Systematic evidence on migrating and extractable food contact chemicals: Most chemicals detected in food contact materials are not listed for use.

Food packaging is important for today's globalized food system, but food contact materials (FCMs) can also be a source of hazardous chemicals migrating into foodstuffs. Assessing the impacts of FCMs on human health requires a comprehensive identification of the chemicals they contain, the food contact chemicals (FCCs). We systematically compiled the "database on migrating and extractable food contact chemicals" (FCCmigex) using information from 1210 studies. We found that to date 2881 FCCs have been detected, in a total of six FCM groups (Plastics, Paper & Board, Metal, Multi-materials, Glass & Ceramic, and Other FCMs). 65% of these detected FCCs were previously not known to be used in FCMs. Conversely, of the more than 12'000 FCCs known to be used, only 1013 are included in the FCCmigex database. Plastic is the most studied FCM with 1975 FCCs detected. Our findings expand the universe of known FCCs to 14,153 chemicals. This knowledge contributes to developing non-hazardous FCMs that lead to safer food and support a circular economy.

Impacts of food contact chemicals on human health: a consensus statement.

Food packaging is of high societal value because it conserves and protects food, makes food transportable and conveys information to consumers. It is also relevant for marketing, which is of economic significance. Other types of food contact articles, such as storage containers, processing equipment and filling lines, are also important for food production and food supply. Food contact articles are made up of one or multiple different food contact materials and consist of food contact chemicals. However, food contact chemicals transfer from all types of food contact materials and articles into food and, consequently, are taken up by humans. Here we highlight topics of concern based on scientific findings showing that food contact materials and articles are a relevant exposure pathway for known hazardous substances as well as for a plethora of toxicologically uncharacterized chemicals, both intentionally and non-intentionally added. We describe areas of certainty, like the fact that chemicals migrate from food contact articles into food, and uncertainty, for example unidentified chemicals migrating into food. Current safety assessment of food contact chemicals is ineffective at protecting human health. In addition, society is striving for waste reduction with a focus on food packaging. As a result, solutions are being developed toward reuse, recycling or alternative (non-plastic) materials. However, the critical aspect of chemical safety is often ignored. Developing solutions for improving the safety of food contact chemicals and for tackling the circular economy must include current scientific knowledge. This cannot be done in isolation but must include all relevant experts and stakeholders. Therefore, we provide an overview of areas of concern and related activities that will improve the safety of food contact articles and support a circular economy. Our aim is to initiate a broader discussion involving scientists with relevant expertise but not currently working on food contact materials, and decision makers and influencers addressing single-use food packaging due to environmental concerns. Ultimately, we aim to support science-based decision making in the interest of improving public health. Notably, reducing exposure to hazardous food contact chemicals contributes to the prevention of associated chronic diseases in the human population.

Removing Critical Gaps in Chemical Test Methods by Developing New Assays for the Identification of Thyroid Hormone System-Disrupting Chemicals-The ATHENA Project.

The test methods that currently exist for the identification of thyroid hormone system-disrupting chemicals are woefully inadequate. There are currently no internationally validated in vitro assays, and test methods that can capture the consequences of diminished or enhanced thyroid hormone action on the developing brain are missing entirely. These gaps put the public at risk and risk assessors in a difficult position. Decisions about the status of chemicals as thyroid hormone system disruptors currently are based on inadequate toxicity data. The ATHENA project (Assays for the identification of Thyroid Hormone axis-disrupting chemicals: Elaborating Novel Assessment strategies) has been conceived to address these gaps. The project will develop new test methods for the disruption of thyroid hormone transport across biological barriers such as the blood-brain and blood-placenta barriers. It will also devise methods for the disruption of the downstream effects on the brain. ATHENA will deliver a testing strategy based on those elements of the thyroid hormone system that, when disrupted, could have the greatest impact on diminished or enhanced thyroid hormone action and therefore should be targeted through effective testing. To further enhance the impact of the ATHENA test method developments, the project will develop concepts for better international collaboration and development in the area of thyroid hormone system disruptor identification and regulation.

A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals.

