Olwenn V. Martin

Science and policy on endocrine disrupters must not be mixed: a reply to a “common sense” intervention by toxicology journal editors

The “common sense” intervention by toxicology journal editors regarding proposed European Union endocrine disrupter regulations ignores scientific evidence and well-established principles of chemical risk assessment. In this commentary, endocrine disrupter experts express their concerns about a recently published, and is in our considered opinion inaccurate and factually incorrect, editorial that has appeared in several journals in toxicology. Some of the shortcomings of the editorial are discussed in detail. We call for a better founded scientific debate which may help to overcome a polarisation of views detrimental to reaching a consensus about scientific foundations for endocrine disrupter regulation in the EU.

A proposed framework for the systematic review and integrated assessment (SYRINA) of endocrine disrupting chemicals.

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.

Dispelling urban myths about default uncertainty factors in chemical risk assessment – sufficient protection against mixture effects?

Assessing the detrimental health effects of chemicals requires the extrapolation of experimental data in animals to human populations. This is achieved by applying a default uncertainty factor of 100 to doses not found to be associated with observable effects in laboratory animals. It is commonly assumed that the toxicokinetic and toxicodynamic sub-components of this default uncertainty factor represent worst-case scenarios and that the multiplication of those components yields conservative estimates of safe levels for humans. It is sometimes claimed that this conservatism also offers adequate protection from mixture effects. By analysing the evolution of uncertainty factors from a historical perspective, we expose that the default factor and its sub-components are intended to represent adequate rather than worst-case scenarios. The intention of using assessment factors for mixture effects was abandoned thirty years ago. It is also often ignored that the conservatism (or otherwise) of uncertainty factors can only be considered in relation to a defined level of protection. A protection equivalent to an effect magnitude of 0.001-0.0001% over background incidence is generally considered acceptable. However, it is impossible to say whether this level of protection is in fact realised with the tolerable doses that are derived by employing uncertainty factors. Accordingly, it is difficult to assess whether uncertainty factors overestimate or underestimate the sensitivity differences in human populations. It is also often not appreciated that the outcome of probabilistic approaches to the multiplication of sub-factors is dependent on the choice of probability distributions. Therefore, the idea that default uncertainty factors are overly conservative worst-case scenarios which can account both for the lack of statistical power in animal experiments and protect against potential mixture effects is ill-founded. We contend that precautionary regulation should provide an incentive to generate better data and recommend adopting a pragmatic, but scientifically better founded approach to mixture risk assessment.

Response to A critique of the European Commission Document, "State of the Art Assessment of Endocrine Disrupters" by Rhomberg and colleagues--letter to the editor.

The European Commission is in the process of preparing regulatory activities for endocrine disrupting chemicals. In support of this process, the European Commission has asked for a summary of the state of endocrine disrupter science which was to be completed within 12 months. A draft version of our science summary was published by the European Commission in the summer of 2011, with the aim of generating feedback from stakeholders. We have received comments from EU member state authorities and from the European Chemical Industry (CEFIC, ECPA) and these were all taken into account in the final version of the science summary. The final version of the science summary was submitted as an annex to our final SOTA ED (Kortenkamp et al., 2011) which was completed on 23 December 2011. In their American Chemistry Council commissioned critique, Rhomberg et al. (2012) focus entirely on the draft version of the science summary, but largely ignore the main body of our report. Rhomberg et al. argue that because we did not use methodological approaches needed for comprehensive substance assessments, our report must be biased. This line of argumentation is deeply flawed. It might be the result of a lack of understanding of the distribution of competences in the European Union which the authors (all of them US or Canadian nationals) may not be familiar with. Rhomberg et al. seem to have assumed that the European Commission would base their policy initiatives on detailed risk assessments of a large number of chemicals, in terms of their endocrine disrupting properties. But the European Commission (the executive arm of the European Union) itself is not responsible for risk assessments of chemicals. Rather, it shapes the general principles of European Union chemicals policy of which risk assessment is but one element. Accordingly, the European Commission did not ask for detailed and in-depth risk assessments for a large number of chemicals to support their policy initiatives, nor is such an analysis needed as a foundation for policy. In the European Union, the task of detailed chemical evaluations and risk assessments falls in the first instance to industry and under well defined circumstances to European agencies such as the European Food Safety Authority or the European Chemicals Agency and to competent authorities of European Union member states. What the European Commission needed, and what it requested us to prepare, was a summary of endocrine disrupter science, primarily with the aim of assessing whether policy initiatives in this area are scientifically justified and called for. Accordingly, they commissioned an assessment of whether endocrine disruption is a problem, and whether there are indications that chemical exposures play a role in endocrine-related health outcomes or wildlife effects. A specific objective in relation to a clause of the European chemicals regulation REACH was to evaluate the scientific basis for the notion that endocrine disrupting substances might cause effects of a concern equivalent to the hazards posed by carcinogens, mutagens and reproductive and developmental toxicants. In line with these requirements, we prepared a science summary to assess the plausibility that xenobiotics might play a role in the aetiology of various health endpoints potentially related to endocrine disrupters. To achieve this aim, our assessment of the scientific evidence was based on the principles proposed by WHO/IPCS (2002) as a basis for attribution of effects to endocrine disruption (report chapter 3.16, p32). In dealing with this problem, it would have been inappropriate to utilize the causal criteria for assessing endocrine disrupters described in chapter 7 of the same report. This seems to have been entirely misunderstood by Rhomberg and colleagues. Rhomberg et al. have also overlooked the fact that we have dealt extensively with the issue of weight of evidence, both in the science summary and in the main part of our report (Kortenkamp et al., 2011). They ignore the complexity of developing weight of evidence approaches and seem to assume that such approaches are already available and agreed upon. However, this is not the case. As we have stressed in our report (Kortenkamp et al., 2011), weight of evidence approaches for endocrine disrupters are yet to Letter to the editor

