Reliability and relevance evaluations of REACH data

Ellen Ingre-Khans; Marlene Ågerstrand; Anna Beronius; Christina Rudén;
2019 | Toxicol. Res.

Regulatory authorities rely on hazard and risk assessments performed under REACH for identifying chemicals of concern and to take action. Therefore, these assessments must be systematic and transparent. This study investigates how registrants evaluate and report data evaluations under REACH and the procedures established by the European Chemicals Agency (ECHA) to support these data evaluations. Data on the endpoint repeated dose toxicity were retrieved from the REACH registration database for 60 substances. An analysis of these data shows that the system for registrants to evaluate data and report these evaluations is neither systematic nor transparent. First, the current framework focuses on reliability, but overlooks the equally important aspect of relevance, as well as how reliability and relevance are combined for determining the adequacy of individual studies. Reliability and relevance aspects are also confused in the ECHA guidance for read-across. Second, justifications for reliability evaluations were mainly based on studies complying with GLP and test guidelines, following the Klimisch method. This may result in GLP and guideline studies being considered reliable by default and discounting non-GLP and non-test guideline data. Third, the reported rationales for reliability were frequently vague, confusing and lacking information necessary for transparency. Fourth, insufficient documentation of a study was sometimes used as a reason for judging data unreliable. Poor reporting merely affects the possibility to evaluate reliability and should be distinguished from methodological deficiencies. Consequently, ECHA is urged to improve the procedures and guidance for registrants to evaluate data under REACH to achieve systematic and transparent risk assessments.

Improving structure and transparency in reliability evaluations of data under REACH: suggestions for a systematic method

Ellen Ingre-Khans; Marlene Ågerstrand; Christina Rudén; Anna Beronius;
2019 | Hum. Ecol. Risk Assess.

The goal of identifying hazardous chemicals registered under the Registration, Evaluation, Authorization and restriction of CHemicals (REACH) Regulation and taking appropriate risk management measures relies on robust data registrations. However, the current procedures for European chemical manufacturers and importers to evaluate data under REACH neither support systematic evaluations of data nor transparently communicate these assessments. The aim of this study was to explore how using a data evaluation method with predefined criteria for reliability and establishing principles for assigning reliability categories could contribute to more structured and transparent evaluations under REACH. In total, 20 peer-reviewed studies for 15 substances registered under REACH were selected for an in-depth evaluation of reliability with the SciRAP tool. The results show that using a method for study evaluation, with clear criteria for assessing reliability and assigning studies to reliability categories, contributes to more structured and transparent reliability evaluations. Consequently, it is recommended to implement a method for evaluating data under REACH with predefined criteria and fields for documenting and justifying the assessments to increase consistency of data evaluations and transparency.

Toxicity studies used in REACH ‐ How accurately are they reported?

Ellen Ingre‐Khans; Marlene Ågerstrand; Anna Beronius; Christina Rudén;
2019 | Toxicol. Res.

Toxicity studies on chemicals registered under REACH are provided as summaries instead of submitting a full study report. Since the registration data are used by regulatory agencies to identify chemicals of concern, the study summaries must accurately reflect the information in studies. A “study summary” should include sufficient information on the objectives, methods, results and conclusions in the full study report to determine the relevance of the study. Sometimes a “robust study summary” is required, which should contain more detailed information to enable an independent assessment of the study. The aim of this investigation is to examine how well published toxicity papers were reflected in study summaries submitted by registrants under REACH. Summaries of 20 published studies (peer‐reviewed studies including one abstract) were examined and broad categories of various types of observed differences were derived. As seen, the extent to which information in the published studies was reported in the study summaries varied. It also varied how accurately the information was reflected. Differences between the published studies and the summaries included simple typing errors, unclear and incomplete reporting as well as the omission of information on for example study design, results or interpretation of the results, which in some of the cases could be considered relevant for the risk assessment. This raises concerns regarding the accuracy of study summaries and their use for decision‐making. Moreover, the possibility for third parties to independently assess and scrutinise the summaries is limited. Considering that we rely on REACH registration data for chemical safety, all data used for risk assessment should be accessible for thorough examination and fully independent assessment.

The Essential Elements of a Risk Governance Framework for Current and Future Nanotechnologies

Stone; Führ; Feindt; Bouwmeester; Linkov; Sabella; Murphy; Bizer; Tran; Ågerstrand M; Fito; Andersen; Anderson; Bergamaschi; Cherrie; Cowan; Dalemcourt; Faure; Gabbert; Gajewicz; Fernandes; Hristozov; Johnston; Lansdown; Linder; Marvin; Mullins; Purnhagen; Puzyn; Jimenez; Scott-Fordsmand; Streftaris; van Tongeren; Voelcker; Voyiatzis; Yannopoulos; Poortvliet.
2018 | Risk Anal.

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.

