Synergistic effects of chemical mixtures: how frequent is rare?

Chemical pollution is characterised by sequential and simultaneous exposure to unintentional complex mixtures. The almost infinite number of real-life mixtures poses major challenges for investigations of all possible exposure scenarios through whole mixture or component-based approaches. As a pragmatic approach in data-poor situations, the application of a Mixture Assessment Factor to single substances assessments under REACH was announced in the European Chemicals Strategy for Sustainability. Current proposals for this factor are based on the assumption that mixtures behave additively, assuming that synergistic interactions are rare. This assumption is based on eight reviews published in the last 30 years. Synergistic deviations from additivity greater than 2-fold were reported in roughly 5% of investigated mixtures. This was more, rather than less, frequent in the handful of suitable studies of low dose mammalian mixture toxicity. This frequency is representative of mixtures toxicology studies in the literature and should not be interpreted as the frequency of synergisms in real world exposures. Understanding the frequency and likelihood of synergisms would entail detailed understanding of the co-occurrence of groups of substances giving rise to such interactions in relevant environmental media. Assumptions that synergistic interactions in real-life mixtures are rare appear to be premature. While further research is required, potential synergisms should not be omitted from debates on the conservatism or otherwise of mixture allocation factor or other regulatory approaches to protect people and environment from mixture effects

Drivers of divergent assessments of bisphenol-A hazards to semen quality by various European agencies, regulators and scientists

The downward revision of the bisphenol A (BPA) Health-based Guidance Value (HBGV) by the European Food Safety Authority (EFSA) has led to disagreements with other regulatory agencies, among them the German Federal Institute for Risk Assessment (BfR). The BfR has recently published an alternative Tolerable Daily Intake (TDI), 1000-times higher than the EFSA HBGV of 0.2 ng/kg/d. While the EFSA value is defined in relation to immunotoxicity, the BfR alternative TDI is based on declines in sperm counts resulting from exposures in adulthood. Earlier, we had used semen quality deteriorations to estimate a BPA Reference Dose (RfD) of 3 ng/kg/d for use in mixture risk assessments of male reproductive health. We derived this estimate from animal studies of gestational BPA exposures which both EFSA and BfR viewed as irrelevant for human hazard characterisations. Here, we identify factors that drive these diverging views. We find that the fragmented, endpoint-oriented study evaluation system used by EFSA and BfR, with its emphasis on data that can support dose-response analyses, has obscured the overall BPA effect pattern relevant to male reproductive effects. This has led to a disregard for the effects of gestational BPA exposures. We also identify problems with the study evaluation schemes used by EFSA and BfR which leads to the omission of entire streams of evidence from consideration. The main driver of the diverging views of EFSA and BfR is the refusal by BfR to accept immunotoxic effects as the basis for establishing an HBGV. We find that switching from immunotoxicity to declines in semen quality as the basis for deriving a BPA TDI by deterministic or probabilistic approaches produces values in the range of 2.4-6.6 ng/kg/d, closer to the present EFSA HBGV of 0.2 ng/kg/d than the BfR TDI of 200 ng/kg/d. The proposed alternative BfR value is the result of value judgements which erred on the side of disregarding evidence that could have supported a lower TDI. The choices made in terms of selecting key studies and methods for dose-response analyses produced a TDI that comes close to doses shown to produce effects on semen quality in animal studies and in human studies of adult BPA exposures

Defective spermatogenesis: Martin et al. respond

This is an Open Access article - Copyright @ National Institute of Environmental Health Science.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)-α–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

Development of an integrated sustainability matrix to depict challenges and trade-offs of introducing bio-based plastics in the food packaging value chain

© 2020 As global plastic pollution is gaining increased attention, the use of bio-based plastics, especially in the food packaging sector, is growing in popularity. While this move is regarded as a solution to plastic pollution, it may shift or create detrimental impacts elsewhere in the production, consumption, management system, a possibility that is underexplored. The aim of the present study is to identify the potential challenges and trade-offs associated with the introduction of bio-based plastics in the food packaging industry, and highlight issues relevant to policy and decision-making processes. We employ a whole system approach to review the literature and assess holistically the performance of bio-based plastics, which looks at the entire lifecycle of bio-based plastic packaging (i.e. production, consumption, management) and considers wider aspects in the environmental, economic, social and technical sustainability domains. Based on our findings, we developed, and present herein, a sustainability decision matrix, a novel guiding tool, which can provide important insights into the potential impacts of the introduction of larger amount of bio-based plastic food packaging in the future and support decision-making processes. In conclusion, our preliminary high-level assessment of the bio-based plastics production, use and management system clearly reveals a number of blind-spots across the entire system that are currently ignored by the use of single-dimensional approaches. This highlights that the sustainability assessment of specific bio-based polymers requires thorough and further research that takes into account the type of feedstock, infrastructure availability, and interactions between sustainability domains, to ensure that the substitution of petrochemical-based plastics with bio-based alternatives in food packaging sector will not lead to unintended consequences

'A moment of science please' activism, community and humour at the March for Science

In April 2017, scientists and science sympathizers held marches in the United Kingdom as part of a coordinated international March for Science movement that was held in over 600 cities worldwide. This article reports from participant-observation studies of the marches that took place in London and Cardiff. Supplemented with data from 37 interviews from marchers at the London event, the article reports on an analysis of the placards, focusing on marchers’ concerns and the language and images through which they expressed those concerns. How did the protesters articulate their concerns and objectives, and how were these articulations used to build a community? The placards did not represent a clear, focused, and unifying message; they instead illustrated disparate concerns ranging from human-induced climate change, Trump and “alternative facts,” and local UK specific political issues concerning the country’s exit from the European Union. Our analysis shows that placards gave a playful and whimsical character to the march, with slogans displaying significant amounts (and moments) of humor, often formulated through insider jokes, scientific puns, or self-deprecating appropriation of negative stereotypes about scientists. We analyze the march through the social movement literature and as a collective identity-building exercise for an (emergent) community of scientists and sympathizers with long-term aims of establishing a louder voice for scientists, and experts, in public discourse

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

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.The authors would like to express their gratitude to the Food Packaging Forum (FPF) for their support in compiling this systematic evidence map. This study was funded by Brunel University London as part of the Brunel Research Initiative & Enterprise Fund (BRIEF) award No. 11683100 , in the context of the ' Closing the Plastic Food Packaging Loop ' project.Scopu

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

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