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In the last 10 years, good evidence has become available to show that the combined effects of endocrine disruptors (EDs) belonging to the same category (e.g., estrogenic, antiandrogenic, or thyroid-disrupting agents) can be predicted by using dose addition. This is true for a variety of end points representing a wide range of organizational levels and biological complexity. Combinations of EDs are able to produce significant effect, even when each chemical is present at low doses that individually do not induce observable effects. However, comparatively little is known about mixtures composed of chemicals from different classes of EDs. Nevertheless, I argue that the accumulated evidence seriously undermines continuation with the customary chemical-by-chemical approach to risk assessment for EDs. Instead, we should seriously consider group-wise regulation of classes of EDs. Great care should be taken to define such classes by using suitable similarity criteria. Criteria should focus on common effects, rather than common mechanisms. In this review I also highlight research needs and identify the lack of information about exposure scenarios as a knowledge gap that seriously hampers progress with ED risk assessment. Future research should focus on investigating the effects of combinations of EDs from different categories, with considerable emphasis on elucidating mechanisms. This strategy may lead to better-defined criteria for grouping EDs for regulatory purposes. Also, steps should be taken to develop dedicated mixtures exposure assessment for EDs.

Distinguishing chemical mixtures in terms of the similarity vs. dissimilarity of their components' mechanisms or modes of action (MOAs) is perceived as a key issue in mixture risk assessment. However, the well-designed study by Vander Ven et al. of a mixture of chemicals producing craniofacial malformations in zebrafish embryos calls the relevance of such distinctions into question. The theoretical importance of separating similar and dissimilar actions derives from the assumptions that underpin dose addition and independent action, the two concepts typically applied to predicting effects of a mixture. Dose addition, a model developed by Loewe and Muischneck , views chemicals that produce the same effects (i.e., similar action) as dilutions of each other. Independent action was conceived by Bliss to address irreversible events, such as mortality, where probabilistic principles apply. With simultaneous exposures to multiple chemicals, these principles are only valid when the constituent chemicals interact with different molecular targets by different mechanisms (i.e., dissimilar action).

To support a mixture risk assessment with a focus on developmental neurotoxicity we evaluated the strength of evidence for associations of cadmium exposures with declines in IQ by conducting a systematic review and confidence rating. We searched peer-reviewed studies published in English between 2012 and July 2021 and identified 15 eligible studies (11 prospective cohort studies, and 4 cross-sectional studies). Of the 10 studies that observed associations of cadmium exposure with child IQ declines, two achieved an overall “High (H)” confidence rating, five a “Medium to High (M/H)”, one a “Medium (M)” and two a “Low (L)” confidence rating. Five studies did not detect significant associations between cadmium exposure and reduced cognitive ability; of these, two received a “High (H)” confidence rating, two an overall rating of “Medium to High (M/H)” and one a “Medium (M)” rating. The null findings reported by the “High (H)” and Medium to High (M/H)” studies could partly be explained by low exposures to cadmium or confounding with high levels of lead. By using a one-compartment toxicokinetic model in a reverse dosimetry approach, we estimated that a daily intake of 0.2 μg/kg body weight/day corresponds to urinary cadmium levels no longer associated with cognitive declines observed in a “High (H)”-confidence study. This estimate is 1.8-fold lower than the current health-based guidance value (HBGV) for kidney toxicity of 0.36 μg/kg bodyweight/day established by the European Food Safety Authority (EFSA). Our value does not have the normative character associated with health-based guidance values and is intended only as a reasonable estimate for the purpose of mixture risk assessments. However, with cadmium exposures in Europe between 0.28 (middle bound) and up to 0.52 μg/kg bodyweight/day (95 th percentile), our review suggests that pregnant women and children are poorly protected against neurodevelopmental effects. This warrants a revision of the current HBGV.

