Chemical exposome and children health: Identification of dose-response relationships from meta-analyses and epidemiological studies.

BACKGROUND: Health impact assessment studies quantifying the impact of the chemical exposome on children's health generally consider a small fraction of the exposome. Synthetizing available dose-response relationships is an essential step to fill this gap. We reviewed the literature for dose-response relationships relating the chemical exposome with children health. METHOD: We focused on 78 substance-outcome pairs for which the level of evidence had previously been classified as 'likely' or 'very likely'. We searched for dose-response relationships for these pairs from meta-analyses and, if none was available, from single epidemiological studies, from which we conducted meta-analyses whenever possible. RESULTS: We identified dose-response relationships for 50 of the 78 prioritized substance-outcome pairs (64%). Dose-response relationships stemmed from meta-analyses for 21 pairs, from de novo meta-analyses for 1 pair and single studies for 28 pairs. Dose-response relationships were available for tobacco (fetal and infant death, congenital heart defects, birth outcomes, orofacial clefts, respiratory health), lead (asthma, cognition, delayed puberty onset and iron deficiency anaemia), polychlorobiphenyls (PCBs) (cognition, respiratory infections and birth outcomes), bisphenol A (cognition), hexachlorobenzene (HCB) (respiratory health), Polybrominated diphenyl ethers (neurodevelopment), DDT (hypospadias, cryptorchidism, miscarriage), pesticides (neurodevelopment), methylmercury (cognition), PFAS (immune system, birth weight, behavior, miscarriage), arsenic (cognition, birth weight, death, respiratory health), cadmium (cognition, birth weight), manganese (behavior), sodium (blood pressure) and thallium (birth weight). For 28 of the 78 substance-outcome pairs (36%), no dose-response relationship was available from epidemiological studies in children. CONCLUSIONS: We identified dose-response relationships for 50 substance-outcome pairs, corresponding to 20 chemicals and 17 health outcomes. These can be used to perform more comprehensive quantitative health impact assessment of the exposome on child health. We also identified 28 substance-outcome pairs corresponding to 'likely' or 'very likely' effects for which research generating dose-response functions in children would be relevant.

A preliminary estimate of the environmental burden of disease associated with exposure to pyrethroid insecticides and ADHD in Europe based on human biomonitoring.

Human biomonitoring (HBM) data indicate that exposure to pyrethroids is widespread in Europe, with significantly higher exposure observed in children compared to adults. Epidemiological, toxicological, and mechanistic studies raise concerns for potential human health effects, particularly, behavioral effects such as attention deficit hyperactivity disorder (ADHD) in children at low levels of exposure. Based on an exposure-response function from a single European study and on available quality-assured and harmonized HBM data collected in France, Germany, Iceland, Switzerland, and Israel, a preliminary estimate of the environmental burden of disease for ADHD associated with pyrethroid exposure was made for individuals aged 0-19 years. The estimated annual number of prevalence-based disability-adjusted life years (DALYs) per million inhabitants were 27 DALYs for Israel, 21 DALYs for France, 12 DALYs for both Switzerland and Iceland, and 3 DALYs for Germany; while the annual ADHD cases per million inhabitants attributable to pyrethroids were 2189 for Israel, 1710 for France, 969 for Iceland, 944 for Switzerland, and 209 for Germany. Direct health costs related to ADHD ranged between 0.3 and 2.5 million EUR yearly per million inhabitants for the five countries. Additionally, a substantial number of ADHD cases, on average 18%, were associated with pyrethroid exposure. Yet, these figures should be interpreted with caution given the uncertainty of the estimation. A sensitivity analysis showed that by applying a different exposure-response function from outside the EU, the population attributable fraction decreased from an average of 18 to 7%. To ensure more robust disease burden estimates and adequate follow-up of policy measures, more HBM studies are needed, along with increased efforts to harmonize the design of epidemiological studies upfront to guarantee meta-analysis of exposure-response functions. This is particularly important for pyrethroids as evidence of potential adverse health effects is continuously emerging.

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.

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.

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.

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.

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.

Tree nut allergy and anxiety related factors modulate food consumption behaviour in peanut-allergic patients: Results of the MIRABEL survey.

BACKGROUND: In the absence of specific data on food consumption of allergic consumers, general population surveys are used for risk assessment. Most of allergy risk assessment's experts advise that an understanding of the food consumption habits of people with food allergies is crucial for correctly estimate the risk. OBJECTIVE: This study aims to detail the food consumption of patients with peanut allergy including products with precautionary allergen labelling (PAL) and to identify the factors influencing their consumption behaviour. METHODS: The MIRABEL study is a multi-center survey of peanut-allergic patients from France, Belgium and Luxemburg. It includes data on medical, socio-demographic, and consumption of different food categories, including products with PAL. Anxiety score and allergy severity level variables were constructed and studied as potential consumption determinants. To study the association of modulator variables with food consumption, a logistic regression model was built to test the association with food category and ingredient choice. RESULTS: 443 of the 785 patients from MIRABEL survey were included in the consumption study. Tree nut allergy, knowledge of threshold dose, label reading and anxiety score significantly influenced the consumption of products which may contain unintended traces of peanut. The direction of influence depended on food categories and ingredient choices. Diet advice by allergists, severity of the allergy and threshold dose determined by oral food challenge did not significantly impact consumption. CONCLUSIONS: and clinical relevance: It showed, for the first time, that consumption of food products by peanut-allergic patients, including those with PAL, is modulated by factors related to anxiety such as label reading and knowledge of threshold and concomitant tree nut allergy. Knowledge of peanut-allergic food behaviours will make it possible to improve risk assessment and help allergists and risk managers to make diet advices.

