# Integration of the exposome concept into health risk assessments: a challenge for health safety agencies

Amélie Crépet, Philippe Quénel, Jeanne Garric, Alain Kaufmann, Jean-Marc Bonmatin, Pascale Duché, Aurélie Mathieu, Madeline Carsique, Julien Jean, Pascal Sanders, et al.

► To cite this version:

Amélie Crépet, Philippe Quénel, Jeanne Garric, Alain Kaufmann, Jean-Marc Bonmatin, et al. Integration of the exposome concept into health risk assessments: a challenge for health safety agencies. Environmental Research, 2025, 286 (3), pp.123036. 10.1016/j.envres.2025.123036. hal-05314178

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# Integration of the exposome concept into health risk assessments: a challenge for health safety agencies

Amélie Crépet<sup>a, *</sup>, Philippe Quénel<sup>b, c</sup>, Jeanne Garric<sup>c, d</sup>, Alain Kaufmann<sup>d, e</sup>, Jean-Marc Bonmatin<sup>e, f</sup>, Pascale Duché<sup>f, g</sup>, Aurélie Mathieu<sup>a, f</sup>, Madeline Carsique<sup>a</sup>, Julien Jean<sup>a</sup>, Pascal Sanders<sup>a</sup>, Jean-Pierre Cravedi<sup>g</sup>, Matthieu Schuler<sup>a</sup>, Robert Barouki<sup>h</sup>

## ARTICLE INFO

### Keywords:

Exposome

Risk assessment

Human health

Regulations

Public policies

Chemicals

## ABSTRACT

The exposome is a concept that aims to study the environmental factors to which individuals are exposed during their lifetime and the role of these factors in the development of chronic diseases. Since the concept emerged in 2005, new data, methods, and tools have been generated by the scientific community to assess the different components of the exposome and their impacts on human health. Currently, one of the main challenges is accounting for the diversity and complexity of exposures and their effects on health in risk assessment, which might be accomplished by integrating the exposome into this process. To this end, a working group was constituted by Anses to develop a strategy to integrate the exposome concept in risk assessment and more generally in the work produced by health safety agencies. We present the principal challenges to be addressed by considering 8 themes covering relevant aspects of the exposome and we made recommendations for each theme: 1) characterization of the exposome in epidemiological surveys; 2) exposome data; 3) risk assessment of chemical mixtures; 4) aggregation of multiple sources and routes of exposure; 5) dynamics of the exposure in the context of time, space, and social factors; 6) establishment of reference values; 7) multiple factors in risk, benefit and health impact assessment; and 8) eco-exposome. Then, we propose practical recommendations with short-, medium-, and long-term time scales to progressively operationalize the exposome into risk assessments implemented by health safety agencies. We also discuss how providing broader exposome input into risk assessment can support risk regulators to incorporate exposome input into risk management.

## 1. Introduction

Health and safety agencies at both the European and international level—e.g., the French Agency for Food, Environmental and Occupational Health & Safety (ANSES), the German Federal Institute for Risk Assessment (BfR), the Dutch National Institute for Public Health and the Environment (RIVM), the United States Environmental Protection Agency (US-EPA), the European Food Safety Agency (EFSA), and the World Health Organization (WHO)—perform monitoring, expert

appraisal, research, and reference in a wide range of fields related to the oversight of human, animal, and plant health (One Health). They provide a cross-functional perspective on health issues when assessing health risks and benefits, in particular through the prism of the human health and social sciences. Their monitoring, vigilance, and surveillance work provides input for risk assessment.

Health and safety agencies assess a broad range of hazards (e.g., chemical, biological, and physical) to which a person may be exposed, intentionally or otherwise, at all ages and times of life, whether the

<footnote><sup>a</sup> French Agency for Food, Environmental and Occupational Health & Safety (ANSES), 14 rue Pierre et Marie Curie, 94701, Maisons-Alfort, France</footnote>

<footnote><sup>b</sup> Rennes university, EHESP, Inserm, IRSET UMR_S 1085, F-3500, Rennes, France</footnote>

<footnote><sup>c</sup> INRAE - Centre de Lyon-Villeurbanne, France</footnote>

<footnote><sup>d</sup> University of Lausanne, The Collaboratory, Switzerland</footnote>

<footnote><sup>e</sup> Centre National de la Recherche Scientifique, Centre de Biophysique Moléculaire, Orléans, F-45071, France</footnote>

<footnote><sup>f</sup> University of Toulon, Laboratory Youth-Physical Activity and Sports-Health (JAP2S), F-83041, Toulon, France</footnote>

<footnote><sup>g</sup> INRAE, Department of Nutrition, Chemical Food Safety and Consumer Behaviour, France</footnote>

<footnote><sup>h</sup> T3S, INSERM UMR-S1124, Université Paris Cité, Paris, France</footnote>

<footnote>* Corresponding author.
E-mail address: amelie.crepet@anses.fr (A. Crépet).</footnote>
exposure occurs at work, while travelling, while engaging in leisure activities, or through consumption of food. The associated risks are assessed independently, and these assessments most often consider a single source (e.g., air, water, food, or dust), a single route of exposure (ingestion, inhalation, or dermal contact), or a single agent. These assessments may lead to simple assumptions about the exposure over time (e.g., that it is a constant exposure, a short-term exposure, or a one-off exposure).

The concept of the exposome was first introduced in 2005 by epidemiologist Christoper Wild (2005), who defined the exposome as a concept that considers the environmental factors encountered over a person's lifetime and the role of these factors in the development of chronic diseases, many of which have become a leading cause of death in high-income countries in recent decades (Institute for Health Metrics and Evaluation (IHME) 2024). Exposure to these environmental factors is mainly determined by socioeconomic factors, lifestyle habits (Ibsen et al., 2021) (tobacco, alcohol consumption, physical activity, diet, etc.), geographical location or occupational activity, etc. The exposome concept could help explain the health status of whole populations by its proposed use of a systemic approach and by complementing the role of the genome with which it may interact (Barouki et al., 2018). Since its emergence as a novel concept, the exposome has been the subject of numerous research projects that form part of a broad continuum of scientific queries addressing the impact of environmental factors on health. This interest in the relevance of the exposome has extended beyond scientific research to include public policy decisions. In 2016 policy-makers in France introduced the exposome concept into public health codes governing the French health care system (Public Health Code, Act of January 28, 2016). However, the exposome concept has not yet been widely integrated into the health risk assessments conducted by health and safety agencies. It is therefore important that these agencies learn how to practically integrate the exposome concept into their risk assessment activities, particularly in terms of how it might impact their regulatory decisions. This requires identifying the opportunities, the best approaches and means for its implementation, and also requires recommendations for targeted professional development and new skills to help the risk assessors implement the changes.

