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. 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. 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. 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.

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. 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. 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. 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. 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.

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.

Focus on risks to human health and the environment from combined exposure to multiple chemicals ("mixture risk assessment") has increased in the last couple of decades. There has been a rise in awareness and concern in the community, especially concerning unintentional environmental exposure to unknown chemical mixtures. The Horizon 2020 project EuroMix has developed methodologies and tools for mixture risk assessment with a focus on component-based approach where substances are grouped based on toxicological considerations. Dose addition is used as the model for calculating the combined toxicity of mixture components. The methodology is anchored in the Adverse Outcome Pathway (AOP) concept, which provides a structured basis for e.g. grouping substances into assessment groups and identifying and collecting relevant toxicity data. The aim of this paper is to describes development of the methodology for mixture risk assessment and to provide detailed methodology for problem formulation, use of AOP networks for development of tiered testing strategies and grouping of substances, as well as considerations for use of dose addition methodology.