Risk Assessment Of Combined Exposure Research Articles

An adverse outcome pathway-based approach to assess the neurotoxicity by combined exposure to current-use pesticides

Exposure to multiple pesticides in daily life has become an important public health concern. However, the combined effects of pesticide mixtures have not been fully elucidated by the conventional toxicological testing used for individual chemicals. Grouping of chemicals by mode of action using common key events (KEs) in the adverse outcome pathway (AOP) as endpoints could be applied for efficient risk assessment of combined exposure to multiple chemicals. The purpose of this study was to investigate whether exposure to multiple pesticides has synergistic neurotoxic effects on mammalian nervous systems. According to the AOP-based approach, we evaluated the effects of 10 current-use pesticides (4 neonicotinoids, 4 pyrethroids and 2 phenylpyrazoles) on the common KEs in AOPs for neurotoxicity, such as KEs involving mitochondrial and proteolytic functions, in a mammalian neuronal cell model. Our data showed that several pyrethroids and phenylpyrazoles partly shared the effects on several common KEs, including decreases in mitochondrial membrane potential and proteasome activity and increases in autophagy activity. Furthermore, we also found that combined exposure to a type-I pyrethroid permethrin or a type-II pyrethroid deltamethrin and the phenylpyrazole fipronil decreased the cell viability and the benchmark doses much more than either single exposure, indicating that the pair exhibited synergistic effects, since the combination indexes were less than 1. These findings revealed that novel pairs of different classes of pesticides with similar effects on common KEs exhibited synergistic neurotoxicity and provide new insights into the risk assessment of combined exposure to multiple chemicals.

P24-36: Risk assessment of combined exposure to mixed plant protection products on the persons involved in their application in the conditions of modern agricultural production

P24-36: Risk assessment of combined exposure to mixed plant protection products on the persons involved in their application in the conditions of modern agricultural production

Risk assessment of combined exposure to lead, cadmium, and total mercury among the elderly in Shanghai, China

Lead (Pb), cadmium (Cd) and total mercury (THg) are toxic heavy metals (THMs) that are widely present in the environment and can cause substantial health problems. However, previous risk assessment studies have rarely focused on the elderly population and have usually targeted a single heavy metal, which might underestimate the long-term accumulative and synergistic effects of THMs in humans. Based on the food frequency questionnaire and inductively coupled plasma mass spectrometry, this study assessed external and internal exposures to Pb, Cd and THg in 1747 elderly people in Shanghai. Probabilistic risk assessment with the relative potential factor (RPF) model was used to assess the neurotoxicity and nephrotoxicity risks of combined THMs exposures. The mean external exposures of Pb, Cd and THg in Shanghai elderly were 46.8, 27.2 and 4.9 μg/day, respectively. Plant-based foods are the main source of Pb and THg exposure, while Cd is mainly from animal-based foods. The mean concentrations of Pb, Cd and THg were 23.3, 1.1 and 2.3 μg/L in the whole blood, and 6.2, 1.0 and 2.0 μg/L in the morning urine, respectively. Combined exposure to THMs leading to 10.0 % and 7.1 % of Shanghai elderly at risk of neurotoxicity and nephrotoxicity. The results of this study have important implications for understanding the profiles of Pb, Cd and THg exposure in the elderly living in Shanghai and provide data support for risk assessment and control of nephrotoxicity and neurotoxicity from combined THMs exposure in the elderly.

Risk Assessment of Combined Exposure to Multiple Chemicals at the European Food Safety Authority: Principles, Guidance Documents, Applications and Future Challenges.

Human health and animal health risk assessment of combined exposure to multiple chemicals use the same steps as single-substance risk assessment, namely problem formulation, exposure assessment, hazard assessment and risk characterisation. The main unique feature of combined RA is the assessment of combined exposure, toxicity and risk. Recently, the Scientific Committee of the European Food Safety Authority (EFSA) published two relevant guidance documents. The first one "Harmonised methodologies for the human health, animal health and ecological risk assessment of combined exposure to multiple chemicals" provides principles and explores methodologies for all steps of risk assessment together with a reporting table. This guidance supports also the default assumption that dose addition is applied for combined toxicity of the chemicals unless evidence for response addition or interactions (antagonism or synergism) is available. The second guidance document provides an account of the scientific criteria to group chemicals in assessment groups using hazard-driven criteria and prioritisation methods, i.e., exposure-driven and risk-based approaches. This manuscript describes such principles, provides a brief description of EFSA's guidance documents, examples of applications in the human health and animal health area and concludes with a discussion on future challenges in this field.