ANSES set up a working group (Exposome WG) to develop a strategy for strengthening the integration of the exposome into the expert appraisal work carried out by health and safety agencies or others expert groups such as the Nordic Expert Group (NEG). The Exposome WG was composed of scientific experts from the ANSES Scientific Board (2020–2023 mandate), and ANSES staff members with expertise in the field of the exposome or risk assessment. The work published in a report (Anses, 2023) by the Exposome WG took account of the comments, feedback and additional information provided during internal and external consultations (in-house workshops for all ANSES staff, presentations and discussions with the main ANSES expert committees, call for comments to other French health agencies) and by the whole ANSES Scientific Board members. The European and national health agencies/institutes such as the European Food Safety Agency (EFSA), the German Federal Institute for Risk Assessment (BfR), the Dutch National Institute for Public Health and the Environment (RIVM), the Czech Republic's Research Centre for Toxic Compounds in the Environment (RECETOX), etc. were also consulted at the beginning of the work but it appeared that the exposome was addressed mainly at the research level and none of them had yet integrated it in their formal appraisal. In this work, the authors as members of the Exposome WG describe the developed strategy to operationalize the exposome concept in the risk assessment process. To date the chemical component of the exposome has been the most widely studied aspect. This paper focuses on not only chemical exposures but also on other health determinants that are frequently considered in risk assessments, including biological and physical agents, psychosocial and socioeconomic context, and organizational constraints.

## 2. Defining the exposome from a health risk assessment perspective

As it pertains to the core risk assessment activities of health and safety agencies, we propose that the exposome be defined as follows: all exposures to chemical, biological, and physical agents, both harmful and beneficial, experienced by a living organism from conception to death which—through their interactions with physiological functions, the living environment, and psychosocial factors—can be used to explain the state of health. Different components related to the exposome concept are incorporated into this proposed definition, including the following: 1) multiple exposure factors and diversity of sources/agents; 2) health risks and benefits; 3) the temporal component of exposures; and 4) social and environmental components. This definition is applicable to both human and non-human organisms (Scholz et al., 2022). In the context of the animal and plant kingdoms, the notion of "psychosocial factors" is not applicable, but aspects related to animal welfare, specific behaviors, and the sensitivity of animals and plants to their environment can be considered. Since the concept was first proposed in 2005, the exposome has evolved from a focus on external environmental exposures to a broader, more integrated framework. It now encompasses both external factors (e.g. pollutants, diet, lifestyle) and internal biological responses (e.g. inflammation, metabolism, microbiome), highlighting the dynamic and cumulative nature of exposures across the life course (Rappaport, 2011; Wild, 2012). More recent literature emphasizes the use of omics and high-resolution tools to characterize the exposome and its effects on health in a more systematic and data-driven way (Miller and Jones, 2014; Vermeulen et al., 2020). The term exposomics has been also introduced and defined (Miller et al., 2025). It can be seen as the science of the exposome developing interdisciplinary methodologies and streams to investigate how combined exposure influence health.

The study of the exposome can be categorized into 4 modules, as shown in Fig. 1. The first module, the ecosystem, represents the environment of the living organism as the source of exposure. This includes an individual's surroundings and can be impacted by the environment's biodiversity. Monitoring the environment of living organisms could therefore provide insights into the types and levels of exposures therein and, more broadly, could help characterize the state of health of the non-human populations living within it.

The second module is the external exposome, which describes the various agents to which humans may be exposed. This is defined by the type, sources, and quantities of a particular agent, as well as by an individual's social, organizational, and physical environment and their lifestyle and activities. Exposure to these factors can be estimated by combining data on quantities of these factors from various sources with data on lifestyle habits (e.g., consumption of food; use of items such as toys, clothing, and furniture; use of cleaning products; pursuit of sports activities; and consumption of tobacco or alcohol, among other behaviors), which may be modulated by the individual's physical and social environment, including the workplace.

The external exposome determines the third module, the internal exposome, which represents measurements of biomarkers of exposure and infection in different biological samples such as blood, urine, or hair. The transition from external to internal exposure is regulated by the infectious/carriage process of biological agents and by the toxicokinetics of chemical and physical agents.

Both the external and the internal exposome will have repercussions on the human body, inducing biological responses at the molecular, cellular, tissue, and organ levels; this represents the fourth module of the exposome. These biological responses can be positive (e.g., cell repair or immune system activation) and/or negative (e.g., oxidative stress or cell death). Whether they are positive or negative depends, in part, on the duration of exposure and the body's ability to adapt. The body will react differently depending on its sensitivity and vulnerability (influenced by such factors as genetics, epigenetics, microbiota, and life stage), and
<figure><img src="image_4.png" /><figcaption>Fig. 1. Four modules to represent the study of the exposome.</figcaption></figure>

these responses can lead to the onset of diseases. Agents of the same type (e.g., a mixture of chemicals) or of a different type (e.g., a chemical agent and a biological agent) may have combined effects or, conversely, they may compete with each other, thus limiting their overall impact on health. In addition, certain factors may be protective of health, such as an individual's access to health care, level of physical activity, or compliance with public health recommendations regarding for example nutrient intakes. All of these components are interrelated, illustrating the complexity of accounting for the exposome in risk assessments.

### 3. Challenges related to the exposome and recommendations for integrating the exposome into health risk assessment

We focus here on 8 themes representing challenges related to the exposome, which we selected for their relevance for incorporation into risk assessment (Fig. 2). Addressing the multiplicity of exposures—along with their temporal, geospatial, and social dynamics—is a core objective of the exposome approach. Meanwhile, the future of risk assessment lies in the integration of multiple sources and exposure routes, chemical mixtures, associated benefits, and social inequalities. Disciplines such as epidemiology, toxicology, data integration and analysis are essential and transversal to both the exposome and risk assessment fields. The establishment of reference values remains one of the key missions of health agencies. Developing the eco-exposome and its connection to the human exposome is also one of current challenge in connection with the One Health concept. Fig. 3 provides, for each of the 8 themes, more detailed recommendations, with time scales designated as short-term (2025–2027), medium-term (2028–2030), or long-term (2030 and later).