BACKGROUND: The issue of endocrine disrupting chemicals (EDCs) is receiving wide attention from both the scientific and regulatory communities. Recent analyses of the EDC literature have been criticized for failing to use transparent and objective approaches to draw conclusions about the strength of evidence linking EDC exposures to adverse health or environmental outcomes. Systematic review methodologies are ideal for addressing this issue as they provide transparent and consistent approaches to study selection and evaluation. Objective methods are needed for integrating the multiple streams of evidence (epidemiology, wildlife, laboratory animal, in vitro, and in silico data) that are relevant in assessing EDCs. METHODS: We have developed a framework for the systematic review and integrated assessment (SYRINA) of EDC studies. The framework was designed for use with the International Program on Chemical Safety (IPCS) and World Health Organization (WHO) definition of an EDC, which requires appraisal of evidence regarding 1) association between exposure and an adverse effect, 2) association between exposure and endocrine disrupting activity, and 3) a plausible link between the adverse effect and the endocrine disrupting activity. RESULTS: Building from existing methodologies for evaluating and synthesizing evidence, the SYRINA framework includes seven steps: 1) Formulate the problem; 2) Develop the review protocol; 3) Identify relevant evidence; 4) Evaluate evidence from individual studies; 5) Summarize and evaluate each stream of evidence; 6) Integrate evidence across all streams; 7) Draw conclusions, make recommendations, and evaluate uncertainties. The proposed method is tailored to the IPCS/WHO definition of an EDC but offers flexibility for use in the context of other definitions of EDCs. CONCLUSIONS: When using the SYRINA framework, the overall objective is to provide the evidence base needed to support decision making, including any action to avoid/minimise potential adverse effects of exposures. This framework allows for the evaluation and synthesis of evidence from multiple evidence streams. Finally, a decision regarding regulatory action is not only dependent on the strength of evidence, but also the consequences of action/inaction, e.g. limited or weak evidence may be sufficient to justify action if consequences are serious or irreversible.

Fishing plastic waste: Knowns and known unknowns.

Plastics entering the marine environment primarily originate from land-based sources, prompting significant attention on single-use plastic packaging. However, fishing plastic waste also contributes substantially to marine plastic pollution, though it is often overlooked in the literature due to the challenges in pinpointing pollution sources. This study addresses this key knowledge gap by synthesizing existing literature to explore and document the knowns and known unknowns surrounding fishing plastic waste's environmental, health, and socio-economic impacts. Through the development of a causal loop diagram, the study offers a preliminary understanding of the issue, serving as a foundation for a deeper exploration of the complexities within the fishing industry's plastic waste dynamics. Finally, the study highlights that short-sighted views and approaches are likely to lead to systemic failures. Therefore, it advocates for strategic and meaningful measures to tackle marine plastic pollution, emphasizing the critical importance of a holistic and integrated understanding of the various plastic waste streams infiltrating and polluting our oceans.

Dispelling urban myths about default uncertainty factors in chemical risk assessment--sufficient protection against mixture effects?

Assessing the detrimental health effects of chemicals requires the extrapolation of experimental data in animals to human populations. This is achieved by applying a default uncertainty factor of 100 to doses not found to be associated with observable effects in laboratory animals. It is commonly assumed that the toxicokinetic and toxicodynamic sub-components of this default uncertainty factor represent worst-case scenarios and that the multiplication of those components yields conservative estimates of safe levels for humans. It is sometimes claimed that this conservatism also offers adequate protection from mixture effects. By analysing the evolution of uncertainty factors from a historical perspective, we expose that the default factor and its sub-components are intended to represent adequate rather than worst-case scenarios. The intention of using assessment factors for mixture effects was abandoned thirty years ago. It is also often ignored that the conservatism (or otherwise) of uncertainty factors can only be considered in relation to a defined level of protection. A protection equivalent to an effect magnitude of 0.001-0.0001% over background incidence is generally considered acceptable. However, it is impossible to say whether this level of protection is in fact realised with the tolerable doses that are derived by employing uncertainty factors. Accordingly, it is difficult to assess whether uncertainty factors overestimate or underestimate the sensitivity differences in human populations. It is also often not appreciated that the outcome of probabilistic approaches to the multiplication of sub-factors is dependent on the choice of probability distributions. Therefore, the idea that default uncertainty factors are overly conservative worst-case scenarios which can account both for the lack of statistical power in animal experiments and protect against potential mixture effects is ill-founded. We contend that precautionary regulation should provide an incentive to generate better data and recommend adopting a pragmatic, but scientifically better founded approach to mixture risk assessment.