Probabilistic Risk Assessment of Combined Exposure to Deoxynivalenol and Emerging Alternaria Toxins in Cereal-Based Food Products for Infants and Young Children in China.

Deoxynivalenol (DON) and emerging Alternaria toxins often co-occur in cereal-based products, but the current risk assessment is commonly conducted for only one type of mycotoxin at a time. Compared to adults, infants and young children are more susceptible to mycotoxins through food consumption, especially with cereal-based food products which are the main source of exposure. This study aimed to perform a probabilistic risk assessment of combined exposure to DON and three major Alternaria toxins, namely including alternariol monomethyl ether (AME), alternariol (AOH), and tenuazonic acid (TeA) through consumption of cereal-based foods for Chinese infants and young children. A total of 872 cereal-based food products were randomly collected and tested for the occurrence of DON and three major Alternaria toxins. The results on mycotoxin occurrence showed the DON, TeA, AOH, and AME was detected in 56.4%, 47.5%, 7.5%, and 5.7% of the samples, respectively. Co-contamination of various mycotoxins was observed in 39.9% of the analyzed samples. A preliminary cumulative risk assessment using the models of hazard index (HI) and combined margin of exposure (MoET) was performed on DON and Alternaria toxins that were present in cereal-based food products for infants and young children in China for the first time. The results showed that only 0.2% and 1.5%, respectively, of individuals exceeded the corresponding reference value for DON and TeA, indicating a low health risk. However, in the case of AME and AOH, the proportion of individuals exceeding the reference value was 24.1% and 33.5%, respectively, indicating the potential health risks. In the cumulative risk assessment of AME and AOH, both HI and MoET values indicated a more serious risk than that related to individual exposure. Further research is necessary to reduce the uncertainties that are associated with the toxicities of the Alternaria toxins and cumulative risk assessment methods.

A user-friendly tool to assess combined exposures to indoor air pollutants in public spaces of children

This manuscript describes the methodology for and early experience in the application of a screening tool to assess health risks from combined exposure to indoor air pollutants in public settings for children such as schools, kindergartens and day-care centres. The user-friendly tool incorporates tiers modified from those of the World Health Organization (WHO) framework for risk assessment of combined exposure to multiple chemicals and includes a spreadsheet for risk calculation as well as a supporting toxicological database of guidance values and points of departure (PODs) for inhalation for selected effects. Supporting resources on exposure assessment include a screening questionnaire to identify optimum sampling strategies and standardized analytical methods.The approach to assessment of combined exposure within the screening tool, including decision rules, assumptions and limitations/uncertainties is addressed, as is the nature of health-effects and reference/toxicity values prioritized for inclusion in the associated toxicological database. Results of early experience in application illustrate how the screening tool contributes as an important component in strategies to assess and manage indoor air pollution in public settings for children.

Evaluation of EFSA training courses on principles in chemical and biological risk assessment

This report evaluates the training courses delivered under the contract OC/EFSA/SCER/2017/01 - Lot 1. Within the period of January 2018 to February 2022 a total of 21 training courses were provided, eight on-site training courses in Parma at EFSA, six virtual training courses during the Covid-19 pandemic and seven eLearning courses comprising various numbers of modules. The courses covered different aspects of chemical and biological risk assessment and related tools, namely i) harmonisation of risk assessment methodologies for human health and ecological risk assessment of combined exposure to multiple chemicals (mixture assessment), ii) risk assessment of the application of nanoscience and nanotechnologies in agro/food/feed (nanotoxicity); iii) science-based criteria for identifying endocrine disruptors in the context of EU legislation on pesticides and biocides (endocrine disruption); iv) principles on genotoxicity on scientific assessment (genotoxicity) and v) computational toxicology approaches and tools (in silico). All tutors were experts in their field and had previously performed training courses on these topics. The target participants of the training courses were members of EFSA’s Scientific Committee/Panels and their working groups as well as employees from national and international regulatory agencies associated with risk assessment of feed and food compounds. Members of the EFSA Networks as well as EFSA scientific staff also participated in the training courses. Courses were evaluated based on the feedback of participants and continuously improved also by integrating updated or new EFSA guidance documents.