#### 3.1. Theme 1: characterization of the exposome in epidemiological studies

The exposome represents a paradigm shift in epidemiological research, offering a comprehensive framework to understand the multifactorial nature of diseases. Numerous researchers from various fields, ranging from perinatal epidemiology to chronic diseases or psychiatry and, more recently, infectious diseases such as COVID-19, have highlighted the potential benefits of characterizing and incorporating the exposome into epidemiological studies (Andra et al., 2016; Buck

<figure><img src="image_5.png" /><figcaption>Fig. 2. Exposome themes which recommendations have been developed, selected for their relevance to risk assessment.</figcaption></figure>

et al., 2013; Daiber et al., 2019; DeBord et al., 2016; Guillien et al., 2021; Guloksuz et al., 2018; Lioy and Rappaport, 2011; Miller and Jones, 2014; Orešić et al., 2020; Rappaport, 2011, 2020; Robinson and Vrijheid, 2015; Vineis, 2015; Vrijheid, 2014) to elucidate the complex interactions between various environmental exposures and health outcomes. For instance, studies have shown that the combined effects of air pollution, dietary habits, and socioeconomic status can significantly influence the risk of developing chronic diseases such as asthma and cardiovascular conditions (Daiber et al., 2019; Guillien et al., 2021). The integration of the exposome also enhances the ability to identify biomarkers of exposure and disease. For instance, the identification of metabolic signatures associated with exposure to environmental
<figure><img src="image_6.png" /><figcaption>Fig. 3. Recommendations for short-, medium-, and long-term actions to strengthen the integration of the exposome into risk assessment.</figcaption></figure>

chemicals can provide insights into the pathways through which these exposures contribute to disease (Orešić et al., 2020). Major research projects integrating the components of the exposome, notably those led by the European Human Exposome Network (EHEN) and the Center for Exposome Research Coordination (CERC) in the US, have begun to produce concrete results. For example, as part of the ATHLETE project on understanding and preventing the health effects of various exposures in early life (de Prado-Bert et al., 2021), investigated the association between more than 100 exposures and epigenetic age acceleration,

whereas Guillien et al. (2021) studied the role of multiple environmental and lifestyle determinants in asthma. The HEDIMED project, whose objective is to identify disease mechanisms and environmental factors related to immune-mediated diseases, has studied the link between the exposome and diabetes (Nurminen et al., 2021). The EXPANSE project studies the impact of the urban exposome (eco-system, lifestyle, social and physico-chemicals) on the major contributors to Europe's burden of disease: Cardio-Metabolic and Pulmonary Disease (Vlaanderen et al., 2021). Nevertheless, theoretical and practical challenges remain,
suggesting that efforts to address them must continue. These efforts should have the following key objectives: 1) further develop infrastructures such as the UK Biobank<fnref n="1" /> following half a million participants since 2006 to collect genetic, environmental, lifestyle, and health data, the EIRENE<fnref n="2" /> infrastructure developing a network of harmonized laboratories for exposome characterization in Europe, and the Network for Exposomics in the United States<fnref n="3" /> coordinating exposome research in US to support the comprehensive exposure assessment activities essential to epidemiological research; 2) apply methods to distinguish between normal physiological variations and environmentally induced changes in biological response measures; 3) develop analytical, bioinformatics, and statistical methods to process, integrate, and analyze multi-dimensional data; and 4) refine training programs to develop and implement these new approaches.

Building from the review of *Stingone et al. (2017)*, we make the following recommendations to address these challenges of the exposome: 1) Existing tools and methodologies related to exposome research should be catalogued, which could be useful for integrating the exposome in epidemiological studies; 2) Data sharing and interdisciplinary collaboration should be promoted as described in *Wright et al. (2024)* to ensure that exposome assessment methods are compatible with fundamental epidemiological principles; 3) The design of new epidemiological studies should consider the variations in exposures over time, particularly during critical and sensitive periods of reproduction and human development, and account for exposures to multiple factors (i.e., various agents, sources, and routes of exposure) as well as the uncertainties associated with these exposures. The development of large longitudinal parent-child studies such as MOBA<fnref n="4" /> in Norway, E3N-E4N<fnref n="5" /> or FILOMENE<fnref n="6" /> just started in France that track exposome changes and health effects across the life course and generations should be promoted; 4) Causal inference in the context of the exposome should be documented; for example, mediation analyses could be used to improve understanding of the mechanistic pathways between exposure and disease, or epidemiological studies could be complemented with toxicological approaches, such as analysis of adverse outcome pathways (AOPs) (Bornehag et al., 2019; Stingone et al., 2017) based on scientific evidence obtained through experimentation. 5) Develop exposome-based intervention studies and innovative methods able to quantify the positive or negative health impact of such prevention strategies (Andrianou et al., 2021; Sonnenschein et al., 2022).

## 3.2. Theme 2: interoperability and analysis of exposome data

The study of the exposome involves the use and combination of various types of data, including but not limited to health effects and toxicity of the exposures, chemicals in food and in environmental sources, living and working habits and conditions, and exposure and effect biomarkers. The accessibility, collection, interoperability, management, and analysis of these heterogeneous data therefore play a central role in taking the exposome into account in risk assessment. To facilitate their use for research, expert appraisal, and communication purposes, the quality and reproducibility of data pertaining to the exposome can be structured on the basis of the FAIR (Findable, Accessible, Interoperable, and Reusable) guiding principles for scientific data management (Wilkinson et al., 2016).

