BackgroundThe 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.MethodsWe 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.ResultsBuilding 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.ConclusionsWhen 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s12940-016-0156-6) contains supplementary material, which is available to authorized users.

In this project, the evidence for the non-monotonic dose-response (NMDR) hypothesis was evaluated by critically reviewing the scientific peer-reviewed literature in the last decade (from 2002 onwards) for substances in the area of food safety. The project was performed according to the systematic review methodology. After a detailed analysis of previous reports published on the issue of NMDRs, a literature search was performed to identify in vivo, in vitro and epidemiological/human studies containing evidence for potential NMDRs. Inclusion and reliability criteria were defined and used to select relevant and reliable studies. Of studies with at least 5 dose groups, dose-response datasets were extracted and analysed by PROAST software package. The resulting dose-response results were evaluated for possible evidence of NMDR by applying six checkpoints. These checkpoints addressed both random and non-random errors. The plausibility of NMDRs was assessed based on the number of fulfilled checkpoints. In total, 202 in vivo datasets (from 49 studies), 311 in vitro datasets (from 91 studies) and 9 epidemiological/human datasets (from 2 studies) were identified. Among them, 179 in vivo and 13 in vitro dose-response datasets were analysed and evaluated using the checkpoints. For 23 in vivo datasets there were data limitations, which made the data unsuitable for dose-response analysis. For the in vitro studies, only continuous dose-response datasets presented in tables were analysed. None of the datasets from epidemiological/human studies could be analysed (one of the epidemiological studies was not analysed due to quantal data and the other due to data limitations).In most of the in vivo datasets, the apparent NMDR might have been caused by a single outlying dose group. In total, only 10 out of the 179 in vivo datasets fulfilled all six checkpoints. The latter datasets included studies on the substances quercetin, resveratrol, alpha-benzene hexachloride, and methylmercury. Review of NMDR of substances for HRA ContributorsAGES: Boehm T., Coja T., Hrdina-Zoedl B., Pacher-Zavisin M., Steinparzer R.ANSES: Charles S., Gouze M.E., Guillou P., Lehegarat L., Manière I., Ormsby J.N., Papadopoulos A., Printemps N., Roudot A.C.RIVM: Smeet E. Acknowledgements:RIVM: Ossendorp B., Vermeire T.IMM: Gornitzki C., Moberg K., Karolinska Institutet University Library Reproduction is authorised provided the source is acknowledged.Permission to reproduce the images must be sought directly from the copyright holder SummaryThe overall objective of this project was to evaluate the evidence for the non-monotonic doseresponse (NMDR) hypothesis by critically reviewing the scientific peer-reviewed literature in the last decade (from 2002 onwards) for substances (other than essential nutrients) in the area of food safety. MethodologyThe project was based on a systematic review including the steps of Preparing the review (review protocol, review question and criteria for study eligibility), Searching for research studies, Selecting the stu...

To improve data availability in health risk assessment of chemicals and fill information gaps there is a need to facilitate the use of non-standard toxicity studies, i.e. studies not conducted according to any standardized toxicity test guidelines. The purpose of this work was to propose criteria and guidance for the evaluation of reliability and relevance of non-standard in vivo studies, which could be used to facilitate systematic and transparent evaluation of such studies for health risk assessment. Another aim was to propose user friendly guidance for reporting of non-standard studies intended to promote an improvement in reporting of studies that could be of use in risk assessment. Requirements and recommendations for the design and execution of in vivo toxicity studies were identified from The Organisation for Economic Co-operation and Development (OECD) test guidelines, and served as basis for the data evaluation criteria and reporting guidelines. Feedback was also collected from experts within the field of toxicity testing and risk assessment and used to construct a two-tiered framework for study evaluation, as well as refine the reporting guidelines. The proposed framework emphasizes the importance of study relevance and an important aspect is to not completely dismiss studies from health risk assessment based on very strict criteria for reliability. The suggested reporting guidelines provide researchers with a tool to fulfill reporting requirements as stated by regulatory agencies. Together, these resources provide an approach to include all relevant data that may fill information gaps and reduce scientific uncertainty in health risk assessment conclusions, and subsequently also in chemical policy decisions.

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This article reviews the current legislative requirements for risk assessment of combined exposure to multiple chemicals via multiple exposure routes, focusing on human health and particularly on foodrelated chemicals. The aim is to identify regulatory needs and current approaches for this type of risk assessment as well as challenges of the implementation of appropriate and harmonized guidance at international level. It provides an overview of the current legal requirements in the European Union (EU), the United States and Canada. Substantial differences were identified in the legal requirements for risk assessment of combined exposure to multiple chemicals and its implementation between EU and non-EU countries and across several regulatory sectors. Frameworks currently proposed and in use for assessing risks from combined exposure to multiple chemicals via multiple routes and different durations of exposure are summarized. In order to avoid significant discrepancies between regulatory sectors or countries, the approach for assessing risks of combined exposure should be based on similar principles for all types of chemicals. OECD and EFSA identified the development of harmonized methodologies for combined exposure to multiple chemicals as a key priority area. The Horizon 2020 project "EuroMix" aims to contribute to the further development of internationally harmonized approaches for such risk assessments by the development of an integrated test strategy using in vitro and in silico tests verified for chemical mixtures based on more appropriate data on potential combined effects. These approaches and testing strategies should be integrated in a scientifically based weight of evidence approach to account for complexity and uncertainty, to improve risk assessment.

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The Science in Risk Assessment and Policy (SciRAP) web-based platform was developed to promote and facilitate structure and transparency in the evaluation of ecotoxicity and toxicity studies for hazard and risk assessment of chemicals. The platform includes sets of criteria and a colour-coding tool for evaluating the reliability and relevance of individual studies. The SciRAP method for evaluating in vivo toxicity studies was first published in 2014 and the aim of the work presented here was to evaluate and develop that method further. Toxicologists and risk assessors from different sectors and geographical areas were invited to test the SciRAP criteria and tool on a specific set of in vivo toxicity studies and to provide feedback concerning the scientific soundness and user-friendliness of the SciRAP approach. The results of this expert assessment were used to refine and improve both the evaluation criteria and the colour-coding tool. It is expected that the SciRAP web-based platform will continue to be developed and enhanced to keep up to date with the needs of end-users.