Background Mixture risk assessments require reference doses for common health endpoints of all the chemicals to be considered together. In support of a mixture risk assessment for male reproductive health, we conducted a systematic review of the literature on associations between exposures to Polychlorinated Biphenyls (PCBs) and declines in semen quality. PCBs can act as Aryl-hydrocarbon Receptor (AhR)-agonists and Androgen Receptor (AR)-antagonists, both mechanisms which can affect sperm parameters. PCBs and other AR-antagonists can produce additive combination effects. Based on these observations our objective was to systematically gather data from animal and human studies to derive a reference dose for declines in semen quality for individual PCB. Methods We systematically reviewed and evaluated the evidence in human epidemiological and experimental animal studies on associations between PCBs and deteriorations in semen quality. Human data and findings from animal studies with PCB mixtures were considered as supporting evidence. Information for individual congeners from animal studies was required for inclusion in mixture risk assessment. Using a robust confidence rating approach, we identified suitable studies to derive reference doses for individual PCB congeners. Results Evaluation of human epidemiological studies revealed several reports of adverse effects on sperm parameters linked to PCB exposures, although some studies reported improved semen quality. Our review of experimental animal studies found that treatments with PCBs affected semen quality, in most cases adversely. We found robust evidence that PCB-118 and -169 were linked to declines in semen quality. Evidence for adverse effects of PCB-126, -132, -149, and -153 was moderate, whereas for PCB-77 it was slight and for PCB-180 indeterminate. Using widely accepted risk assessment procedures, we estimated reference dose values of 0.0029 µg/kg/day for PCB-118 and 0.00533 µg/kg/day for PCB-169. In addition, we derived values for PCB-126: 0.000073 µg/kg/day, PCB-132: 0.0228 µg/kg/day, PCB-149: 0.656 µg/kg/day, and PCB-153: 0.0058 µg/kg/day. Conclusions We found robust evidence for links between PCB exposure and deteriorations in semen quality, and derived reference doses for a set of congeners. We intend to use these values in combination with congener-specific exposure data in a mixture risk assessment for declines in semen quality, involving several other antiandrogenic chemicals.

Endocrine-disrupting chemicals (EDCs) are exogenous chemicals that interfere with hormone action, thereby increasing the risk of adverse health outcomes, including cancer, reproductive impairment, cognitive deficits and obesity. A complex literature of mechanistic studies provides evidence on the hazards of EDC exposure, yet there is no widely accepted systematic method to integrate these data to help identify EDC hazards. Inspired by work to improve hazard identification of carcinogens using key characteristics (KCs), we have developed ten KCs of EDCs based on our knowledge of hormone actions and EDC effects. In this Expert Consensus Statement, we describe the logic by which these KCs are identified and the assays that could be used to assess several of these KCs. We reflect on how these ten KCs can be used to identify, organize and utilize mechanistic data when evaluating chemicals as EDCs, and we use diethylstilbestrol, bisphenol A and perchlorate as examples to illustrate this approach.

A severe decline in child births has occurred over the past half century, which will lead to considerable population declines, particularly in industrialized regions. A crucial question is whether this decline can be explained by economic and behavioural factors alone, as suggested by demographic reports, or to what degree biological factors are also involved. Here, we discuss data suggesting that human reproductive health is deteriorating in industrialized regions. Widespread infertility and the need for assisted reproduction due to poor semen quality and/or oocyte failure are now major health issues. Other indicators of declining reproductive health include a worldwide increasing incidence in testicular cancer among young men and alterations in twinning frequency. There is also evidence of a parallel decline in rates of legal abortions, revealing a deterioration in total conception rates. Subtle alterations in fertility rates were already visible around 1900, and most industrialized regions now have rates below levels required to sustain their populations. We hypothesize that these reproductive health problems are partially linked to increasing human exposures to chemicals originating directly or indirectly from fossil fuels. If the current infertility epidemic is indeed linked to such exposures, decisive regulatory action underpinned by unconventional, interdisciplinary research collaborations will be needed to reverse the trends.This article discusses trends in human reproductive behaviour and health that are associated with infertility. These changes have occurred over a period of only a couple of generations, so environmental factors are suggested to have a role.