Our main recommendations with regard to handling of exposome data are as follows: 1) Existing data sets relevant to the assessment of the

exposome should be catalogued as proposed by the French GD4H initiative<fnref n="7" /> or the Dutch GECCO<fnref n="8" /> infrastructure; 2) Harmonized and validated questionnaires should be used to generate exposome data. Standardized descriptions of the data should ensure a shared understanding of the information presented and facilitate data connection. For example, the NIEHS is funding projects to enable the health community to accelerate the development of data and metadata standards as well as associated tools<fnref n="9" />; 3) Computational methods should be developed based on artificial intelligence (AI) for data mapping, mining, and analysis in including associated uncertainty. For example, AI is used to analyze the link between the exposome and chronic disease (Isola et al., 2024), to improve data quality, chemical identification and detection in exposomics studies (Petrick and Shomron, 2022); 4) Open access to the data, as well as open access to the models used for their analysis, should be allowed, in accordance with current open data policies; 5) The sustainability and security of data storage conditions should be ensured to enable future re-use of the data (Al Kez et al., 2022).

## 3.3. Theme 3: risk assessment of chemical mixtures

In real-world settings, populations are continuously exposed to a complex mixture of substances, and the precise composition of this mixture, the conditions of exposure, and the possible combined effects are often unknown. As a result, risk assessment, which is still mainly carried out on a substance-by-substance basis, needs to move toward an approach that considers mixture exposures and their health effects. In recent years, this question has become increasingly important and has contributed, in the context of chemical exposure, to the development of mixture risk assessment approaches, also called cumulative risk assessment (Boobis et al., 2008; EFSA, 2007, 2008; EFSA Scientific Committee et al., 2019; Fox et al., 2017; International Programme on Chemical Safety and Inter-Organization Programme for the Sound Management of Chemicals, 2009). These approaches were successfully applied in assessments of compounds belonging to the same class of chemicals with similar toxicological targets or common modes/mechanisms of action, such as dioxins and polychlorinated biphenyls (Hulin et al., 2020), phthalates (Clewell et al., 2020; EFSA CEP Panel et al., 2019), and more widely to certain pesticides (Boon et al., 2008; EFSA et al., 2020a, 2020b; Sprong et al., 2020). They are mainly based on the principle of additivity of effects, which is regarded as a conservative approach. On the other hand, very few studies combine several exposure routes (inhalation, ingestion and dermal contact combined) and/or several categories of substances (to give just the example of dietary exposure: contaminants, additives, residues, toxins or newly-formed products) (Bopp et al., 2018; Crépet et al., 2022; Drakvik et al., 2020; Evans et al., 2016; Sprong et al., 2023a).

Incorporating mixture exposures into risk assessments for the purpose of characterization of the exposures and their hazards remains challenging. Our main recommendations for chemical mixtures risk assessment are as follows: 1) Risk assessment of specific sets of mixtures can be carried out by prioritizing groups of substances (EFSA et al., 2021). The grouping and prioritization of chemicals can be done using data sets of external exposure (Boon et al., 2008; Sprong et al., 2020) or internal exposure (Rodriguez Martin et al., 2023), hazard data pertaining to a common target, health effects, mode of action (EFSA et al., 2020a, 2020b), or a combination of exposure and hazard data sets (Crépet et al., 2019); 2) The effects and toxicokinetics of the prioritized mixtures should be determined using innovative and high-throughput methods, such as "omics" approaches, new approach methodologies (NAMs), AOP networks, quantitative Adverse Outcome Pathway (qAOP), Quantitative Structure-Activity Relationship (QSAR) models,

<footnote n="1">¹ https://www.ukbiobank.ac.uk/.</footnote>

<footnote n="2">² www.eirene.eu.</footnote>

<footnote n="3">³ NEXUS: Exposomics in the US -</footnote>

<footnote n="4">⁴ https://www.fhi.no/en/ch/studies/moba/.</footnote>

<footnote n="5">⁵ https://www.e3n-generations.fr/.</footnote>

<footnote n="6">⁶ https://www.sfpediatrie.com/actualites/cohorte-pediatrique-filomene.</footnote>

<footnote n="7">⁷ https://gd4h.ecologie.gouv.fr/.</footnote>

<footnote n="8">⁸ Geoscience and health cohort consortium (GECCO) - GECCO.</footnote>

<footnote n="9">⁹ https://grants.nih.gov/grants/guide/rfa-files/RFA-ES-23-002.html.</footnote>
epidemiological mixture models, or Physiologically Based Kinetic (PBK) models (Fu et al., 2021; Jia et al., 2022; Viant et al., 2019); For example, Caporale et al. (2022) identified a set of common endocrine-disrupting chemicals from a mother child cohort that was then tested in a number of experimental models which revealed a combined toxic effect for the nervous system 3) Risk assessors should estimate the possible risk for prioritized chemical mixtures. They should build on proposed methods and risk indicators such as mixture reference point index (mRPI), total margin of exposure (MOET) (EFSA Scientific Committee et al., 2019), and provide management options (Crépet et al., 2022; Sprong et al., 2020, 2023a, 2023b). For example, Crépet et al. (2022) prioritized a mixture of 19 contaminants from a breastmilk survey, estimated the risk related to the nervous system development and identified five chemicals which contribute the most to the risk. Reducing exposure to these risk drivers would significantly decrease the associated risk. Backhaus (2023) proposed a mixture assessment factor (MAF) to be applied as a protection factor in a priori risk assessment.

### 3.4. Theme 4: aggregated exposure from multiple sources and multiple routes

Populations can be exposed to substances from several sources (e.g., food, water, indoor/outdoor air, articles, and consumer products). These exposures originate from general and occupational environments and enter the body via several routes, such as ingestion, inhalation, or dermal contact. Overall exposure can be estimated by determining internal exposure using measurements of biomarkers in biological samples (e.g., blood, urine, or hair) (Elonheimo et al., 2023; Gilles et al., 2021; Govarts et al., 2023). Measuring biomarkers of exposure is an effective approach to directly integrate the different sources and routes of exposure and the toxicokinetics of the substances. However, measuring exposure biomarkers alone does not provide information on the contribution of the different sources of exposure, which is essential for defining management options for mitigating risks. For this purpose, estimates of external exposures can be aggregated where data on substance concentrations in the various sources are combined with data on individual behaviors (e.g., time spent inside/outside/at workplace, food consumption, or use of cosmetics) (U.S. Environmental Protection Agency, 2001). The general principle for aggregating exposure involved creating a new population by integrating data from multiple surveys related to each exposure source, typically using Monte Carlo simulations (Kennedy et al., 2015; Paustenbach, 2000; Safford et al., 2015; Vanacker et al., 2020a, 2020b; Zartarian et al., 2017). Several tools have been developed in recent years to assist exposure and risk assessors but only few integrate several sources and routes (Schlüter et al., 2022a). For example, for general population, SHEDS integrates direct exposure via dermal contact, inhalation, and incidental ingestion with dietary intake from food and drinking water (Isaacs et al., 2014). In Europe, the MCRA platform has been improved to account for several sources for pesticides exposures and to link with the EFSA OPEX model (Kennedy et al., 2019; Zwartsen et al., 2025; EFSA et al., 2022). MCRA is in the context of PARC program (Marx-Stoelting et al., 2023) being enhanced to link dietary chemical exposure with exposure from cosmetics, air, and dust, and to apply physiologically based kinetic (PBK) models for estimating internal doses.

