Publications

Societies worldwide are investing considerable resources into the safe development and use
of nanomaterials. Although each of these protective efforts is crucial for governing the risks
of nanomaterials, they are insufficient in isolation. What is missing is a more integrative governance
approach that goes beyond legislation. Development of this approach must be evidence
based and involve key stakeholders to ensure acceptance by end users. The challenge is
to develop a framework that coordinates the variety of actors involved in nanotechnology and
civil society to facilitate consideration of the complex issues that occur in this rapidly evolving
research and development area. Here, we propose three sets of essential elements required
to generate an effective risk governance framework for nanomaterials. (1) Advanced tools to
facilitate risk-based decision making, including an assessment of the needs of users regarding
risk assessment, mitigation, and transfer. (2) An integrated model of predicted human behavior
and decision making concerning nanomaterial risks. (3) Legal and other (nano-specific
and general) regulatory requirements to ensure compliance and to stimulate proactive approaches
to safety. The implementation of such an approach should facilitate and motivate
good practice for the various stakeholders to allow the safe and sustainable future development
of nanotechnology.

Evaluation of the reliability and relevance of toxicity and ecotoxicity studies is an integral step in the assessment of the hazards and risks of chemicals. This evaluation is inherently reliant on expert judgment, which often leads to differences between experts’ conclusions regarding how individual studies can contribute
to the body of evidence. The conclusions of regulatory assessment, such as establishing safe exposure levels for humans and the environment and calculations of margins of exposure, may have large consequences for which chemicals are permitted on the market and their allowed uses. It is therefore important that such assessments are based on all reliable and relevant scientific data, and that assessment principles and assumptions, such as expert judgment, are transparently applied. It is not possible nor desirable to completely eliminate expert judgment from the evaluation of (eco)toxicity studies. However, it is desirable to introduce measures that increase structure and transparency in the evaluation process so as to provide scientifically robust risk assessments that can be used for regulatory decision making. In this article we present results from workshop exercises with Nordic experts to illustrate how experts’ evaluations regarding the reliability and relevance of (eco)toxicity studies for risk assessment may vary and discuss methods intended to promote structure and transparency in the evaluation process.

The interactions between academic research and regulatory assessment of chemicals may in theory seem straightforward: researchers perform studies, and these studies are used by regulators for decision-making. However, in practice the situation is more complex, and many factors decide a research study’s regulatory use. According to several EU chemical legislations, all available and relevant studies can be used in hazard and risk assessment of chemicals. However, in practice, standard tests conducted under GLP and sponsored and provided by industry are predominantly used. Peer-reviewed studies from independent sources are often disregarded or disputed since they often do not comply with regulatory data requirements and quality criteria. There are several possible reasons for this, one being that academic research is reported in a way that does not fit the regulatory requirements. To help bridge such a gap, the aim of this paper is to give an overview of the general workings of chemicals legislation and propose a set of actions to increase the usability of research data. In the end, this may increase the use of academic research for decision-making and ultimately result in more science-based policies. From a policy perspective, useful scientific evidence are those studies that are sufficiently reliable and relevant. This is not in contradiction to the aims of research and generally accepted scientific standards.

Environmental hazard and risk assessment serve as the basis for regulatory decisions to protect the environment from unintentional adverse effects of chemical substances including nanomaterials. This process requires reliable and relevant environmental hazard data upon which classification and labelling can be based and Predicted No-Effect Concentration (PNEC) values can be estimated. In a regulatory context ecotoxicological data is often recommended to be generated according to accepted and validated test guidelines, preferably also following Good Laboratory Practice. However, engineered nanomaterials are known to behave very differently in ecotoxicity tests compared to the conventional soluble chemicals, for which most guidelines were developed. Therefore non-guideline tests, or tests following modified test guidelines, can provide valuable information and should not per se be considered less adequate for regulatory use. Here we propose a framework for reliability and relevance evaluation of ecotoxicity data for nanomaterials that take into account the challenges and characterisation requirements associated with testing of these substances. The nanoCRED evaluation criteria, and accompanying guidance, were developed to be used in combination with those developed through the ‘Criteria for Reporting and Evaluating Ecotoxicity Data (CRED)’ project. This approach can accommodate all types of nanomaterials, all types of aquatic ecotoxicity studies, and qualitative as well as quantitative data evaluation requirements. Furthermore, it is practically feasible to implement and directly applicable in European as well as international regulatory frameworks.

