concentrations were in same order of magnitude as those of the French ENNS biomonitoring survey. Dietary exposure, especially from cereals and animal products, was the major source of exposure. For the 1% of adults most highly exposed, dermal exposure to permethrin through medicinal and veterinary products was an important source of exposure. Considering alterations of motor, sensory and autonomic division, all individual margins of exposure were higher than 100, suggesting that no neurotoxic risk associated with the cumulative aggregate exposure to these four pyrethroids is expected for the French adult population.

Cumulative dietary risk assessment overarching different regulatory silos using a margin of exposure approach: A case study with three chemical silos.

Risk assessment of chemicals occurring in our diet is commonly performed for single chemicals without considering exposure to other chemicals. We performed a case study on risk assessment of combined dietary exposure to chemicals from different regulatory silos, i.e. pesticides (PPRs), persistent organic pollutants (POPs) and food additives (FAs). Chemicals were grouped into the cumulative assessment group (CAG) liver steatosis using a component-based approach. Based on literature, the CAG included 144 PPRs, 49 POPS and 7 FAs for which concentration data were available. For each silo, chronic combined dietary exposure was assessed for adults and children of nine European countries following the most commonly used exposure methodologies in Europe and by using a relative potency factor approach. For risk characterization, a Margin of Exposure (MOE) was calculated. To overarch the risk across silos, a normalised combined margin of exposure (nMOET) approach was proposed. This case study demonstrated that risk assessment of combined exposure to chemicals can be performed within regulatory silos. It also highlighted important differences in the conservatism of exposure scenarios, the derivation of point of departures and the subsequent acceptable MOEs between the silos. To overarch the risk despite these differences, a nMOET approach can be used.

The MCRA toolbox of models and data to support chemical mixture risk assessment.

A model and data toolbox is presented to assess risks from combined exposure to multiple chemicals using probabilistic methods. The Monte Carlo Risk Assessment (MCRA) toolbox, also known as the EuroMix toolbox, has more than 40 modules addressing all areas of risk assessment, and includes a data repository with data collected in the EuroMix project. This paper gives an introduction to the toolbox and illustrates its use with examples from the EuroMix project. The toolbox can be used for hazard identification, hazard characterisation, exposure assessment and risk characterisation. Examples for hazard identification are selection of substances relevant for a specific adverse outcome based on adverse outcome pathways and QSAR models. Examples for hazard characterisation are calculation of benchmark doses and relative potency factors with uncertainty from dose response data, and use of kinetic models to perform in vitro to in vivo extrapolation. Examples for exposure assessment are assessing cumulative exposure at external or internal level, where the latter option is needed when dietary and non-dietary routes have to be aggregated. Finally, risk characterisation is illustrated by calculation and display of the margin of exposure for single substances and for the cumulation, including uncertainties derived from exposure and hazard characterisation estimates.

Combining data from heterogeneous surveys for aggregate exposure: Application to children exposure to lead in France.

To assess human health risks related to the environment, it is necessary to aggregate exposure from multiple sources. The objective of this paper was to propose a relevant approach to combine data from heterogeneous populations and methodologies. Five different methods based on Monte-Carlo simulations were tested and compared. Differences were: taking into account or not stratification variable, timeline to assign exposure factors and concentration and way to account for concentration correlations. The methods were applied to estimate lead exposure from food, dust, soil, air, and tap water or French children aged between six months and three years old. Comparing results' uncertainty, it is recommended to 1) select a reference population representative of the target population, 2) select stratification variables to combine surveys, and 3) simulate a new population by randomly sampling individuals in the reference population and simultaneously assigning human exposure factors and environmental concentrations from other surveys in integrating correlations (MC1S). No difference was observed when taking into account correlations using vectors of determinist data from one survey or rank of correlations with the Iman-Conover method. Regardless the methods used to combine data, dust was the main exposure source, followed by soil and in a less extent by food. Exposures from air and tap water were found to be insignificant for most children.

Frequentist and Bayesian approaches for food allergen risk assessment: risk outcome and uncertainty comparisons.