Nevertheless, considering multiple sources and routes is more and more promoted in the field of regulatory and academic chemical risk assessment. With the development of the Chemical Strategy for Sustainability (CSS), several regulatory reforms are under implementation. These reforms will enhance data collection, sharing and harmonization between EU agencies, in particular with the development of a Common Data Platform for biomarkers of exposure. In addition, EFSA recently finalized its ExpoAdvance Rodmap which aims to achieve a harmonized crosscutting methodology and regulatory guidance for aggregate exposure assessments covering all relevant sources and routes of exposure to chemicals, in close cooperation with European and international

partners (Lamon et al., 2024). Additionally, combining occupational and non-occupational exposure is still a challenge for risk assessment (Lentz et al., 2015; Ottenbros et al., 2024)

Risk assessment should consider the diversity of sources and routes in integrating available exposure data. Combining all available information is challenging in linking external exposures with biomarkers of internal exposures, and therefore we recommend the following approaches to achieve this: 1) External data should be organized to enable their combination to estimate aggregate exposure from several sources and routes. 2) Mathematical, kinetic models and operational tools should be promoted to aggregate exposure and to account for uncertainties. Obtained results should be linked with internal exposure from biomarkers of exposure and main sources identified in particular for vulnerable population to propose management options (Vanacker et al., 2020b). 2) The exposure and risk assessors from the different communities, whether they are occupational/general or external/-internal assessors, should develop better communication and collaborations, as addressed in the EFSA roadmap (Lamon et al., 2024); 3) Large-scale national surveys should be launched to explore exposure from several sources in combination with biomarkers of exposure and effect as proposed in the UK Biobank<fnref n="10" /> or the All of Us program in United States<fnref n="11" />;

### 3.5. Theme 5: dynamic exposure assessment: temporal, geospatial and socioeconomic

The exposome concept incorporates changes in exposure over time and inequalities in environmental exposure. Inequalities can occur over the course of an individual's lifetime, with windows of increased sensitivity such as the fetal period or the first few years of life (Robinson et al., 2018; Robinson and Vrijheid, 2015). Inequalities in environmental exposure can also be defined as spatial inequalities among populations. For example, individuals in a specific population may live on sites that are highly contaminated, whether as a result of natural contamination (e.g., high geochemical background in arsenic, uranium, cadmium, asbestos, or radon) or due to human activities (such as industrial waste or pesticide use). Exposures may also vary according to social inequalities. For example, higher levels of exposure to certain substances may occur in urban populations or populations with lower socioeconomic status, or levels of exposure may be equivalent between populations but the impact on health may be greater depending on the socioeconomic status of individuals within a population (Deguen et al., 2022).

Risk assessment must therefore consider temporal and geographic variability and the diversity of individuals in terms of their socioeconomic determinants. Our main recommendations for doing this are as follows: 1) Temporal, geographical, and socioeconomic modelling of exposures and new risk indicators should be proposed to reflect the variety of exposures occurring over an individual's lifetime, including periods of high sensitivity as well as geographical and social inequalities. These models are needed to produce and analyze individual exposure data on a spatial scale and a temporal scale; for example, the extent of the exposure may be monitored via sensor systems, and the fate of contamination in the environment over time could be predicted using newly developed spatial and dynamic multimedia models (Caudeville et al., 2012, 2021; Ciffroy et al., 2016; McKone, 1993); 2) Digital models and tools should be developed to help in the analysis of large combined data sets of spatial and temporal exposure factors; These models can be used to identify areas of highest concern and prioritize public action. A number of examples illustrate the use of geospatial and temporal data sets mostly in the field of air pollution (Hagedorn et al., 2025; Hu et al., 2025; Li et al., 2020, 2025; Schlüter et al., 2022b; Valipour Shokouhi

<footnote n="10">¹⁰ https://www.ukbiobank.ac.uk/.</footnote>

<footnote n="11">¹¹ https://allofus.nih.gov/.</footnote>
et al., 2024) 3) To address the health disparities among populations, the needs and specificities of different social groups should be considered in order to achieve precision medicine in which strategies are targeted to specific populations by geographic region, referred to as "geomedicine". This allows identification of territorial risk factors to implement prevention actions for particular social groups according to their vulnerabilities (Sandoval et al., 2018; Senier et al., 2017). Moreover, development of citizen-led participatory science focus groups oriented toward discussions of risk management strategies would boost the empowerment of concerned populations (Israel et al., 2010; Jeanjean et al., 2023).

### 3.7. Theme 7: exposome-based risk, benefit and health impact assessment: multiple factors

The exposome also describes the health effects of interactions between different types of factors, such as chemical, biological, or physical agents and psychosocial or socioeconomic factors. Many chemicals are immunostimulants or have a suppressive effect on the immune system, thereby interfering with the response to infections such as the viral infection associated with COVID-19 (Grandjean et al., 2020; Wu et al., 2021). The microbiome is one of several other determinants to play a role in the occurrence of a variety of diseases, particularly in the development of gastrointestinal cancer, as highlighted recently (Duijster et al., 2021). Moreover, research focused on the development and progression of COVID-19 revealed a link between both the chemical exposome and social exposome and severe forms of COVID-19 (Coker et al., 2020; Hu et al., 2021; Konstantinoudis et al., 2021). Several studies have indicated that an individual's socioeconomic situation can influence the level of exposure to chemicals as well as their impact on health (Tyrrell et al., 2013; Vidal et al., 2022). In one recent study it was noted that psychosocial stress had an effect on epigenetic markers (Cao-Lei et al., 2020). These findings may at least partially account for the long-term effects of the exposome, including the impact of the exposome across generations (Nilsson et al., 2018). In addition, interactions between chemical factors and physical factors, such as sunlight, heat, radiation, and noise, have been observed to affect both human health and eco-systems (Mokrzyński et al., 2021; Rider et al., 2014; Roberts et al., 2017; Zhao et al., 2013).