Outcome of the public consultation on the draft EFSA ‘Guidance Document on Scientific criteria for grouping chemicals into assessment groups for human risk assessment of combined exposure to multiple chemicals’

The European Food Safety Authority (EFSA) carried out a public consultation to receive input from the scientific community and all interested parties on the draft guidance of the working group of the Scientific Committee ‘Guidance Document on Scientific criteria for grouping chemicals into assessment groups for human risk assessment of combined exposure to multiple chemicals’. The background and the Terms of Reference were prepared by EFSA staff and the working group of the Scientific Committee was set up in 2019. The draft guidance was developed by the working group and endorsed by the Scientific Committee for public consultation at its plenary meeting of 17 April 2021. The written public consultation for this document was opened from 29 May to 10 July 2021. EFSA received responses from 12 interested parties (industry, industry associations, NGOs, consultancy companies, national scientific advisory bodies and individual scientists). EFSA and its Scientific Committee wish to thank all stakeholders for their contributions. In addition, EFSA organised an International Workshop on “Risk Assessment of Combined Exposure to Multiple Chemicals” on 18, 19 and 20 October 2021 to discuss specifically hazard-based criteria and prioritisation methods from the guidance document as well future challenges in the area of risk assessment of combined exposure to multiple chemicals. This report presents the comments received from the public consultation and the international workshop and addressed after consideration by the working group of the Scientific Committee and by the Scientific Committee at its Plenary meeting of 17 November 2021.

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.

Exploring the utility of the Threshold of Toxicological Concern (TTC) as a screening approach for complex substances

The Threshold of Toxicological Concern (TTC) has been applied to assess chemical safety for use, particularly in the food safety area. Although the TTC was developed for application to an individual chemical structure, more recently this concept has been suggested for the assessment of combined exposures to multiple chemicals. This study evaluated the potential for applying the TTC to a specific type of co-exposure, that of a complex substance of variable composition which contains multiple constituents, following the World Health Organization/International Programme on Chemical Safety framework for risk assessment of combined exposure to multiple chemicals. The results indicated that the TTC threshold was lower (i.e., more conservative) than regulatory thresholds derived for the same substance or even its most toxic constituent, providing assurance that the TTC could meet the requirements for a conservative screening process. This case study indicates that the TTC concept can be a useful tool to screen for potential risks from complex substances, with the consideration of additional aspects such as variability in chemical constituents and their relative proportions within the substance.

A common adverse outcome pathway for toxic metals inducing nephrotoxicity to aid human health risk assessment of chemical mixtures

Background: There is evidence that chronic exposure to certain metals may induce nephrotoxicity in humans, even at relatively low doses. However, there is no consensus on the biological processes involved and the human health risk assessment is complicated by frequently occurring combined exposure to metal mixtures. We aimed to address these issues by developing a common Adverse Outcome Pathway (AOP) for toxic metals and nephrotoxicity.Methods: We focused on four toxic metals, i.e. arsenic, cadmium, lead and mercury, prioritized in the context of the Horizon2020 project on Human Biomonitoring in Europe and labelled as substances of high concern by the World Health Organization. First, renal dysfunction due to proximal tubular damage was identified as their common adverse outcome using available risk assessment reports. Subsequently, the AOP was developed by collecting evidence from experimental studies.Results: We identified the following common pathway via which these metals most likely induce nephrotoxicity: thiol binding induces oxidative stress and mitochondrial dysfunction, which results in cytochrome c release followed by apoptosis in the proximal tubuli of the kidney. Evaluation of the weight-of-evidence using modified Bradford-Hill criteria, including assessment of the relevance of doses tested in experimental studies, revealed a high confidence in this AOP.Conclusions: The developed AOP enhances mechanistic understanding of metal-induced nephrotoxicity and provides scientific evidence for a causal relationship between the adverse effect and effect biomarkers. Furthermore, it can be a useful tool to facilitate and improve risk assessment of combined exposure to different metals, because it enables determination of key events that are most perturbed by the studied metals and that could be used for bioassays in the future.

