Christina Rudén

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.

Five charges against the precautionary principle

We defend the precautionary principle against five common charges, namely that it is ill-defined, absolutist, and a value judgement, increases risk-taking, and marginalizes science. We argue, first, that the precautionary principle is, in principle, no more vague or ill-defined than other decision principles and like them it can be made precise through elaboration and practice. Second, the precautionary principle need not be absolutist in the way that has been claimed. A way to avoid this is through combining the precautionary principle with a specification of the degree of scientific evidence required to trigger precaution, and/or with some version of the de minimis rule. Third, the precautionary principle does not lead to increased risk-taking, unless the framing is too narrow, and then the same problem applies to other decision rules as well. Fourth, the precautionary principle is indeed value-based, but only to the same extent as other decision rules. Fifth and last, the precautionary principle is not unscientific other than in the weak sense of not being exclusively based on science. In that sense all decision rules are unscientific.

Prioritising pharmaceuticals for environmental risk assessment: Towards adequate and feasible first-tier selection.

The presence of pharmaceuticals in the aquatic environment, and the concerns for negative effects on aquatic organisms, has gained increasing attention over the last years. As ecotoxicity data are lacking for most active pharmaceutical ingredients (APIs), it is important to identify strategies to prioritise APIs for ecotoxicity testing and environmental monitoring. We have used nine previously proposed prioritisation schemes, both risk- and hazard-based, to rank 582 APIs. The similarities and differences in overall ranking results and input data were compared. Moreover, we analysed how well the methods ranked seven relatively well-studied APIs. It is concluded that the hazard-based methods were more successful in correctly ranking the well-studied APIs, but the fish plasma model, which includes human pharmacological data, also showed a high success rate. The results of the analyses show that the input data availability vary significantly; some data, such as logP, are available for most API while information about environmental concentrations and bioconcentration are still scarce. The results also suggest that the exposure estimates in risk-based methods need to be improved and that the inclusion of effect measures at first-tier prioritisation might underestimate risks. It is proposed that in order to develop an adequate prioritisation scheme, improved data on exposure such as degradation and sewage treatment removal and bioconcentration ability should be further considered. The use of ATC codes may also be useful for the development of a prioritisation scheme that includes the mode of action of pharmaceuticals and, to some extent, mixture effects.

Registration, Evaluation, and Authorization of Chemicals (REACH) Is but the First Step—How Far Will It Take Us? Six Further Steps to Improve the European Chemicals Legislation

Objectives In this commentary we analyze how much data will in fact be generated within REACH. Conclusions We conclude that the data requirements for many end points still have not been determined but depend on prioritization criteria and waiving practices that will be decided in the years to come. We propose six important steps toward an improved REACH: a) Clarify prioritization and waiving criteria. Implement decisions to ensure that sufficient data are obtained to make first hazard assessments of as many substances and end points as possible. b) Increase data requirements. Introduce data requirements similar to those currently required for substances produced or imported in quantities of ≥ 10 metric tons/year for substances produced or imported in quantities of ≥ 1 metric tons/year. c) Develop the tests and approaches needed to satisfy the information requirements taking into account resource limitations and the aim to reduce animal testing. d) Promote substitution of high risk chemicals. Create an effective process for identifying substances of very high concern and for making the appropriate risk management decisions for these substances. e) Address the control of substances incorporated in articles. And f) acknowledge uncertainties. Systematically report lack of data and include this as a basis for risk management.

Improving environmental risk assessment of human pharmaceuticals.

This paper presents 10 recommendations for improving the European Medicines Agencys guidance for environmental risk assessment of human pharmaceutical products. The recommendations are based on up-to-date, available science in combination with experiences from other chemical frameworks such as the REACH-legislation for industrial chemicals. The recommendations concern: expanding the scope of the current guideline; requirements to assess the risk for development of antibiotic resistance; jointly performed assessments; refinement of the test proposal; mixture toxicity assessments on active pharmaceutical ingredients with similar modes of action; use of all available ecotoxicity studies; mandatory reviews; increased transparency; inclusion of emission data from production; and a risk management option. We believe that implementation of our recommendations would strengthen the protection of the environment and be beneficial to society. Legislation and guidance documents need to be updated at regular intervals in order to incorporate new knowledge from the scientific community. This is particularly important for regulatory documents concerning pharmaceuticals in the environment since this is a research field that has been growing substantially in the last decades.