When proposing prevention and regulatory actions, it is essential to balance the nutritional benefits of food with potential risks from toxic substances through a comprehensive risk-benefit analysis. A well-known example is the need to integrate both risk and benefit estimates when developing dietary recommendations for fish consumption. While fish are an important source of omega-3 fatty acids, a nutrient considered beneficial to human health, consumers may also be exposed to methylmercury, a toxic chemical (Guevel et al., 2008; Sirot et al., 2011). Currently, as only nutritional aspects are taken into account, a reform of the health claims evaluation process for foods should be considered (EFSA Panel on Dietetic Products, 2021). This reform should jointly assess the health risks and benefits associated with multiple nutritional and contaminant components of the food or diet under evaluation (Makris and Chourdakis, 2024).

In addition, positive lifestyle habits -such as physical activity - and individual's surroundings, such as the presence of green spaces, may be more comprehensively integrated into the exposome framework and risk assessment when relevant.

Guidelines for quantifying the global burden of disease proposed by the WHO in 1994 (Murray, 1994) encompass measurement of the burden of diseases and risk factors on physical and psychosocial health in a comprehensive and generalizable manner. These guidelines allow investigators to compare harm from different types of exposure and help decision-makers set priorities for public health actions. Consideration of health impacts related to a variety of exposures can be coupled with an economic analysis of the associated costs, in order to measure the health costs and benefits of implementing or not implementing the various

options for risk management, and to assist decision-makers in their choices of management strategies (Nedellec et al., 2016; Ougier et al., 2021).

Our main recommendations is to develop exposome-based risk and impact assessment as follows: 1) Relevant interactions among multiple factors should be considered in risk assessment. Methods and procedures proposed by The (U.S. Environmental Protection Agency (EPA) 2025) offers methods and procedures for cumulative risk assessment planning and problem formulation that may provide a useful foundation.; 2) The social and economic factors should be taken into account as overarching determinants of exposures in risk assessment and management (Vineis Paolo, 2022; Vineis and Barouki, 2022); 3) Changes in exposure throughout an individual's lifetime and across generation should be better considered into risk assessment to identify key exposures to reduce during vulnerable periods such as early-life (Poore et al., 2017). In addition, key lifelong determinants with a positive impact—such as those contributing to healthy aging—should also be investigated (Mikkola et al., 2023); 4) Benefits and risks of certain behaviors and exposures should be weighed in a more comprehensive way in risk assessment and management; 5) Extending risk assessments with the use of burden-of-disease indicators and assessing the socioeconomic impacts of management options will help to prioritize public health actions to reduce or eliminate health risks (Plass et al., 2025; Wan et al., 2025).

### 3.6. Theme 6: establishment of reference values

To characterize the link between exposure to a chemical and the occurrence of an adverse effect, several types of reference values (RVs) based on health criteria have been established by reference bodies across Europe and internationally (including EFSA, WHO, US-EPA, ECHA, and ANSES). These RVs include reference dose/concentration (RfD/RfC), occupational exposure limit (OEL), biological limit value (BLV), indoor air quality guideline (IAQG), and drinking water guidance, among others. RVs are used to assess potential risks by comparing them with exposure levels, and to help choose management measures to protect the health of the general population as well as workers. They can also be used for developing health guidance values for drinking water and indoor air quality guidelines in households and workplaces.

RVs are specific to a substance, duration, and route, and apply to the entire study population (either the general population or workers). They are based on the concept of a critical effect, selected from among all of the relevant adverse effects, and are defined as the effect occurring at the lowest dose in the most sensitive population. When justified, it may be necessary to identify and account for the subpopulations with the greatest sensitivities, such as children or pregnant women, to establish the RV.

Our main recommendations for integrating the exposome in the establishment of RVs are as follows: 1) Strengthen the combination of different types of data: in silico, in vitro, in vivo, and epidemiological data to determine the level of evidence between exposure and effect (Colzin et al., 2024); 2) Develop RVs, and their establishment methods, to consider when relevant mixtures and the variety of exposure routes. Also establish RVs more on internal doses determined from measurement data obtained in biological matrices (Apel et al., 2023; Lamkarkach et al., 2021; Ougier et al., 2021). 3) A systematic approach should take into account sensitive populations (e.g., fetuses, children, or pregnant women) and when relevant include those populations who have, to date, not be considered (e.g., the elderly, patients with chronic diseases, overweight or obese individuals, people who are taking contraceptives, or individuals with infections) (Fernández-Martín and Tarazona, 2025). 4) The use of probabilistic approaches should be increased to incorporate uncertainty and inter- and intra-individual variability and to apply meta-analyses to gather information from multiple studies (EFSA Scientific Committee et al., 2017; Lu et al., 2023; WHO/IPCS, 2018; Zurlinden, T.).
### 3.8. Theme 8: the eco-exposome

In addition to the assessment of risks to human health, the assessment of ecological risks requires an exhaustive vision of the degradation of the natural environment of animals and plants through exposure to multiple chemicals and physical and biological stressors. The concept of the eco-exposome was first introduced as part of a report on exposure science from the National Research Council in 2012 (National Research Council, 2012). They extended the concept of the exposome by defining the eco-exposome as "the extension of exposure science from the point of contact between stressor and receptor inward into the organism and outward to the general environment, including the ecosphere." In 2017, Escher et al. (2017) extended the concept of the exposome to the exposure of ecosystems with inclusion of ecological issues. Consequently, the eco-exposome is likely to become one of the building blocks of risk assessment, both of human health and of ecosystems, making it possible to relate complex external exposure scenarios (Escher et al., 2017; Hines et al., 2019) and toxicological effects via an AOP approach. Indeed, in recent studies using analytical and molecular techniques, the effects of multiple stressors were investigated in many animal and plant species, allowing integration of interactions between species, including humans. These studies offered broad perspectives for a better understanding of the dynamics of the eco-exposome (Escher et al., 2017; Gao, 2021).