Science and policy on endocrine disrupters must not be mixed: a reply to a "common sense" intervention by toxicology journal editors.

The "common sense" intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU.

Unpacking the complexity of the polyethylene food contact articles value chain: A chemicals perspective.

Polyethylene (PE) is the most widely used type of plastic food packaging, in which chemicals can potentially migrate into packaged foods. The implications of using and recycling PE from a chemical perspective remain underexplored. This study is a systematic evidence map of 116 studies looking at the migration of food contact chemicals (FCCs) across the lifecycle of PE food packaging. It identified a total of 377 FCCs, of which 211 were detected to migrate from PE articles into food or food simulants at least once. These 211 FCCs were checked against the inventory FCCs databases and EU regulatory lists. Only 25% of the detected FCCs are authorized by EU regulation for the manufacture of food contact materials. Furthermore, a quarter of authorized FCCs exceeded the specific migration limit (SML) at least once, while one-third (53) of non-authorised FCCs exceeded the threshold value of 10 µg/kg. Overall, evidence on FCCs migration across the PE food packaging lifecycle is incomplete, especially at the reprocessing stage. Considering the EU's commitment to increase packaging recycling, a better understanding and monitoring of PE food packaging quality from a chemical perspective across the entire lifecycle will enable the transition towards a sustainable plastics value chain.

A new consensus on reconciling fire safety with environmental & health impacts of chemical flame retardants.

Flame retardants are chemical substances that are intended to mitigate fire safety risks posed by a range of goods including furniture, electronics, and building insulation. There are growing concerns about their effectiveness in ensuring fire safety and the potential harms they pose to human health and the environment. In response to these concerns, on 13 June 2022, a roundtable of experts was convened by the UKRI Six Clean Air Strategic Priorities Fund programme 7. The meeting produced a Consensus Statement that summarises the issues around the use of flame retardants, laying out a series of policy recommendations that should lead to more effective fire safety measures and reduce the human and environmental health risks posed by these potentially toxic chemicals.

A vision for safer food contact materials: Public health concerns as drivers for improved testing.

Food contact materials (FCMs) and food contact articles are ubiquitous in today's globalized food system. Chemicals migrate from FCMs into foodstuffs, so called food contact chemicals (FCCs), but current regulatory requirements do not sufficiently protect public health from hazardous FCCs because only individual substances used to make FCMs are tested and mostly only for genotoxicity while endocrine disruption and other hazard properties are disregarded. Indeed, FCMs are a known source of a wide range of hazardous chemicals, and they likely contribute to highly prevalent non-communicable diseases. FCMs can also include non-intentionally added substances (NIAS), which often are unknown and therefore not subject to risk assessment. To address these important shortcomings, we outline how the safety of FCMs may be improved by (1) testing the overall migrate, including (unknown) NIAS, of finished food contact articles, and (2) expanding toxicological testing beyond genotoxicity to multiple endpoints associated with non-communicable diseases relevant to human health. To identify mechanistic endpoints for testing, we group chronic health outcomes associated with chemical exposure into Six Clusters of Disease (SCOD) and we propose that finished food contact articles should be tested for their impacts on these SCOD. Research should focus on developing robust, relevant, and sensitive in-vitro assays based on mechanistic information linked to the SCOD, e.g., through Adverse Outcome Pathways (AOPs) or Key Characteristics of Toxicants. Implementing this vision will improve prevention of chronic diseases that are associated with hazardous chemical exposures, including from FCMs.

Bisphenol A and declining semen quality: A systematic review to support the derivation of a reference dose for mixture risk assessments.