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

Marlene Ågerstrand; Sofie Christiansen; Annika Hanberg; Christina Rudén; Lars Andersson; Sjur Andersen; Henrik Appelgren; Christine Bjørge; Ian Henning Clausen; Dag Markus Eide; Nanna B. Hartmann; Trine Husøy; Halldór Pálmar Halldórsson; Marianne van der Hagen; Ellen Ingre‐Khans; Adam David Lillicrap; Vibe Meister Beltoft; Anna‐Karin Mörk; Mari Murtomaa‐Hautala; Elsa Nielsen; Kristín Ólafsdóttir; Jaana Palomäki; Hinni Papponen; Emilie Marie Reiler; Helene Stockmann‐Juvala; Tiina Suutari; Henrik Tyle; Anna Beronius
2018 | J Appl Toxicol | 1-3

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.

Making the most of expert judgment in hazard and risk assessment of chemicals

2017 | Toxicology

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.

An academic researcher’s guide to increased impact on regulatory assessment of chemicals.

Ågerstrand ; Sobek A; Lilja K; Linderoth M; Wendt-Rasch L; Wernersson A-S; Rudén C.
2017 | Environ. Sci.: Processes Impacts

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.

NanoCRED: A transparent framework to assess’ the regulatory adequacy of ecotoxicity data for nanomaterials – Relevance and reliability revisited

Nanna B. Hartmann; Marlene Ågerstrand; Hans-Christian Holten Lützhøft; Anders Baun
2017 | NanoImpact | 6 (81-89)

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.

Towards the review of the European Union Water Framework management of chemical contamination in European surface water resources

Brack, W.; Dulio, V.; Ågerstrand, M.; Allan, I.; Altenburger, R.; Brinkmann, M.; Bunke, D.; Burgess, R.M.; Cousins, I.T.; Escher, B.I.; Hernández, F.J.; Hewitt, L.M.; Hilscherová, K.; Hollender, J.l.; Hollert, H.; Kase, R.; Klauer, B.; Lindim, C.; Herráez, D.L.; Miège, C.; Munthe, J.; O'Toole, S.; Posthuma, L.; Rüdel, H.; Schäfer, R.B.; Sengl, M.; Smedes, F.; van de Meent, D.; van den Brink, P.J.; van Gils, J.; van Wezel, A.P.; Vethaak, A.D.; Vermeirssen, E.l.; von der Ohe, P.C.; Vrana, B.
2017 | Sci. Total Environ. | 576 (720-737)

Refining tools to bridge the gap between academia and chemical regulation: perspectives for WikiREACH

Agerstrand, M; Brenig, M; Fuhr, M; Schenten, J
2017 | Environ. Sci.-Process Impacts | 19 (12) (1466-1473)
impact , improve , information-system , pharmaceuticals , reach , risk assessment , swedish environmental classification
Regulatory hazard and risk assessments of chemical substances have to include all reliable and relevant data to be credible and complete. However, screening the literature for appropriate studies and extracting data is burdensome. Therefore, reducing impediments by making data easily and readily accessible to risk assessors could result in more comprehensive hazard and risk assessments. In this paper, we study WikiPharma, a database that aggregates ecotoxicity data for pharmaceuticals, extracted from peerreviewed studies. The use of the WikiPharma database is explored to develop strategies on how similar tools can bridge between science and policy by providing risk assessors with easily accessible summary data. Specifically, adapting the concept of WikiPharma to industrial chemicals regulated under the REACH regulation is discussed. Experiences with WikiPharma show that there is interest in using peerreviewed studies in regulatory decision-making. However, tools like WikiPharma require constant updates. Hence, as for "WikiREACH", effective incentives are needed to motivate researchers to feed in relevant data for regulatory assessments. Besides, support by automated processes can aid in the labourintensive activity of gathering data. To ensure that such a tool is continuously maintained and compatible with the regulatory system, and thereby useful for hazard and risk assessments of chemicals, it would benefit from being developed in collaboration with the major stakeholders in the field, i.e. regulatory agencies, academia, industry, scientific journals, and providers of research network platforms.

Transparency of chemical risk assessment data under REACH

Ellen Ingre-Khans; Marlene Ågerstrand; Anna Beronius; Christina Rudén
2016 | Environ. Sci.: Processes Impacts (12)

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.

Assessing the relevance of ecotoxicological studies for regulatory decision making

Christina Rudén; Julie Adams; Marlene Ågerstrand; Theo CM Brock; Veronique Poulsen; Christian E Schlekat; James R Wheeler; Tala R Henry
2016 | Integr Environ Assess Manag

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.

Contact information

Visiting addresses:

Geovetenskapens Hus,
Svante Arrhenius väg 8, Stockholm

Arrheniuslaboratoriet, Svante Arrhenius väg 16, Stockholm (Unit for Analytical and Toxicological Chemistry)

Mailing address:
Department of Environmental Science and Analytical Chemistry (ACES)
Stockholm University
106 91 Stockholm

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stella.papadopoulou@aces.su.se