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.

In vitro-in silico-based probabilistic risk assessment of combined exposure to bisphenol A and its analogues by integrating ToxCast high-throughput in vitro assays with in vitro to in vivo extrapolation (IVIVE) via physiologically based pharmacokinetic (PBPK) modeling

Combined risk assessment of endocrine effects of bisphenol A (BPA) and its analogues, such as bisphenols S, F, and AF (BPS, BPF, and BPAF), is challenging due to lack of related common toxicity metrics. This study conducted a population-based in vitro-to-in vivo extrapolation using physiologically based pharmacokinetic (PBPK) models coupled with Monte Carlo simulations to convert ToxCast in vitro estrogen receptor (ER) assays to human equivalent doses (HEDs). The ER pathway-based HEDs were compared with HEDs from animal studies and used to assess the combined risks for different populations across different countries/regions in a probabilistic manner. The estimated ER pathway-based HEDs for the four bisphenols (BPs) matched the animal-derived HEDs. The HEDs for the ER gene transcription (the common biological process target among BPs) were 0.40 (2.5th–97.5th percentiles: 0.06–5.42), 4.43 (0.69–53.84), 3.30 (0.51–626.57), and 1.12 (0.16–9.73) mg/kg/day for BPA, BPS, BPF, and BPAF, respectively. Results suggest a potentially moderate concern for combined risks of activating the ER pathway for toddlers and adults with high dietary exposures. This study presents in vitro-based credible HEDs for the four BPs and represents an advancement in the application of in vitro–in silico-based alternative approaches in human health risk assessment.

Recommendations for international harmonisation, implementation and further development of suitable scientific approaches regarding the assessment of mixture effects

Legal frameworks lay down requirements for risk assessment of combined exposure to multiple chemicals and their implementation where scientific methods are accepted by responsible authorities. In order to protect human health, an assessment of potential risks that might result from co-exposure to multiple chemical substances is requested by European legislation. Several approaches for risk assessment of mixtures of chemicals have been proposed, but none has been widely implemented in regulatory risk assessments, so far. EuroMix, an EU Horizon 2020 funded project, contributed to the improvement of internationally harmonised approaches for risk assessment of chemical mixtures. Based on in vitro and in silico tests, an integrated test strategy involving hazard and exposure assessment was developed and a web tool to conduct such assessments was provided. One further task within EuroMix was to make recommendations for international harmonisation, implementation and further development of suitable scientific approaches regarding the assessment of mixture effects. This paper briefly describes objectives and outcome of the EuroMix project as well as recent findings from OECD, WHO and EFSA addressing combined exposure to multiple chemicals. Building on this, five steps addressing further development needs and implementation of existing tools especially for risk managers and policy makers are proposed.