To support a mixture risk assessment with a focus on male reproductive health, we conducted a systematic review of associations between bisphenol A (BPA) exposures and declines in semen quality, based on animal and epidemiological studies. Contrary to a widely held view that there is "conflicting" evidence of such associations, our review and confidence rating approach reveals that animal studies provide convincing evidence of declines of semen quality after gestational BPA exposures. Many of the reported negative findings can be attributed to deficiencies in study sensitivity, insufficient control of background contamination and probable confounding through hormonal interference due to the use of soy-containing diets. We did not evaluate animal studies of adult BPA exposures. Divergent findings in "medium to high" and "medium" confidence epidemiological studies can be explained in terms of differences in exposure conditions. We attempted the estimation of a BPA reference dose based on animal studies. Due to variations in the no-observed adverse effect levels (NOAELs) in high confidence studies, possible reference doses ranged from 0.0001 to 0.0099 µg/kg/d. In choosing 0.003 µg/kg/d we struck a balance between caution suggested by studies at the lower end of the doses and the weight of evidence from studies with higher NOAELs. This weighting was motivated by the intended use of the value in a mixture risk assessment which meant arriving at a reasonable estimate of BPA exposures likely without effects on semen quality. We realise that our approach does not conform with the standards necessary for deriving tolerable daily intakes (TDIs) for single chemical exposures, which is not our interest here. BPA exposures currently experienced by European populations and beyond are in excess of 0.003 µg/kg/d and even fall in the range where some epidemiological studies observed effects on semen quality as a result of BPA exposures in adulthood.

Unpacking the complexity of the PET drink bottles value chain: A chemicals perspective.

Chemicals can migrate from polyethylene terephthalate (PET) drink bottles to their content and recycling processes may concentrate or introduce new chemicals to the PET value chain. Therefore, even though recycling PET bottles is key in reducing plastic pollution, it may raise concerns about safety and quality. This study provides a systematic evidence map of the food contact chemicals (FCCs) that migrate from PET drink bottles aiming to identify challenges in closing the plastic packaging loop. The migration potential of 193 FCCs has been investigated across the PET drink bottles lifecycle, of which 150 have been detected to migrate from PET bottles into food simulants/food samples. The study reveals that much research has focused on the migration of antimony (Sb), acetaldehyde and some well-known endocrine-disrupting chemicals (EDCs). It indicates and discusses the key influential factors on FCCs migration, such as physical characteristics and geographical origin of PET bottles, storage conditions, and reprocessing efficiency . Although, safety and quality implications arising from the recycling of PET bottles remain underexplored, the higher migration of Sb and Bishphenol A has been reported in recycled (rPET) compared to virgin PET. This is attributed to multiple contamination sources and the variability in the collection, sorting, and decontamination efficiency. Better collaboration among stakeholders across the entire PET bottles lifecycle is needed to ensure sustainable resource management and food contact safety of rPET.

Overview of intentionally used food contact chemicals and their hazards.

Food contact materials (FCMs) are used to make food contact articles (FCAs) that come into contact with food and beverages during, e.g., processing, storing, packaging, or consumption. FCMs/FCAs can cause chemical contamination of food when migration of their chemical constituents (known as food contact chemicals, FCCs) occurs. Some FCCs are known to be hazardous. However, the total extent of exposure to FCCs, as well as their health and environmental effects, remain unknown, because information on chemical structures, use patterns, migration potential, and health effects of FCCs is often absent or scattered across multiple sources. Therefore, we initiated a research project to systematically collect, analyze, and publicly share information on FCCs. As a first step, we compiled a database of intentionally added food contact chemicals (FCCdb), presented here. The FCCdb lists 12'285 substances that could possibly be used worldwide to make FCMs/FCAs, identified based on 67 FCC lists from publicly available sources, such as regulatory lists and industry inventories. We further explored FCCdb chemicals' hazards using several authoritative sources of hazard information, including (i) classifications for health and environmental hazards under the globally harmonized system for classification and labeling of chemicals (GHS), (ii) the identification of chemicals of concern due to endocrine disruption or persistence related hazards, and (iii) the inclusion on selected EU- or US-relevant regulatory lists of hazardous chemicals. This analysis prioritized 608 hazardous FCCs for further assessment and substitution in FCMs/FCAs. Evaluation based on non-authoritative, predictive hazard data (e.g., by in silico modeling or literature analysis) highlighted an additional 1411 FCCdb substances that could thus present similar levels of concern, but have not been officially classified so far. Lastly, for over a quarter of all FCCdb chemicals no hazard information could be found in the sources consulted, revealing a significant data gap and research need.

