Endocrine disruptors: criteria, testing and assessment
Sep. 21, 2016
Endocrine disruptors, their definition and criteria as well as feasible options for testing and assessment, have been extensively worked on and discussed in science and regulatory panels. The debate has engaged the public and national and global political agendas.
Meanwhile, the WHO/IPCS definition of an endocrine disruptor is unanimously agreed upon:
“An exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse effects in an intact organism, or its progeny, or (sub)populations.”
Consequently, distinct adverse effects and their causal relationship to substance exposure, by a proven endocrine mode of action, need to be established.
By contrast, the scientific criteria for their identification have been the object of fierce and tedious detailed discussions. Finally, on 15 June, the European Commission presented its long-awaited draft scientific criteria to identify endocrine disruptors (EDCs) in the field of plant protection products and biocides.
This announcement was preceded by an expert meeting, organised by the Federal Institute for Risk Assessment (BfR) in Berlin in April. The meeting resulted in a consensus paper, essentially suggesting the presented criteria.
It must be noted that these criteria are not yet adopted. In the context of the plant protection products Regulation, the draft legal text will be voted on by the member states. In that of the biocidal products Regulation, it will be discussed by a group of member state experts before going to the Commission. The legal text may still see further changes before its ultimate adoption, which is foreseen the end of 2016 or early 2017. For the sake of consistency, it is envisaged that both texts will be presented simultaneously to the Parliament and Council by the Commission.
Option two has been selected from four, which were under discussion. The options were:
• option 1: no policy change (interim criteria);
• option 2: identification according to WHO/IPCS definition;
• option 3: WHO definition plus additional categories; and
• option 4: WHO definition with the inclusion of potency.
Thus, in principle the WHO definition without consideration of potency is the selected approach. Further, the ground for possible derogations under the plant protection products (PPPs) legislation is expected to be adjusted. This is to take into account the latest scientific knowledge and make the best use of available evidence, including information related to exposure and corresponding risk.
However, overall the hazard-based approach for PPPs and biocides, for the general public, will be maintained, meaning substances can be banned without taking into account exposure or risk assessment. Exceptions for professional uses may be granted. But only if negligible risk can be demonstrated, or the necessity of the substance to combat serious pests, which cannot be contained by other available means (PPPs and biocides); or there are disproportionate negative impacts of non-approval of the substance on society, when compared to the risks (biocides only).
This is in contrast to the position advocated by European industry, which argues that the WHO/IPCS definition alone is not sufficient for making a clear distinction between substances of high concern that pose a risk to human health and environment, and those that don’t. All available and relevant scientific information, including potency, should be considered when evaluating a substance for its potential endocrine-disrupting properties.
However, NGOs say that the burden of proof for a substance to be identified as an EDC seems rather high, and that causality is difficult to prove.
Meanwhile, until final scientific criteria are agreed on and adopted, interim criteria for toxicology still apply for PPPs/biocides. Carcinogenic category 2 and toxic for reproduction category 2 – shall be considered as EDC, or toxic for reproduction category 2 and specific effects on target organs – may be considered as EDC. However none are available for wildlife.
Current regulatory developments worldwide
A community strategy for EDCs was developed by the Commission in 1999. It involves regular updates on implementation, including a priority list of substances for further evaluation. In 2014, the roadmap on “Defining criteria for identifying endocrine disruptors in the context of the implementation of the plant protection products Regulation and biocidal products Regulation” was presented.
It included a public consultation (report published in July 2015) and an impact assessment (IA) (published in June 2016), to evaluate health, socio-economic and environmental impacts of the different options for the criteria and their implementation in the respective legislations.
The IA was supported by two studies, which selected substances and screened them for their potential to be identified as EDCs according to the options. And an assessment of the potential impacts on health, environment, trade, agriculture and socio-economics was made. The screening is guided by a methodology developed by the Commission’s JRC (Joint Research Centre) in 2013.
Several pieces of legislation are relevant with regard to EDCs in the European Union.
In addition to the plant protection products and the biocidal products Regulations, REACH and the cosmetics Regulation are highly important.
Under REACH Article 57f, EDCs are eligible as SVHCs with an equivalent level of concern as for PBT or CMR substances. Thus, generally they might be subject to authorisation, including a socio-economic analysis.
By January, Echa had selected about 300 chemicals for additional manual screening by the national authorities, for further regulatory action. An important focus was substances with endocrine-disrupting potential. Substances were selected by an automated IT screening of any data available, meaning the complete REACH registration database, existing lists and other databases, publications, Qsar model data, and data on exposure and uses.
To this end, a related “screening definition” document was issued in January 2016, specifying the scenarios for identifying potential endocrine disrupting substances. It is emphasised that no single scenario is considered sufficiently robust for selecting a substance for manual screening. Thus the scenarios should be considered in a weight-of-evidence approach. In a nutshell, the following scenario categories were applied:
• check if the substance itself, or a constituent, impurity or additive can be found in published/external lists of suspected EDCs (Commission, WHO, TEDX or SIN) or are structurally similar to substances in these lists;
• use of models to predict if the molecular structure of the substance itself, and its constituents, impurities or additives trigger specific structural EDC alerts, such as those based on the Danish Qsar models, developed by the Technical University of Denmark;
• check the self and harmonised classification, suggesting suspected endocrine disrupting effects, such as the presence of specific target organ toxicity classifications for endocrine organs;
• analyse information in the registration dossiers and chemical safety reports, by screening text patterns typically associated with evidence for/indications of endocrine disrupting properties (for example, repeated dose toxicity, toxicity to reproduction, fertility and developmental toxicity, long-term aquatic toxicity); and
• positive findings in external experimental data generated with assays, for example, ToxCastTM in vitro data (see further below).
