Sources of exposure to Bisphenol A

In July 2010 the Swedish government commissioned the Swedish Chemicals Agency (KemI) to investigate the need as well as possible conditions for a national ban on bisphenol A (BPA) in certain plastic products. The investigation was carried out in collaboration with the Swedish Food Administration (SLV). As part of the investigation KemI asked the instiutet of Environmental Medicine (IMM) at Karolinska institutet to review and evaluate the available literature on exposure to BPA from different products. The report presents the result of that review. The purpose of this report is to summerize information on potential sources of exposure to BPA in the general population. Available scientific literature relevant to the investigation, as well as risk assessment documents from different authorities and expert groups was reveiwd. Additional expertise concerning dermal uptake and exposure has been kindly provided by Professor Gunnar Johanson at IMM. Some conculsions about which exposure source seem to be the most significant are made. However, it is beyond the scope of this investigation to provide a complete exposure assessment for BPA. Data gaps and future research needs are presented

Risk Assessment of Endocrine Disrupting Compounds

During the past decade a growing number of chemicals have been identified as having endocrine disrupting properties in laboratory studies. Also, associations between exposure to such substances and endocrine-related health effects in the general population, as well as in wildlife, have been increasingly reported. This implies that past chemical regulation has failed to adequately protect human health and the environment. Endocrine disrupting compounds (EDCs) have lately been identified as substances of very high concern that should be phased out in new European (EU) legislations for e.g. industrial chemicals, plant protection products and biocides. There is thus an increased pressure on regulatory agencies to be able to efficiently and reliably identify, characterize and risk assess EDCs. However, risk assessment of EDCs has proven complicated, in part due to the complex toxicity exhibited by substances that can interact with the endocrine system, and also because there are currently no generally agreed upon criteria within the EU or internationally that direct how to specifically identify compounds with endocrine disrupting properties. The aim of this thesis project has been to identify how scientific uncertainties concerning the toxicity of EDCs can be reduced or handled to make health risk assessments of EDCs more transparent, systematic, and reliable. To that end literature studies were conducted that investigated the risk assessment process for EDCs within different regulatory frameworks in the EU, as well as the underlying toxicity data available to risk assessors and how the use of all available toxicity data can be improved. The much debated EDC bisphenol A (BPA) was used for a case study in a large part of this work. A comparison of different regulatory frameworks within the EU showed that the regulatory risk assessment process, including underlying policies, criteria and requirements may differ for EDCs belonging to different regulatory groups, e.g. industrial chemicals, plant protection products or pharmaceuticals. The investigations within this project also showed that non-standard research studies, i.e. studies not conducted according to standardized regulatory test guidelines, fill data gaps and contribute information that could be particularly important for the identification and risk assessment of EDCs. However, non-standard studies were often criticized for having methodological limitations or being insufficiently reported, limiting their use in regulatory risk assessment. Regulatory agencies commonly gave more weight to standard than non-standard studies in risk assessment of BPA, despite the growing amount of research indicating that toxic effects at low doses were being overlooked. A framework of criteria and guidelines intended to enable transparent and systematic evaluation of non-standard research studies, as well as guidance for how to report in vivo research to meet the requirements for regulatory risk assessment, was proposed. These tools are intended to facilitate the use of non-standard research studies in regulatory risk assessment and hopefully improve the reliability of risk assessment conclusions for EDCs

Development of the SciRAP Approach for Evaluating the Reliability and Relevance of in vitro Toxicity Data

Efficient and successful integration of data generated from non-animal test methods must rely on reliable and relevant data. It is important therefore to develop tools and criteria that facilitate scientifically sound, structured, and transparent evaluation of reliability and relevance of in vitro toxicity data to efficiently inform regulatory hazard and risk assessment. The Science in Risk Assessment and Policy (SciRAP) initiative aims to promote such overarching goals. We present the work to develop and refine the SciRAP tool for evaluation of reliability and relevance of in vitro studies for incorporation on the SciRAP web-based platform ( www.scirap.org ). In the SciRAP approach, reliability evaluation is based on criteria for reporting quality and methodological quality, and is explicitly separated from relevance evaluation. The SciRAP in vitro tool (version 1.0) was tested and evaluated during an expert test round (April 2019-September 2020) on three in vitro studies by thirty-one experts from regulatory authorities, industry and academia from different geographical areas and with various degree of experience in in vitro research and/or human health risk assessment. In addition, the experts answered an online survey to collect their feedback about the general features and desired characteristics of the tool for further refinement. The SciRAP in vitro tool (version 2.0) was revised based on the outcome of the expert test round (study evaluation and online survey) and consists of 24 criteria for evaluating " reporting quality " (reliability), 16 criteria for " methodological quality " (reliability) , and 4 items for evaluating relevance of in vitro studies. Participants were generally positive about the adequacy, flexibility, and user-friendliness of the tool. The expert test round outlined the need to (i) revise the formulation of certain criteria; (ii) provide new or revised accompanying guidance for reporting quality and methodological quality criteria in the " test compounds and controls ," " test system ," and " data collection and analysis " domains; and (iii) provide revised guidance for relevance items, as general measures to reduce inter-expert variability. The SciRAP in vitro tool allows for a structured and transparent evaluation of in vitro studies for use in regulatory hazard and risk assessment of chemicals