Ten years of research on synergisms and antagonisms in chemical mixtures: A systematic review and quantitative reappraisal of mixture studies.

BACKGROUND: Several reviews of synergisms and antagonisms in chemical mixtures have concluded that synergisms are relatively rare. However, these reviews focused on mixtures composed of specific groups of chemicals, such as pesticides or metals and on toxicity endpoints mostly relevant to ecotoxicology. Doubts remain whether these findings can be generalised. A systematic review not restricted to specific chemical mixtures and including mammalian and human toxicity endpoints is missing. OBJECTIVES: We conducted a systematic review and quantitative reappraisal of 10 years' of experimental mixture studies to investigate the frequency and reliability of evaluations of mixture effects as synergistic or antagonistic. Unlike previous reviews, we did not limit our efforts to certain groups of chemicals or specific toxicity outcomes and covered mixture studies relevant to ecotoxicology and human/mammalian toxicology published between 2007 and 2017. DATA SOURCES, ELIGIBILITY CRITERIA: We undertook searches for peer-reviewed articles in PubMed, Web of Science, Scopus, GreenFile, ScienceDirect and Toxline and included studies of controlled exposures of environmental chemical pollutants, defined as unintentional exposures leading to unintended effects. Studies with viruses, prions or therapeutic agents were excluded, as were records with missing details on chemicals' identities, toxicities, doses, or concentrations. STUDY APPRAISAL AND SYNTHESIS METHODS: To examine the internal validity of studies we developed a risk-of-bias tool tailored to mixture toxicology. For a subset of 388 entries that claimed synergisms or antagonisms, we conducted a quantitative reappraisal of authors' evaluations by deriving ratios of predicted and observed effective mixture doses (concentrations). RESULTS: Our searches produced an inventory of 1220 mixture experiments which we subjected to subgroup analyses. Approximately two thirds of studies did not incorporate more than 2 components. Most experiments relied on low-cost assays with readily quantifiable endpoints. Important toxicity outcomes of relevance for human risk assessment (e.g. carcinogenicity, genotoxicity, reproductive toxicity, immunotoxicity, neurotoxicity) were rarely addressed. The proportion of studies that declared additivity, synergism or antagonisms was approximately equal (one quarter each); the remaining quarter arrived at different evaluations. About half of the 1220 entries were rated as "definitely" or "probably" low risk of bias. Strikingly, relatively few claims of synergistic or antagonistic effects stood up to scrutiny in terms of deviations from expected additivity that exceed the boundaries of acceptable between-study variability. In most cases, the observed mixture doses were not more than two-fold higher or lower than the predicted additive doses. Twenty percent of the entries (N = 78) reported synergisms in excess of that degree of deviation. Our efforts of pinpointing specific factors that predispose to synergistic interactions confirmed previous concerns about the synergistic potential of combinations of triazine, azole and pyrethroid pesticides at environmentally relevant doses. New evidence of synergisms with endocrine disrupting chemicals and metal compounds such as chromium (VI) and nickel in combination with cadmium has emerged. CONCLUSIONS, LIMITATIONS AND IMPLICATIONS: These specific cases of synergisms apart, our results confirm the utility of default application of the dose (concentration) addition concept for predictive assessments of simultaneous exposures to multiple chemicals. However, this strategy must be complemented by an awareness of the synergistic potential of specific classes of chemicals. Our conclusions only apply to the chemical space captured in published mixture studies which is biased towards relatively well-researched chemicals. SYSTEMATIC REVIEW REGISTRATION NUMBER: The final protocol was published on the open-access repository Zenodo and attributed the following digital object identifier, doi: https://doi.org//10.5281/zenodo.1319759 (https://zenodo.org/record/1319759#.XXIzdy7dsqM).

Effects of music in exercise and sport: A meta-analytic review.