Application of these scenarios led to the selection of more than 100 substances. These were ranked according to total tonnage for full registrations, which resulted in the selection of 75 of them.
The cosmetics Regulation is currently still under review, and so far EDCs are not restricted in any way. Now that the criteria for the identification of EDCs are available, the review should be completed soon.
No precise data requirements are foreseen for any European regulation, but studies can be requested at any time and at any level of the assessment. Requested studies are mostly based on the OECD Conceptual Framework for Testing and Assessment of Endocrine Disruptors, and detailed guidance for the assessment is provided in the comprehensive OECD guidance document No 150: Guidance Document on Standardised Test Guidelines for Evaluating Chemicals for Endocrine Disruption.
In parallel to the process of defining the scientific criteria, individual proposals have been put forward by different European nations. These vary considerably, not least in that some are more risk-based and some are strictly hazard-based. However, in general, European proposals mostly focus on a hazard-based assessment, proposing endocrine disrupting properties as cut-off criterion with few exceptions.
Currently, assessment is mostly conducted on a case-by-case basis.
In the US, the EPA takes an opposite approach with its comprehensive, two-tiered screening programme, which is still followed by regular risk-based assessment. This Endocrine Disruptor Screening Programme (EDSP) intends to cover oestrogen, androgen and thyroid hormonal systems with respect to human safety and wildlife.
Tier 1 aims at the identification and classification of potential EDCs by in vitro and in vivo assays (series 890, EDSP Test Guidelines). Tier 2 focuses on the establishment of concentration- or dose-response relationships, with several test guidelines finalised in August 2015.
The initial tier 1 list of 67 chemicals to be screened was issued in 2009, followed by list 2 in 2014. This is made up of 109 substances. It is strongly emphasised that the lists are not intended to be lists of suspected chemicals, but instead are based on a potentially high level of exposure (pesticide active ingredients and HPV chemicals, used as pesticide inert ingredients).
Results of tier 1 assays are reviewed together with other scientifically relevant information (Osri), leading to a decision on eventual further tier 2 testing. A review of tier 2 data will, in turn, directly support risk assessments for registration and actions.
In July 2015, the EPA published the first results from screening 52 chemicals from the tier 1 list. This identified a potential for interaction with endocrine pathways (EAT) for 32 of the chemicals, and further required actions on tier 2 testing for 18 chemicals.
It has been recommended that more modern, alternative approaches replace some of the EDSP tier 1 screening assays. Therefore, an efficient and robust screening programme is under development, applying high throughput in vitro screening assays and computational and in silico model alternatives, for example, ToxCast models, especially envisaged to be applied to third draft list of chemicals.
In China, an agro-industrial standard, Evaluation Method of the Endocrine Disruption Effects of Pesticides, became available in late 2014. It was reviewed by the Ministry of Agriculture, and has been implemented from 1 April. The guidance includes two tiers and seven toxicological study types, and intends to screen for probable endocrine disrupting properties of pesticides, applying methods similar to the ones developed by the US EPA.
An action plan for water pollution prevention by the State Council was implemented in 2015, including a national survey on production and uses of environmental endocrine disruptors before the end of 2017. The aim is to eliminate, restrict or substitute EDCs.
In Japan, the Ministry of Environment has, for a long time, been promoting research on the mechanisms of endocrine disruption, environmental monitoring, as well as the development of test methods, hazard and risk assessment, risk management, information sharing and risk communication on the substances.
Several projects have been launched in the country, such as SPEED’98 and ExTEND (Extended Tasks on Endocrine Disruption). The ministry updated this in 2016. If results suggest that a substance has endocrine disrupting properties, it will be regulated under Japan’s Chemical Substance Control Law (CSCL) and can be subject to restrictions or even banned.
In recent years, Japan has been actively collaborating with the US on the development of test guidelines for the US EDSP. Like the US, Japan advocates risk-based assessment.
Implications and recommendations for global registrations
The foreseen EU criteria for EDCs will most certainly affect global trade, as they will apply to products imported into the EU, which in turn will trigger a WTO notification.
Although their implementation in the respective EU legislations is not directly linked to other global regulatory programmes, this will influence the overall discussion on the assessment and regulation of EDCs, as part of a larger global policy debate.
The intended Transatlantic Trade and Investment Partnership (TTIP) between the European Union and the US aims to reduce trade barriers, and thus also harmonise approaches to assessment. This is to avoid a situation where the criteria and methods applied under one regulation could lead to a different result under another. In parallel, it had been announced that the US and EU are seeking a harmonised approach on EDCs in a pilot programme.
In conclusion, weight-of-evidence and expert assessments, tailored for respective regulatory programmes, are still required for the evaluation of endocrine disrupting properties of a substance. It is strongly recommended that studies are constructed carefully in order to meet global requirements and avoid redundant testing, not least with regard to animal welfare. Results obtained by studies for one regulatory programme should be considered and dealt with like any other.
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