The aim of this study is to scrutinize the transparency, i.e. the accessibility and comprehensibility, of information on substances registered under REACH. Data on repeated dose toxicity and hazard assessment conclusions were extracted for 60 substances from the REACH registration database available on the ECHA website. The data were compiled in a database for systematically evaluating the transparency of information related to the conclusions on hazard or risk. In addition, CSRs were requested from ECHA for five substances. The transparency of information on the hazard and risk of substances was found to be limited for several reasons. First, certain information was removed due to confidentiality and certain fields were not published because they could contain confidential information although the information had not been claimed confidential. Also, the extent to which registrants reported information varied, and the presentation of some data and certain terminology required further clarification. In addition, the data source for the majority of the key and supporting studies could not be identified due to confidentiality. Since registrants are only required to summarise studies, it cannot be verified whether all relevant information from non-public industry reports have been reported. Lastly, certain information related to the hazard and risk assessment were only reported in the CSR which is only available upon request; a time-consuming and work-intensive process. As information on registered chemicals is currently provided to the public, it is difficult to follow steps that are undertaken in the hazard and risk assessment. This limits the possibility for a third party to evaluate the assessment.

Regulatory policies in many parts of the world either recognize the utility of, or mandate, that all available studies be considered in Environmental Assessment (ERA) of chemicals, including studies from the peer-reviewed literature. Consequently, a vast array of different studies and data types need to be considered. The first steps in the evaluation process involve determining whether the study is relevant to the ERA and sufficiently reliable. Relevance evaluation is typically performed using existing guidance but involves application of 'expert judgement' by risk assessors. In this paper we reviewed published guidance for relevance evaluation and based on the practical experience within the group of authors we identified additional aspects and further developed already proposed aspects that should be considered when conducting a relevance assessment for ecotoxicological studies. The overarching key aspect of relevance concerns the ability to directly or indirectly use the study in ERA with the purpose to address specific protection goals and ultimately regulatory decision-making. Since ERA schemes are based on the appropriate linking of exposure and effect estimates, important features of ecotoxicological studies relate to exposure relevance and biological relevance. Exposure relevance addresses the representativeness of the test substance, environmental exposure media and exposure regime. Biological relevance deals with the environmental significance of the test organism and the endpoints, the ecological realism of the test conditions simulated in the study, as well as a mechanistic link of treatment-related effects for endpoints to the protection goal identified in the ERA. In addition, uncertainties associated with relevance should be considered in the assessment. A systematic and transparent assessment of relevance is needed for regulatory decision-making. The relevance aspects also need to be considered by scientists to facilitate the studies use in ERA.

The aim of this review was to investigate if and how the application of weight of evidence (WoE) evaluation or systematic review (SR) in chemical risk assessment is promoted within different regulatory frameworks in the European Union. Legislative and relevant guidance documents within nine regulatory frameworks were scrutinized and compared. WoE evaluation or SR is promoted in seven of the investigated frameworks but sufficient guidance for how to perform these processes is generally lacking. None of the investigated frameworks give enough guidance for generating robust and reproducible WoE evaluations or SRs. In conclusion, the foundation for use of WoE evaluation and SR is laid in the majority of the investigated frameworks, but there is a need to provide more structured and detailed guidance. In order to make the process of developing guidance as efficient as possible, and to ensure smooth transfer of risk assessment's between frameworks if a chemical is risk assessed both as, for example, a biocide and an industrial chemical, it is recommended that guidance is developed jointly by the European regulatory agencies.