Regular physical activity has multifarious benefits for physical and mental health, and music has been found to exert positive effects on physical activity. Summative literature reviews and conceptual models have hypothesized potential benefits and salient mechanisms associated with music listening in exercise and sport contexts, although no large-scale objective summary of the literature has been conducted. A multilevel meta-analysis of 139 studies was used to quantify the effects of music listening in exercise and sport domains. In total, 598 effect sizes from four categories of potential benefits (i.e., psychological responses, physiological responses, psychophysical responses, and performance outcomes) were calculated based on 3,599 participants. Music was associated with significant beneficial effects on affective valence (g = 0.48, CI [0.39, 0.56]), physical performance (g = 0.31, CI [0.25, 0.36]), perceived exertion (g = 0.22, CI [0.14, 0.30]), and oxygen consumption (g = 0.15, CI [0.02, 0.27]). No significant benefit of music was found for heart rate (g = 0.07, CI [-0.03, 0.16]). Performance effects were moderated by study domain (exercise > sport) and music tempo (fast > slow-to-medium). Overall, results supported the use of music listening across a range of physical activities to promote more positive affective valence, enhance physical performance (i.e., ergogenic effect), reduce perceived exertion, and improve physiological efficiency. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

Recommendations for the conduct of systematic reviews in toxicology and environmental health research (COSTER).

BACKGROUND: There are several standards that offer explicit guidance on good practice in systematic reviews (SRs) for the medical sciences; however, no similarly comprehensive set of recommendations has been published for SRs that focus on human health risks posed by exposure to environmental challenges, chemical or otherwise. OBJECTIVES: To develop an expert, cross-sector consensus view on a key set of recommended practices for the planning and conduct of SRs in the environmental health sciences. METHODS: A draft set of recommendations was derived from two existing standards for SRs in biomedicine and developed in a consensus process, which engaged international participation from government, industry, non-government organisations, and academia. The consensus process consisted of a workshop, follow-up webinars, email discussion and bilateral phone calls. RESULTS: The Conduct of Systematic Reviews in Toxicology and Environmental Health Research (COSTER) recommendations cover 70 SR practices across eight performance domains. Detailed explanations for specific recommendations are made for those identified by the authors as either being novel to SR in general, specific to the environmental health SR context, or potentially controversial to environmental health SR stakeholders. DISCUSSION: COSTER provides a set of recommendations that should facilitate the production of credible, high-value SRs of environmental health evidence, and advance discussion of a number of controversial aspects of conduct of EH SRs. Key recommendations include the management of conflicts of interest, handling of grey literature, and protocol registration and publication. A process for advancing from COSTER's recommendations to developing a formal standard for EH SRs is also indicated.

Testicular dysgenesis syndrome and the estrogen hypothesis: a quantitative meta-analysis.

BACKGROUND: Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. OBJECTIVES: We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-alpha-mediated mode of action was specifically explored. RESULTS: We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. CONCLUSIONS: The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population.

Human health and endocrine disruption: a simple multicriteria framework for the qualitative assessment of end point specific risks in a context of scientific uncertainty.

Endocrine disruption remains one of the most controversial contemporary environmental issues. While the desired level of protection is ultimately a societal choice, endocrine toxicity could result in a wide spectrum of adverse health effects. Although the application of the causal framework of weight-of-evidence approaches to complex toxicological issues has incited much interest, no international criteria or guidance have yet been developed. In this context, the evidence on end point-specific risks to human health contained in the International Program on Chemical Safety Global assessment of the State-of-Science on Endocrine Disruptors report was updated and assessed qualitatively using three simple criteria relevant to the practical application of the precautionary principle (PP): incidence trends, association, and consequence. The current degree of knowledge was then ranked according to ignorance, uncertainty, and risk. The main sources of scientific uncertainty in relation to incidence trends were associated with the evolution of diagnostic criteria or diagnostic tests, while genetic susceptibility is often proposed as an explanation for the wide geographic variations in the incidence of some diseases. Such genetic polymorphisms are also offered as a potential explanation for some of the inconsistent findings or lack of clear dose-response gradients described under the association criterion. The methodology yielded a relative paucity of data addressing directly the impact for adverse human health effect from both individual and public health perspectives. Results are discussed within the context of the application of the PP. Within a participatory context, this simple framework could provide a useful decision-making tool to both communicate scientific uncertainty to the wider public and manage uncertain risks.