However, the incorporation of the eco-exposome concept into environmental risk assessments requires that several challenges be addressed with the development of new tools and new evaluation methodologies; our main recommendations are as follows: 1) In particular, molecular and analytical platforms should be developed to study the eco-exposome. Such platforms should be capable to develop advanced and harmonized methods based on non-targeted and targeted analyses for environmental matrices as proposed in Norman Network<fnref n="12" />; 2) In terms of new methodologies, an interdisciplinary systemic approach should be developed to assess the pressures and impacts of exposures on environmental quality and the functioning of ecosystems. This systemic approach will enable to account for interactions between multiple stressors such as interactions between microplastics, pharmaceuticals and personal care products (Atugoda et al., 2021), chemicals such as metals and PAHs in the aquatic environment (Gauthier et al., 2014), or chemical and biological agents (Bailey et al., 2018; Billet et al., 2021; Haas et al., 2018; Schlüter et al., 2022b). 3) Similar to risk assessments in human health, risk assessments should account for the vulnerability of animal or plant populations in realistic exposure scenarios (e.g., accounting for duration of exposure time or specific geographical environment of exposure) (De Lange et al., 2010), which would allow the development of values considered acceptable in environmental matrices that are truly protective of organisms and the functioning of ecosystems; 4) Research involving assessment of the eco-exposome should focus on the consequences of adaptation of animals, plants, and microorganisms to anthropogenic pressures, including factors associated with climate change, which has been designated a necessary aspect in the One Health vision (Cunningham et al., 2017; Gibbs, 2014). The One Health concept has proposed an integrated and unifying approach to sustainably balance and optimize the health of people, animals, and ecosystems.

## 4. Strategy to integrate the exposome into health risk assessment

### 4.1. A progressive introduction into health risk assessment

Because of the complexity of the exposome, we recommend the gradual integration of the exposome by risk assessors into the various stages of health risk assessment (HRA). To support this process, we have

identified and prioritized key components of the exposome based on the 8 themes discussed in previous section and developed in Fig. 3. These components can be introduced in HRA, in order of priority (Fig. 4): 1) the multiple sources and routes of exposure; 2) the exposure to mixtures; 3) the multiple factors (e.g., chemical, biological, organizational, physical, and psychological factors) and risk benefit assessment; 4) the temporal dimension of the exposures; 5) socioeconomic factors 6) geographical aspects; and 7) the eco-exposome.

This order of priority can be adapted to the factor(s), the health outcome(s) and the associated question(s) under consideration in the expert appraisal work carried out by health and safety agencies or other expert groups. Thus, the components of the exposome that should be considered in an expert appraisal can be selected and defined during the 3 steps of the planning phase. These steps include 1) the context of the formal request; 2) the question being asked and if necessary, its reformulation; and 3) the data, methods, and tools used. We propose that, during this planning phase, a questioning step should be added to discuss the relevance of using an exposome approach to address the question being asked. A decision tree (as shown in Fig. 5) can be used in the planning phase, in order to review the different components that can be introduced according to the subject of the formal request, the available data and methods, and the associated timetable. Criteria or thresholds can be used to decide to include or exclude an exposome component into the expert appraisal. For example: exposure from multiple sources must be considered only if the other sources contribute to at least 10 % of the total exposure (U.S. Environmental Protection Agency (EPA) 2001). The information on source contribution can come from previous literature, expert elicitation or can be calculated using a deterministic approach. The inclusion of other factors in the HRA must be driven by the health effect(s) or disease(s) under consideration, etc.

### 4.2. Key practical recommendations for integrating exposome in health agency activities

In addition to scientific considerations, the decision to include or exclude an exposome component also depends on the capacity of health agencies to address the exposome. Several aspects must be taken into account, including organizational structure, available human and technical resources, and the level of expertise among agency staff. Here, we present 5 key practical recommendations that would enable health agencies to successfully take the exposome into account in their expert appraisal work and more generally in their activities.

### 4.3. Organize cross-functional links between entities

We recommend setting up a cross-functional activity devoted to the exposome, in order to strengthen collaboration between the various units/departments or agencies commonly organized by exposure source (e.g., food, water, or air) or by agent type (e.g., physical or chemical). In accordance with the steps in the decision tree (Fig. 5), this cross-functional activity should systematically question the introduction of the exposome components and organize a cross-functional approach to address the formal request.

### 4.4. Acculturate staff and expert committee members

Strengthening the way in which the exposome is considered in an agency's activities requires a phase of acculturation of staff as well as expert committees and working groups. To achieve this, agencies could offer presentations, specific training programs, and workshops. Involvement of agencies' staff in research projects related to the exposome is also recommended, in order to contribute to staff training. Furthermore, members of expert committee panels could receive training in new skills, particularly in ecology, ecotoxicology, artificial intelligence, spatial modelling, and social sciences, which would enable these components to be better integrated.

<footnote n="12">¹² WELCOME TO THE NORMAN NETWORK | NORMAN.</footnote>
<figure><img src="image_7.png" /><figcaption>Fig. 4. Gradual integration of exposome components into various stages of health risk assessment (HRA), in order of priority.</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>Fig. 5. Decision tree to be used in the planning phase of the expert appraisal. HRA: health risk assessment.</figcaption></figure>

4.5. Organize, make available, and analyze data

We recommend that the data produced and managed by agencies be organized, communicated, and provided in accordance with the FAIR principles. We encourage the standardization of data as well as methods and tools for their collection and storage, among European organizations at both national and international levels through dedicated projects such as European Food Information Resource (EuroFIR) (Bell et al., 2012), Common Open Data Platform on Chemicals (European

Commission and Directorate-General for European Health Data Space (EHDS), Green Data for Health (GreenData4All), and Risk Assessment modelling and Knowledge Integration Platform (RAKIP) (Plaza-Rodríguez et al., 2018). Sustainable data management must be implemented to minimize the environmental footprint of computing centers. Introduction of human resources with expertise in IT, data management, and data science will help the scientists who produce and use the data to streamline access to and use of these data.
## 4.6. Develop operational methods and tools

Taking the exposome into account generates additional costs in terms of the amount of time it takes to respond to formal requests and the human resources required, which can be offset by development of user-friendly operational tools, including software. We recommend developing expertise in the use of existing software and strengthening the development of operational tools within and between the agencies.