Scientific challenges in the risk assessment of food contact materials

Background: Food contact articles (FCAs) are manufactured from food contact materials (FCMs) that include plastics, paper, metal, glass, and printing inks. Chemicals can migrate from FCAs into food during storage, processing, and transportation. Food contact materials’ safety is evaluated using chemical risk assessment (RA). Several challenges to the RA of FCAs exist. Objectives: We review regulatory requirements for RA of FCMs in the United States and Europe, identify gaps in RA, and highlight opportunities for improving the protection of public health. We intend to initiate a discussion in the wider scientific community to enhance the safety of food contact articles. Discussion: Based on our evaluation of the evidence, we conclude that current regulations are insufficient for addressing chemical exposures from FCAs. RA currently focuses on monomers and additives used in the manufacture of products, but it does not cover all substances formed in the production processes. Several factors hamper effective RA for many FCMs, including a lack of information on chemical identity, inadequate assessment of hazardous properties, and missing exposure data. Companies make decisions about the safety of some food contact chemicals (FCCs) without review by public authorities. Some chemical migration limits cannot be enforced because analytical standards are unavailable. Conclusion: We think that exposures to hazardous substances migrating from FCAs require more attention. We recommend a) limiting the number and types of chemicals authorized for manufacture and b) developing novel approaches for assessing the safety of chemicals in FCAs, including unidentified chemicals that form during or after production. https://doi.org/10.1289/EHP644

New approach to weight‐of‐evidence assessment of ecotoxicological effects in regulatory decision‐making

Ecological risk assessments and risk management decisions are only as sound as the underlying information and processes to integrate them. It is important to develop transparent and reproducible procedures a priori to integrate often-heterogeneous evidence. Current weight-of-evidence (WoE) approaches for effects or hazard assessment tend to conflate aspects of the assessment of the quality of the data with the strength of the body of evidence as a whole. We take forward recent developments in the critical appraisal of the reliability and relevance of individual ecotoxicological studies as part of the effect or hazard assessment of prospective risk assessments and propose a streamlined WoE approach. The aim is to avoid overlap and double accounting of criteria used in reliability and relevance with that used in current WoE methods. The protection goals, problem formulation, and evaluation process need to be clarified at the outset. The data are first integrated according to lines of evidence (LoEs), typically mechanistic insights (e.g., cellular, subcellular, genomic), in vivo experiments, and higher-tiered field or observational studies. Data are then plotted on the basis of both relevance and reliability scores or categories. This graphical approach provides a means to visually assess and communicate the credibility (reliability and relevance of available individual studies), quantity, diversity, and consistency of the evidence. In addition, the external coherence of the body of evidence needs to be considered. The final step in the process is to derive an expression of the confidence in the conclusions of integrating the information considering these 5 aspects in the context of remaining uncertainties. We suggest that this streamlined approach to WoE for the effects or hazard characterization should facilitate reproducible and transparent assessments of data across different regulatory requirements. Integr Environ Assess Manag 2017;13:573-579.