PBPK and population modelling to interpret urine cadmium concentrations of the French population.

As cadmium accumulates mainly in kidney, urinary concentrations are considered as relevant data to assess the risk related to cadmium. The French Nutrition and Health Survey (ENNS) recorded the concentration of cadmium in the urine of the French population. However, as with all biomonitoring data, it needs to be linked to external exposure for it to be interpreted in term of sources of exposure and for risk management purposes. The objective of this work is thus to interpret the cadmium biomonitoring data of the French population in terms of dietary and cigarette smoke exposures. Dietary and smoking habits recorded in the ENNS study were combined with contamination levels in food and cigarettes to assess individual exposures. A PBPK model was used in a Bayesian population model to link this external exposure with the measured urinary concentrations. In this model, the level of the past exposure was corrected thanks to a scaling function which account for a trend in the French dietary exposure. It resulted in a modelling which was able to explain the current urinary concentrations measured in the French population through current and past exposure levels. Risk related to cadmium exposure in the general French population was then assessed from external and internal critical values corresponding to kidney effects. The model was also applied to predict the possible urinary concentrations of the French population in 2030 assuming there will be no more changes in the exposures levels. This scenario leads to significantly lower concentrations and consequently lower related risk.

An integrative risk assessment approach for persistent chemicals: a case study on dioxins, furans and dioxin-like PCBs in France.

For persistent chemicals slowly eliminated from the body, the accumulated concentration (body burden), rather than the daily exposure, is considered the proper starting point for the risk assessment. This work introduces an integrative approach for persistent chemical risk assessment by means of a dynamic body burden approach. To reach this goal a Kinetic Dietary Exposure Model (KDEM) was extended with the long term time trend in the exposure (historic exposure) and the comparison of bioaccumulation with body burden references for toxicity. The usefulness of the model was illustrated on the dietary exposure to PolyChlorinatedDibenzo-p-Dioxins (PCDDs), PolyChlorinatedDibenzoFurans (PCDFs) and PolyChlorinated Biphenyls (PCBs) in France. Firstly the dietary exposure to these compounds was determined in 2009 and combined with its long term time trend. In order to take differences between the kinetics of PCDD/F and dl-PCBs into account, three groups of congeners were considered i.e. PCDD/Fs, PCB 126 and remaining dl-PCBs. The body burden was compared with reference body burdens corresponding to reproductive, hepatic and thyroid toxicity. In the case of thyroid toxicity this comparison indicated that in 2009 the probability of the body burden to exceed its reference ranged from 2.8% (95% CI: 1.5-4.9%) up to 3.9% (95% CI: 2.7-7.1%) (18-29 vs. 60-79year olds). Notwithstanding the decreasing long-term time trend of the dietary dioxin exposure in France, this probability still is expected to be 1.5% (95% CI: 0.3-2.5%) in 2030 in 60-79 olds. In the case of reproductive toxicity the probability of the 2009 body burden to exceed its reference ranged from 3.1% (95% CI: 1.4-5.0%) (18-29year olds) to 3.5% (95% CI: 2.2-5.2%) (30-44year olds). In 2030 this probability is negligible in 18-29year olds, however small though significant in 30-44year olds (0.7%, 95% CI: 0-1.6%). In the case of hepatic toxicity the probability in 2009 even in 60-79year olds already was negligible. In conclusion this approach indicates that in France dioxin levels in food form a declining, though still present, future health risk with respect to thyroid and reproductive toxicity.

Identification of pesticide mixtures to which French agricultural workers and farm-owners are exposed: Results from the Agriculture and Cancer (AGRICAN) cohort study.

Farmers, particularly in Europe, are exposed to multiple pesticides during their working life. Such exposures can cause adverse health outcomes. We aimed to identify the main pesticide mixtures to which French agricultural workers are exposed and to classify farmers into clusters based on their mixture exposure profile. The AGRICAN cohort includes farm-owners and farm workers enrolled from 2005 to 2007, with information on exact years of beginning and end of pesticide use on 11 crops and five livestock. We estimated duration of exposure to 390 pesticides identified with the PESTIMAT crop-exposure matrix for 16,905 male pesticide users from 1950 to 2009. We used a Sparse Non-negative Matrix Under-approximation to identify the main pesticide mixtures based on exposure duration, and then applied hierarchical agglomerative clustering to classify farmers sharing similar profiles of co-exposure to the mixtures. SNMU suggested 6 optimal numbers of mixtures (4, 7, 11, 15, 27, 38) explaining from 29 to 91 % of total variance. We selected 27 mixtures. Mixtures contained between four to 22 pesticides and mostly concerned the use of pesticides on wheat/barley, vineyards, corn, fruit and vegetables or on multiple crops together. We selected 11 clusters composed of 395 to 4521 farmers. Some had a higher proportion of individuals working on specific crops (as vineyard or corn), while others were characterized by the diversity of crops (cluster 8:"Permanent crops, potatoes and tobacco"). This is the first study to identify pesticide mixtures in farmers and to classify them into clusters based on their mixture exposure profiles. The next step will be to study the associations between pesticide mixtures and health outcomes such as prostate cancer in AGRICAN.

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.

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.

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.

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.

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.

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.

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.