## 4.7. Consolidate collaboration and partnerships

To achieve the objective of integrating the exposome and eco-
exposome into their activities, agencies will need to rely on special-
ized research teams at the European level and at both national and in-
ternational levels. The agencies should continue to strengthen their
collaborations through synergistic partnerships, create common data
platforms, develop scientific and laboratory networks, and participate in
national-, EU-, and international-level projects related to the exposome
(e.g., Environmental Exposure Assessment Research Infrastructure
(EIREINE), European Human Exposome Network (EHEN), and Interna-
tional Human Exposome Network (IHEN). For example, the participa-
tion of ANSES to the IHEN project made it possible to develop specific
actions related to the integration of the exposome into risk assessment
into the developed exposome roadmap.

# 5. Conclusion

Consideration of the exposome in risk assessment is still relatively
unstructured. As the exposome is systemic in nature, it is made up of
different components that can be studied by a variety of disciplines and
using a wide range of approaches and techniques, some but not all of
which are already used in risk assessment. Our objective with this
commentary was to identify the data, methods, and tools needed to
address the challenges of the exposome and to recommend the best
strategies to put into practice. Our recommendations ultimately involve
proposing a more comprehensive risk assessment approach, which
considers the reality of exposures in terms of the diversity of exposure
factors and sources in a specific social and environmental context, and
which integrates inter-individual and intra-individual variability over
an individual's lifetime.

The resulting recommendations are intended to strengthen and
structure the process for integration of the exposome into the agencies'
different activities, in order to address the challenges of the One Health
approach and tomorrow's societal issues through a comprehensive sci-
entific approach to risk assessment. These recommendations are aimed
at all individuals with a role in the risk assessments conducted by health
and safety agencies (such as researchers, assessors, experts, and data
producers). They also apply to funding bodies and those who implement
policies related to risk assessments produced by regional to national and
European health agencies. Funding research that supports the trans-
lation of exposome knowledge into risk assessment and management
strategies should be prioritized.

The integration of the exposome into the agencies' activities is an
ambitious goal that needs to be carried out progressively and with the
support of adequate human and financial resources. This is a complex
challenge because deployment of the recommendations implies that
changes to the agencies' practices will need to be implemented, and that
their teams and expert group members will need targeted training to
attain new skills and change their cultural perceptions. Suitable methods
and tools must be further developed to ensure that the integration of the
exposome into risk assessment becomes fully operational. Development
work also need to be integrated upstream, from the beginning of the
exchanges with the parties commissioning the expert appraisal—such as
ministries and authorized stakeholders—and in the early phases of
reformulating the questions and planning how the formal request will be
addressed. In the agencies' other core activities, incorporating the

exposome concept into their research, reference, monitoring, and vigilance work should be accompanied by the systematic application of the FAIR principles to optimize the management, organization, collection, and analysis of data generated or used by the agencies.

This effort of providing broader exposome input in risk assessment is already under way, led by several initiatives in Europe and the United States such as the European One Health framework for infectious diseases, the international One Health Joint Plan of Action (OH JPA), EHEN, EIRENE, the European Partnership for the Assessment of Risks from Chemicals (PARC) (Marx-Stoelting et al., 2023), the Human Exposome Map, the All of Us Research Program, the European chemical strategy for sustainability, and the "one substance, one assessment" package from the European Chemicals Agency (ECHA), the European Food Safety Authority (EFSA), the European Environment Agency (EEA) and the European Medicines Agency (EMA) (Authority EFS et al., 2022). These initiatives should help contribute to the development of innovative analytical methods, a new generation of toxicology testing, and new integrated approaches to risk assessment in humans, animals, plants, and the environment, particularly taking into consideration the multi-source, multi-route, and multi-substance exposures over an individual's lifetime. If the data produced and managed by these initiatives are organized under the FAIR principles, it will provide essential information for integrating the exposome in the agencies' risk assessments.

In addition to risk assessment strategies, risk management paradigms will also need to be revised to integrate the exposome. This integration may also have an impact on the components (assessment/monitoring/management) of risk governance. One of the missions of health and safety agencies is to support the governing members by providing their expertise. Any changes resulting from the implementation of these recommendations may then be translated into public policies, as well as being incorporated into consumer behaviors and the practices of economic players such as industry and public administrations.

## CRediT authorship contribution statement

**Amélie Crépet:** Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Conceptualization. **Philippe Quénel:** Writing – review & editing, Writing – original draft, Validation, Methodology, Conceptualization. **Jeanne Garric:** Writing – review & editing, Writing – original draft, Validation, Methodology, Conceptualization. **Alain Kaufmann:** Writing – review & editing, Writing – original draft, Validation, Methodology, Conceptualization. **Jean-Marc Bonmatin:** Writing – review & editing, Writing – original draft, Validation, Methodology, Conceptualization. **Pascale Duché:** Writing – review & editing, Writing – original draft, Validation, Methodology, Conceptualization. **Aurélie Mathieu:** Writing – review & editing, Writing – original draft, Validation, Methodology. **Madeline Carsique:** Visualization, Project administration. **Julien Jean:** Writing – review & editing, Writing – original draft, Visualization, Methodology, Conceptualization. **Pascal Sanders:** Writing – review & editing, Writing – original draft, Validation, Methodology, Conceptualization. **Jean-Pierre Cravedi:** Writing – review & editing, Writing – original draft, Validation, Methodology, Conceptualization. **Matthieu Schuler:** Writing – review & editing, Writing – original draft, Validation, Supervision, Project administration, Methodology, Conceptualization. **Robert Barouki:** Writing – review & editing, Writing – original draft, Validation, Supervision, Methodology, Conceptualization.

## Declaration of competing interest

The authors declare the following financial interests/personal re-
lationships which may be considered as potential competing interests:
Amelie Crepet reports administrative support was provided by National
Agency for Food Environmental and Occupational Health and Safety. If
there are other authors, they declare that they have no known
competing financial interests or personal relationships that could have
appeared to influence the work reported in this paper.

## Data availability

No data was used for the research described in the article.

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