Peer-reviewed probabilistic methods already predict the probability of an allergic reaction resulting from an accidental exposure to food allergens, however, the methods calculate it in different ways. The available methods utilize the same three major input parameters in the risk model: the risk is estimated from the amount of food consumed, the concentration of allergen in the contaminated product and the distribution of thresholds among allergic persons. However, consensus is lacking about the optimal method to estimate the risk of allergic reaction and the associated uncertainty. This study aims to compare estimation of the risk of allergic reaction and associated uncertainty using different methods and suggest improvements. Four cases were developed based on the previous publications and the risk estimations were compared. The risk estimation was found to agree within 0.5% with the different simulation cases. Finally, an uncertainty analysis method is also presented in order to evaluate the uncertainty propagation from the input parameters to the risk.

Linking Probabilistic Exposure and Pharmacokinetic Modeling To Assess the Cumulative Risk from the Bisphenols BPA, BPS, BPF, and BPAF for Europeans.

The bisphenols S, F, and AF (BPS, BPF, and BPAF) are used to replace the endocrine disrupting chemical bisphenol A (BPA) while exerting estrogenic effects of comparable potency. We assessed the cumulative risk for the aforementioned BPs in Europe and compared the risk before and after the year 2011, which was when the first BPA restrictions became effective. For this, we probabilistically modeled external exposures from food, personal care products (PCPs), thermal paper, and dust (using the tools MCRA and PACEM for exposures from food and PCPs, respectively). We calculated internal concentrations of unconjugated BPs with substance-specific PBPK models and cumulated these concentrations normalized by estrogenic potency. The resulting mean internal cumulative exposures to unconjugated BPs were 3.8 and 2.1 ng/kg bw/day before and after restrictions, respectively. This decline was mainly caused by the replacement of BPA by BPS in thermal paper and the lower dermal uptake of BPS compared to BPA. However, the decline was not significant: the selected uncertainty intervals overlapped (P2.5-P97.5 uncertainty intervals of 2.7-4.9 and 1.3-6.3 ng/kg bw/day before and after restrictions, respectively). The upper uncertainty bounds for cumulative exposure were higher after restrictions, which reflects the larger uncertainty around exposures to substitutes compared to BPA.

Gender, prick test size and rAra h 2 sIgE level may predict the eliciting dose in patients with peanut allergy: Evidence from the Mirabel survey.

BACKGROUND: Peanut allergy management is based on active avoidance and access to emergency treatment including self-injectable adrenaline. Knowing the dose at which a patient is likely to react is crucial for risk assessment and could significantly improve management by integrating a personalized approach. OBJECTIVE: To develop a threshold dose distribution curve model from routinely collected data. METHODS: The MIRABEL survey is an observational study of 785 patients with peanut allergy/sensitization conducted in France, Belgium and Luxemburg. The current analysis included the 238 participants for whom medical and oral food challenge data were available. Several statistical models (Kaplan-Meier, Cox model, Weibull and Lognormal with predictive factors, basic Weibull and Lognormal) were compared to select the best model and predictive factor combination associated with the threshold doses. Inferences were made with a Bayesian approach. RESULTS: Patients were mainly children (mean age: 9 years [IQR: 6-11]; 87% < 16 years) and males (62%). Median Ara h2 s IgE was of 8kUA/L [IQR: 1-55] and median skin prick test size of 10 mm [IQR: 7-13]. OFC was positive in 204 patients (86%). The median threshold dose was of 67 mg of peanut protein [IQR: 16-244]. The dose at which 1% of the patients are likely to react with objective symptoms was 0.26 [0.03; 2.24] mg of peanut protein. Gender, size of the skin prick test (SPT) and Ara h 2 specific IgE level had a significant impact on the threshold dose distribution curve. The Cox model was the most effective to predict threshold doses with this combination of factors. Girls react to lower doses than boys with a beta coefficient associated to the risk and a 95% credible interval of 0.44 [0.04; 0.77]. The higher the size of the SPT and the Ara h 2 specific IgE level are, the higher the risk of reacting to a small amount of peanut, with beta coefficients associated to the risk and 95% credible intervals of 0.05 [0.02; 0.08] and 0.01 [0.01; 0.02], respectively. CONCLUSION AND CLINICAL RELEVANCE: According to the model, routinely collected data could be used to estimate the threshold dose. The consequences could be the identification of high-risk patients who are susceptible to react to small amounts of peanut and a personalized management of peanut allergy integrating the risk of allergic reaction. Limitations of this study are that assessors of OFC outcome were aware of SPT and Arah2 results, and a further validation study is required to confirm the predictive value of these parameters.