Hygienic Assessment of Surface and Groundwater Quality in the Zabaykalsky Krai

Introduction. The supply of high quality potable water to the population living within the geochemical provinces remains an important problem since the imbalance of chemical elements is a risk factor for various diseases and syndromes. The purpose of the study was to analyze the quality of surface and groundwater related to the geochemical characteristics of the region and to assess public health risks. Materials and methods. Water quality was analyzed in the areas of the Zabaykalsky Krai characterized by the presence of geochemical anomalies. Non-carcinogenic risk assessment of combined exposure to multiple chemicals in drinking water was carried out in accordance with the requirements of R 2.1.10.1920–04. Results. We established the excess of maximum permissible concentrations for such elements as iron (1.1–5.1 MPC), fluorides (1.1–2 MPC), nitrates (2.2 MPC), manganese (5.1 MPC), zinc (2.5–4.6 MPC), and cadmium (1.3–1.5 MPC). Higher than acceptable values of non-carcinogenic hazard quotients were attributed to the effects of nitrites (HQ = 1.5) and arsenic (HQ = 3.4) on the child population in the Kirinsky district. The total hazard index (THI) exceeded the permissible one for children in the Kyrinsky (5.05), Borzinsky (1.92), Chitinsky (1.19), and Tungokochensky (1.24) districts, the urban-type settlements of Zabaykalsk (2.07) and Priargunsk (1.62), and the towns of Petrovsk-Zabaykalsky (1.1) and Chita (1.87). Arsenic, fluorine, iron, and nitrites in water contributed the most to the risk level. Conclusions. The priority water pollutants included heavy metals, nitrites, arsenic, manganese, iron salts, and fluorides due to local natural geochemical features and industrial pollution. The assessment of the total non-carcinogenic risk based on hazard quotients showed that the children were at higher risk for toxic effects of those chemicals on the immune system, teeth, bone tissue, cardiovascular system, gastrointestinal tract, skin, reproductive, respiratory, and hematopoietic systems, liver, kidney, central nervous and musculoskeletal systems.

Dose–response analysis of toxicological and pharmacological mixtures with the model deviation ratio method: Problems and solutions

Risk assessment for mixtures of chemicals requires to investigate the magnitude of their potential adverse effects on living organisms. This is usually done by assessing how experimental toxicological mixture data depart from the model of Loewe additivity. Several recent scientific studies propose to perform this task using an ad hoc method known as model deviation ratio (MDR) method. Moreover, the first official European regulatory document for the study of combined exposures explicitly recommends the use of the MDR method (EFSA Scientific Committee et al. Guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals. EFSA Journal, 2019).We show here that the MDR method is not rooted in statistical principles and can lead to erroneous claims. We show however that the distribution of the MDR can be evaluated by simulations and show how this allows us to devise and carry out a bona fide statistical test. The proposed method accounts for uncertainty in the estimation of ED/EC50 and does not require a minimum sample size. The computer code developped in this study is made available as an R package called MDR.

Animal Health Risk assessment of multiple chemicals in essential oils for farm animals

This technical report implements the EFSA MIXTOX guidance document for animal health risk assessment of combined exposure to multiple chemicals in essential oilsusing whole mixture and component-based approaches (WMA and CBA).The harmonised step wise approaches from the MIXTOX guidance are applied to the problem formulation, exposure assessment, hazard assessment and risk characterisation using conservative scenarios, available data and tools. Options for the refinement of the CBA are proposed for the exposure assessment and hazard assessment (toxicity and toxicokinetic data and models) steps as well as for the application of risk characterisation methods.For exposure assessment, exposure metrics are derived for the whole mixture or for each component of the assessment groupusing the maximum proposed use levels of the essential oil in feedcombined with the feed consumption patterns corrected for body weight for each farm animal species. For hazard assessment, combined chronic toxicity on a species-specific basis requires data collection of reference points from chronic tolerance studies in each farm species or (sub)-chronic toxicity studies on test species. For the WMA, the chronic toxicity of the whole mixture is used and divided by uncertainty factors.For the component-based approach, the chronic toxicity for each substance in each assessment group is collected. For risk characterisation using WMA and CBA, a margin of exposure approach and a combined margin of exposure approach are applied respectively.Options for refining the approachesfor the component-based approach are proposedincluding the use ofspecific toxic effectsfor the grouping of chemicals as well as the use of toxicokinetic data and generic physiologically-based kinetic models for farm animal species.