Reporting and evaluation criteria as means towards a transparent use of ecotoxicity data for environmental risk assessment of pharmaceuticals

Ecotoxicity data with high reliability and relevance are needed to guarantee the scientific quality of environmental risk assessments of pharmaceuticals. The main advantages of a more structured approach to data evaluation include increased transparency and predictability of the risk assessment process, and the possibility to use non-standard data. In this collaboration, between the research project MistraPharma and the German Federal Environment Agency, a new set of reporting and evaluation criteria is presented and discussed. The new criteria are based on the approaches in the literature and the OECD reporting requirements, and have been further developed to include both reliability and relevance of test data. Intended users are risk assessors and researchers performing ecotoxicological experiments, but the criteria can also be used for education purposes and in the peer-review process for scientific papers. This approach intends to bridge the gap between the regulator and the scientists needs and way of work.

Comparison of four different methods for reliability evaluation of ecotoxicity data: a case study of non-standard test data used in environmental risk assessments of pharmaceutical substances

BackgroundStandard test data are still preferred and recommended for regulatory environmental risk assessments of pharmaceuticals even though data generated by non-standard tests could improve the scientific basis of risk assessments by providing relevant and more sensitive endpoints.The aim of this study was to investigate if non-standard ecotoxicity data can be evaluated systematically in risk assessments of pharmaceuticals. This has been done by evaluating the usefulness of four reliability evaluation methods, and by investigating whether recently published non-standard ecotoxicity studies from the open scientific literature fulfill the criteria that these methods propose.ResultsThe same test data were evaluated differently by the four methods in seven out of nine cases. The selected non-standard test data were considered reliable/acceptable in only 14 out of 36 cases.ConclusionsThe four evaluation methods differ in scope, user friendliness, and how criteria are weighted and summarized. This affected the outcome of the data evaluation.The results suggest that there is room for improvements in how data are reported in the open scientific literature. Reliability evaluation criteria could be used as a checklist to ensure that all important aspects are reported and thereby increasing the possibility that the data could be used for regulatory risk assessment.

Bias in toxicology

The potential for bias, i.e., influences that cause results to deviate systematically from the truth is substantial both in toxicological research and in the performance of standardized toxicological testing. In this contribution, major potential sources of bias in toxicological research and testing are identified. Due to the lack of empirical studies of bias in toxicology, very little is known about its prevalence and impact. Areas to consider for such studies are pointed out, and it is suggested that such investigations should be given priority.

The substitution principle.

According to the substitution principle, hazardous chemicals should be replaced by less hazardous alternatives. In this paper, the major issues concerning the more precise definition of the principle are analyzed, and a general purpose definition is proposed. It is claimed that the priority between reducing hazard, functionality and economical considerations in the application of the substitution principle is a matter for adjustment in each particular case that cannot be settled beforehand. None of these objectives can have absolute priority over the others, but the substitution principle is aimed at increasing the priority given to the reduction of hazards to human health and the environment. Major methods to promote and implement the principle are summarized, current legislative approaches are discussed, and proposals for efficient implementation are made. It is emphasized that the primary responsibility for avoiding hazardous substances and processes rests with industry.

Bad Reporting or Bad Science? Systematic Data Evaluation as a Means to Improve the Use of Peer-Reviewed Studies in Risk Assessments of Chemicals

ABSTRACT In this study we assess the applicability of a set of reliability criteria proposed by Ågerstrand et al. This was done by evaluating the reliability of 12 non-standard peer-reviewed ecotoxicity and toxicity studies for Bisphenol A. There was an overall agreement between the evaluator and the authors of the papers regarding the result of the evaluations. This suggests that the criteria offer enough guidance to be a useful and consistent evaluation tool. It provides a transparent and structured approach, and ensures that a minimum and similar set of criteria is used. The evaluation of the peer-reviewed ecotoxicity and toxicity studies concludes that important information is sometimes missing, and therefore the studies do not always meet common regulatory requirements regarding reporting. Whether this is due to insufficient reporting or due to poorly performed studies is not known. To improve the reporting, and thereby promote reliability and reproducibility, researchers, reviewers, and editors are recommended to use the suggested criteria as a guideline. In conclusion, in order to improve the reliability of peer-reviewed studies, and to increase their use in regulatory risk assessments of chemicals, the dialog between regulators, researchers, and editors regarding how to evaluate and report studies needs to be strengthened.