Sensitivity analysis to derive a food consumption point estimate for deterministic food allergy risk assessment.

One of the input parameters in food allergy risk assessment is the amount of a given food consumed at an eating occasion. There is no consensus on how to use food consumption data when assessing the risk from unintended allergen presence in food products. A sensitivity analysis was performed to establish the optimal food consumption estimate for a deterministic food allergy risk assessment. Exposure was calculated for consumption percentiles (50th percentile, P50 to maximum) using the iFAAM consumption database in conjunction with an allergen concentration range from 1 to 1000 ppm. The resulting allergen intakes were compared to the allergic population reference doses proposed by Taylor et al. (2014) for 10 major allergenic foods. Optimal consumption percentiles were defined as those which predicted an intake below the relevant reference dose and met the defined acceptable risk level confirmed by probabilistic risk assessments. Analysis showed that, for 99% of the food groups, the P50 consumption met our criteria, while the P75 did so for 100% of the food groups. We suggest that the P75 is the optimal point estimate for use in deterministic food allergy risk assessment. It meets the safety objective and is adequately conservative for a public health context.

Selecting mixtures on the basis of dietary exposure and hazard data: application to pesticide exposure in the European population in relation to steatosis.

Populations are exposed to mixtures of pesticides through their diet on a daily basis. The question of which substances should be assessed together remains a major challenge due to the complexity of the mixtures. In addition, the associated risk is difficult to characterise. The EuroMix project (European Test and Risk Assessment Strategies for Mixtures) has developed a strategy for mixture risk assessment. In particular, it has proposed a methodology that combines exposures and hazard information to identify relevant mixtures of chemicals belonging to any cumulative assessment group (CAG) to which the European population is exposed via food. For the purposes of this study, food consumption and pesticide residue data in food and drinking water were obtained from national surveys in nine European countries. Mixtures of pesticides were identified by a sparse non-negative matrix underestimation (SNMU) applied to the specific liver steatosis effect in children from 11 to 15 years of age, and in adults from 18 to 64 years of age in nine European countries. Exposures and mixtures of 144 pesticides were evaluated through four different scenarios: (1) chronic exposure with a merged concentration dataset in the adult population, (2) chronic exposure with country-specific concentration datasets in the adult population, (3) acute exposure with a merged concentration dataset in the adult population, and (4) chronic exposure with a merged concentration dataset in the paediatric population. The relative potency factors of each substance were calculated to express their potency relative to flusilazole, which was chosen as the reference compound. The selection of mixtures and the evaluation of exposures for each country were carried out using the Monte Carlo Risk Assessment (MCRA) software. Concerning chronic exposure, one mixture explained the largest proportion of the total variance for each country, while in acute exposure, several mixtures were often involved. The results showed that there were 15 main pesticides in the mixtures, with a high contribution of imazalil and dithiocarbamate. Since the concentrations provided by the different countries were merged in the scenario using merged concentration data, differences between countries result from differences in food consumption behaviours. These results support the approach that using merged concentration data to estimate exposures in Europe seems to be realistic, as foods are traded across European borders. The originality of the proposed approach was to start from a CAG and to integrate information from combined exposures to identify a refined list of mixtures with fewer components. As this approach was sensitive to the input data and required significant resources, efforts should continue regarding data collection and harmonisation among the different aspects within the pesticides regulatory framework, and to develop methods to group substances and mixtures to characterise the risk.