Human risk assessment of multiple chemicals using component‐based approaches: A horizontal perspective

This technical report implements the EFSA MIXTOX guidance document for human risk assessment of combined exposure to multiple chemicals(i.e.regulated compounds and contaminants)using component-based approaches.Alow tier risk assessment methodologyfor regulated compounds and contaminants with non-cancer effects, is describedusing available harmonised methods, tools and data sources. For exposure assessment, exposure metrics can be collected or calculated from previous EFSA opinions or monitoring data from available tools(e.g. EFSA pesticide residue information, occurrence data from Member States, EFSA comprehensive consumption database, JECFA and JMPR monographs etc..). Harmonisation of the reporting of exposure metricsis proposed using the upper bound and the lower bound of the 95th centiles.For hazard assessment,it is assumed that for all compounds reference values as health-based guidance values (HBGV)are available and represent conservative estimates for regulated products and contaminants with non-cancer effects.The OpenFoodTox database is proposed as a simple open source tool which provides HBGVsfor acuteand chronic effects asacute reference dose(AfRD) and the acceptable or tolerable daily intake(ADI, TDI) respectively. For risk characterisation, the Hazard Index (HI) is applied as a low tier harmonised approach using the dose addition default assumption for combined toxicity.HIs are derived as the sum of the ratios between hazard and exposure metrics. EFSA's MIXTOX reporting table summarising the findings of the risk assessment is provided. For non-cancer effects, HIswith values below 1 are interpreted as of low concern whereas HIsabove1 suggest either the need to refine the risk assessment or a risk management consideration.options for refining the approaches include exposure-criteria,risk-criteria and grouping based on specific toxicological effects as well as the use of toxicokinetic data and physiologically-based kinetic models.

Chemical pollution of baby food products in the Russian Federation

One of the main problems of nutrition of children and adolescents is to assess chemical contamination of baby food products and the establishment of the relation with the health of the child population. With the entering different chemical compounds in the body of the child there can be observed disorders of the nervous, urinary, cardiovascular system, gastrointestinal tract, as well as metabolic deteriorations, degenerative processes in parenchymal organs and bone destruction. The aim of the study was to analyze data on chemical contamination of baby food products in the Russian Federation for 2012-2014. The analysis was executed on the data of Federal Information Fund of social and hygienic monitoring of the Russian Federation. There were identified priority pollutants (toxic elements, nitrites, nitrates, nitrosamines, pesticides, hydroxymethylfurfural, mycotoxins) and risk areas (the Lipetsk region, the Krasnodar Territory, the Republic of Adygea, city of Moscow, Tatarstan, the Kabardino-Balkar Republic, the Ryazan region). There are detected contamination levels not exceeding MAC (in the dynamics of the three years offollow up, on average 22%), requiring their hygienic assessment. There were determined the baby food products containing most common occurred chemical contaminants: fruits and vegetables products, canned products, canned meat, cereals, dairy products, liquid and adapted and partially adapted milk formalas. Identified data indicate to a need for further studies of chemical substances in products for children’s nutrition in order to establish the causal relationships with a various diseases and the substantiation of methodological approaches to the risk assessment of combined exposure to chemical contaminants in concentrations up to the MPC on health of children, including infants.

Guidance on harmonised methodologies for human health, animal health and ecological risk assessment of combined exposure to multiple chemicals.

This Guidance document describes harmonised risk assessment methodologies for combined exposure to multiple chemicals for all relevant areas within EFSA's remit, i.e. human health, animal health and ecological areas. First, a short review of the key terms, scientific basis for combined exposure risk assessment and approaches to assessing (eco)toxicology is given, including existing frameworks for these risk assessments. This background was evaluated, resulting in a harmonised framework for risk assessment of combined exposure to multiple chemicals. The framework is based on the risk assessment steps (problem formulation, exposure assessment, hazard identification and characterisation, and risk characterisation including uncertainty analysis), with tiered and stepwise approaches for both whole mixture approaches and component‐based approaches. Specific considerations are given to component‐based approaches including the grouping of chemicals into common assessment groups, the use of dose addition as a default assumption, approaches to integrate evidence of interactions and the refinement of assessment groups. Case studies are annexed in this guidance document to explore the feasibility and spectrum of applications of the proposed methods and approaches for human and animal health and ecological risk assessment. The Scientific Committee considers that this Guidance is fit for purpose for risk assessments of combined exposure to multiple chemicals and should be applied in all relevant areas of EFSA's work. Future work and research are recommended.