A critical step in systematic reviews of potential health hazards is the structured evaluation of the strengths and weaknesses of the included studies; risk of bias is a term often used to represent this process, specifically with respect to the evaluation of systematic errors that can lead to inaccurate (biased) results (i.e. focusing on internal validity). Systematic review methods developed in the clinical medicine arena have been adapted for use in evaluating environmental health hazards; this expansion raises questions about the scope of risk of bias tools and the extent to which they capture the elements that can affect the interpretation of results from environmental and occupational epidemiology studies and in vivo animal toxicology studies, (the studies typically available for assessment of risk of chemicals). One such element, described here as “sensitivity”, is a measure of the ability of a study to detect a true effect or hazard. This concept is similar to the concept of the sensitivity of an assay; an insensitive study may fail to show a difference that truly exists, leading to a false conclusion of no effect. Factors relating to study sensitivity should be evaluated in a systematic manner with the same rigor as the evaluation of other elements within a risk of bias framework. We discuss the importance of this component for the interpretation of individual studies, examine approaches proposed or in use to address it, and describe how it relates to other evaluation components. The evaluation domains contained within a risk of bias tool can include, or can be modified to include, some features relating to study sensitivity; the explicit inclusion of these sensitivity criteria with the same rigor and at the same stage of study evaluation as other bias-related criteria can improve the evaluation process. In some cases, these and other features may be better addressed through a separate sensitivity domain. The combined evaluation of risk of bias and sensitivity can be used to identify the most informative studies, to evaluate the confidence of the findings from individual studies and to identify those study elements that may help to explain heterogeneity across the body of literature.

Systematic review (SR) is a rigorous, protocol-driven approach designed to minimise error and bias when summarising the body of research evidence relevant to a specific scientific question. Taking as a comparator the use of SR in synthesising research in healthcare, we argue that SR methods could also pave the way for a “step change” in the transparency, objectivity and communication of chemical risk assessments (CRA) in Europe and elsewhere. We suggest that current controversies around the safety of certain chemicals are partly due to limitations in current CRA procedures which have contributed to ambiguity about the health risks posed by these substances. We present an overview of how SR methods can be applied to the assessment of risks from chemicals, and indicate how challenges in adapting SR methods from healthcare research to the CRA context might be overcome. Regarding the latter, we report the outcomes from a workshop exploring how to increase uptake of SR methods, attended by experts representing a wide range of fields related to chemical toxicology, risk analysis and SR. Priorities which were identified include: the conduct of CRA-focused prototype SRs; the development of a recognised standard of reporting and conduct for SRs in toxicology and CRA; and establishing a network to facilitate research, communication and training in SR methods. We see this paper as a milestone in the creation of a research climate that fosters communication between experts in CRA and SR and facilitates wider uptake of SR methods into CRA.

There is increasing awareness that the value of peer-reviewed scientific literature is not consistent, resulting in a growing desire to improve the practice and reporting of studies. This is especially important in the field of ecotoxicology, where regulatory decisions can be partly based on data from the peer-reviewed literature, with wide-reaching implications for environmental protection. Our objective is to improve the reporting of ecotoxicology studies so that they can be appropriately utilized in a fair and transparent fashion, based on their reliability and relevance. We propose a series of nine reporting requirements, followed by a set of recommendations for adoption by the ecotoxicology community. These reporting requirements will provide clarity on the the test chemical, experimental design and conditions, chemical identification, test organisms, exposure confirmation, measurable endpoints, how data are presented, data availability and statistical analysis. Providing these specific details will allow for a fuller assessment of the reliability and relevance of the studies, including limitations. Recommendations for the implementation of these reporting requirements are provided herein for practitioners, journals, reviewers, regulators, stakeholders, funders, and professional societies. If applied, our recommendations will improve the quality of ecotoxicology studies and their value to environmental protection.