A call for action: Improve reporting of research studies to increase the scientific basis for regulatory decision-making

Publisher's version (útgefin grein)This is a call for action to scientific journals to introduce reporting requirements for toxicity and ecotoxicity studies. Such reporting requirements will support the use of peer‐reviewed research studies in regulatory decision‐making. Moreover, this could improve the reliability and reproducibility of published studies in general and make better use of the resources spent in research.Nordic Council of Minister

The MCRA toolbox of models and data to support chemical mixture risk assessment

A model and data toolbox is presented to assess risks from combined exposure to multiple chemicals using probabilistic methods. The Monte Carlo Risk Assessment (MCRA) toolbox, also known as the EuroMix toolbox, has more than 40 modules addressing all areas of risk assessment, and includes a data repository with data collected in the EuroMix project. This paper gives an introduction to the toolbox and illustrates its use with examples from the EuroMix project. The toolbox can be used for hazard identification, hazard characterisation, exposure assessment and risk characterisation. Examples for hazard identification are selection of substances relevant for a specific adverse outcome based on adverse outcome pathways and QSAR models. Examples for hazard characterisation are calculation of benchmark doses and relative potency factors with uncertainty from dose response data, and use of kinetic models to perform in vitro to in vivo extrapolation. Examples for exposure assessment are assessing cumulative exposure at external or internal level, where the latter option is needed when dietary and non-dietary routes have to be aggregated. Finally, risk characterisation is illustrated by calculation and display of the margin of exposure for single substances and for the cumulation, including uncertainties derived from exposure and hazard characterisation estimates.</p

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.The workshops that supported the writing of this manuscript were funded by the Swedish Foundation for Strategic Environmental Research “Mistra”. LNV was funded by Award Number K22ES025811 from the National Institute of Environmental Health Sciences of the National Institutes of Health. TJW was funded by The Clarence Heller Foundation (A123547), the Passport Foundation, the Forsythia Foundation, the National Institute of Environmental Health Sciences (grants ES018135 and ESO22841), and U.S. EPA STAR grants (RD83467801 and RD83543301). JT was funded by the Academy of Finland and Sigrid Juselius. UH was funded by the Danish EPA. KAK was funded by the Canada Research Chairs program grant number 950–230607

Application of AOPs to assist regulatory assessment of chemical risks - Case studies, needs and recommendations

While human regulatory risk assessment (RA) still largely relies on animal studies, new approach methodologies (NAMs) based on in vitro, in silico or non-mammalian alternative models are increasingly used to evaluate chemical hazards. Moreover, human epidemiological studies with biomarkers of effect (BoE) also play an invaluable role in identifying health effects associated with chemical exposures. To move towards the next generation risk assessment (NGRA), it is therefore crucial to establish bridges between NAMs and standard approaches, and to establish processes for increasing mechanistically-based biological plausibility in human studies. The Adverse Outcome Pathway (AOP) framework constitutes an important tool to address these needs but, despite a significant increase in knowledge and awareness, the use of AOPs in chemical RA remains limited. The objective of this paper is to address issues related to using AOPs in a regulatory context from various perspectives as it was discussed in a workshop organized within the European Union partnerships HBM4EU and PARC in spring 2022. The paper presents examples where the AOP framework has been proven useful for the human RA process, particularly in hazard prioritization and characterization, in integrated approaches to testing and assessment (IATA), and in the identification and validation of BoE in epidemiological studies. Nevertheless, several limitations were identified that hinder the optimal usability and acceptance of AOPs by the regulatory community including the lack of quantitative information on response-response relationships and of efficient ways to map chemical data (exposure and toxicity) onto AOPs. The paper summarizes suggestions, ongoing initiatives and third-party tools that may help to overcome these obstacles and thus assure better implementation of AOPs in the NGRA

Factors Modulating COVID-19 : A Mechanistic Understanding Based on the Adverse Outcome Pathway Framework

Addressing factors modulating COVID-19 is crucial since abundant clinical evidence shows that outcomes are markedly heterogeneous between patients. This requires identifying the factors and understanding how they mechanistically influence COVID-19. Here, we describe how eleven selected factors (age, sex, genetic factors, lipid disorders, heart failure, gut dysbiosis, diet, vitamin D deficiency, air pollution and exposure to chemicals) influence COVID-19 by applying the Adverse Outcome Pathway (AOP), which is well-established in regulatory toxicology. This framework aims to model the sequence of events leading to an adverse health outcome. Several linear AOPs depicting pathways from the binding of the virus to ACE2 up to clinical outcomes observed in COVID-19 have been developed and integrated into a network offering a unique overview of the mechanisms underlying the disease. As SARS-CoV-2 infectibility and ACE2 activity are the major starting points and inflammatory response is central in the development of COVID-19, we evaluated how those eleven intrinsic and extrinsic factors modulate those processes impacting clinical outcomes. Applying this AOP-aligned approach enables the identification of current knowledge gaps orientating for further research and allows to propose biomarkers to identify of high-risk patients. This approach also facilitates expertise synergy from different disciplines to address public health issues.publishedVersionPeer reviewe