In 2002, the joint International Programme on Chemical Safety (IPCS) of the World Health Organization (WHO), the United Nations Environment Programme (UNEP), and the International Labour Organisation (ILO) published a report titled Global Assessment of the State-of-the-Science of Endocrine Disruptors (http://www.who.int/ipcs/publications/new_issues/endocrine_disruptors/en/). Since 2002, intense scientific work has improved our understanding of the impacts of endocrine-disrupting chemicals (EDCs) on human and wildlife health, such that in 2012, the UNEP and WHO, in collaboration with international experts, have produced an updated document on EDCs, State of the Science of Endocrine Disrupting Chemicals - 2012 (http://www.who.int/ceh/publications/endocrine/en/index.html) that includes scientific information on human and wildlife impacts and lists key concerns for decision makers and others concerned about the future of human and wildlife health.

Regulatory systems must better provide for risks from exposure to multiple chemicals Humans and wildlife are continuously exposed to multiple chemicals from different sources and via different routes, both simultaneously and in sequence. Scientific evidence for heightened toxicity from such mixtures is mounting, yet regulation is lagging behind. Ensuring appropriate regulation of chemical mixture risks will require stronger legal stimuli as well as close integration of different parts of the regulatory systems in order to meet the data and testing requirements for mixture risk assessment.

Dose addition, a commonly used concept in toxicology for the prediction of chemical mixture effects, cannot readily be applied to mixtures of partial agonists with differing maximal effects. Due to its mathematical features, effect levels that exceed the maximal effect of the least efficacious compound present in the mixture, cannot be calculated. This poses problems when dealing with mixtures likely to be encountered in realistic assessment situations where chemicals often show differing maximal effects. To overcome this limitation, we developed a pragmatic solution that extrapolates the toxic units of partial agonists to effect levels beyond their maximal efficacy. We extrapolated different additivity expectations that reflect theoretically possible extremes and validated this approach with a mixture of 21 estrogenic chemicals in the E-Screen. This assay measures the proliferation of human epithelial breast cancers. We found that the dose-response curves of the estrogenic agents exhibited widely varying shapes, slopes and maximal effects, which made it necessary to extrapolate mixture responses above 14% proliferation. Our toxic unit extrapolation approach predicted all mixture responses accurately. It extends the applicability of dose addition to combinations of agents with differing saturating effects and removes an important bottleneck that has severely hampered the use of dose addition in the past.

This Guidance document describes harmonised risk assessment methodologies for combined exposure to multiple chemicals for all relevant areas within EFSA's remit, i.e. human health, animal health and ecological areas. First, a short review of the key terms, scientific basis for combined exposure risk assessment and approaches to assessing (eco)toxicology is given, including existing frameworks for these risk assessments. This background was evaluated, resulting in a harmonised framework for risk assessment of combined exposure to multiple chemicals. The framework is based on the risk assessment steps (problem formulation, exposure assessment, hazard identification and characterisation, and risk characterisation including uncertainty analysis), with tiered and stepwise approaches for both whole mixture approaches and component‐based approaches. Specific considerations are given to component‐based approaches including the grouping of chemicals into common assessment groups, the use of dose addition as a default assumption, approaches to integrate evidence of interactions and the refinement of assessment groups. Case studies are annexed in this guidance document to explore the feasibility and spectrum of applications of the proposed methods and approaches for human and animal health and ecological risk assessment. The Scientific Committee considers that this Guidance is fit for purpose for risk assessments of combined exposure to multiple chemicals and should be applied in all relevant areas of EFSA's work. Future work and research are recommended. This publication is linked to the following EFSA Supporting Publications article: http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2019.EN-1589/full, http://onlinelibrary.wiley.com/doi/10.2903/sp.efsa.2019.EN-1602/full