保健・化学物質対策

DEALING WITH POTENTIAL ENDOCRINE DISRUPTING CHEMICALS - THE DEVELOPMENT OF REGULATORY APPROACHES IN EUROPE

Michael Roberts and Christina Lye
Independent Consultants,
United Kingdom

Michael Roberts Christina Lye

Introduction - defining the issue

Effects of endocrine disrupting chemicals (EDCs) - substances in the environment that can disrupt hormone or endocrine systems and lead to adverse effects - have been evident since the 1940s, when eggshell thinning and egg breakages in certain bird species were reported (Vethaak and Legler, 2013). In Europe, as elsewhere, large population declines were observed in the marine mollusk Nucella lapillus due to masculinization of females by exposure to the anti-fouling paint ingredient tributyltin (TBT) in the1980-90s (Gibbs & Bryan, 1996; Matthiessen & Gibbs, 1998). Lye et al. (1997) linked induction of the egg yolk protein, vitellogenin, in male flounder (Platichthys flesus) to exposure to sewage effluent in the estuary of the River Tyne in England. Further research in the UK on freshwater and estuarine fish species demonstrated widespread oestrogenic or feminizing impacts, from a range of chemicals present in effluent (Jobling & Sumpter, 1993; Jobling et al., 1998, 2002; Matthiesen et al. 2002; Kirby et al., 2004; Stolzenberg et al., 2013). Feminisation of marine fish species in offshore waters was also observed (Allen et al., 1999; Bateman et al., 2004; Stentiford & Feist, 2005; Scott et al., 2007). Elsewhere, female mosquitofish (Gambusia affinis holbrooki) downstream from kraft paper mills displayed masculinization of the anal fin, an androgen-dependent trait. (Howell & Denton, 1989; Cody & Bortone, 1997; Bortone & Cody, 1999; Parks et al., 2001)). Pulp and paper mill effluents also had the potential to suppress or inhibit reproductive capacity in male and female fish. The endocrine capability in the effluent remained even after elimination of chlorine bleaching compounds and improving treatment, suggesting that compounds present in the wood itself were responsible for the effects (Munkittrick et al. 1998). Further research confirmed that sterols released from the processed wood pulp were the prime suspect. Bacteria in water and river sediments converted the sterols to make androgen hormones, which then contaminated the water and influence fish development (Jenkins et al., 2001, 2003).

These and other concerns led to the adoption in 1998 of a resolution by the European Parliament, calling on the European Commission (EC) to amend the EU's legislative framework and, in December 1999, the adoption by the EU of the Community Strategy for Endocrine Disrupters (COM (1999) 706) (Stolzenberg et al., 2013).

The EU Community Strategy


The Strategy adresses the key requirements of further research, international co-operation, public communication and appropriate policy action via a series of short-, medium- and long-term actions.

Short-term actions over a period of 1-2 years aimed to establish a priority list of EDCs, together with a monitoring programme for listed chemicals. It also provided for the establishment of information exchange and international co-ordination, together with the provision of public information and stakeholder consultation.

Medium-term actions were envisaged to take place over a 2-4 year period and were aimed at the identification and assessment of EDCs, the development of new and improved test methods, together with research and development on mechanisms of action, causal links, risk/exposure assessment and monitoring tools.

In the longer-term, over 4 years or more, the Strategy aimed at the adaptation or amendment of EU legislation on chemicals, consumer health and environmental protection.

The Strategy undertook to provide progress reports at regular intervals; the most recent was published in August 2011 (see: http://ec.europa.eu/environment/chemicals/endocrine/pdf/sec_2011_1001.pdf). Among the Conclusions of this report, it was noted that although much EU legislation had specific provision, there was a need to agree approaches for the identification and assessment of EDCs; in addition, EU legislation currently had limited opportunities for the integrated assessment of cumulative effects of EDCs.

The current EU legislative framework concerning EDCs and important recent changes

As noted by (Stolzenberg et al., 2013), the development of a priority list under the Community Strategy concluded that most known or suspected EDCs were already subject to some form of regulation or legislative approach in the EU, although not necessarily related to them being endocrine disrupters.

The Strategy has led to the inclusion of specific provisions on EDCs in various pieces of legislation. In chronological order these are: the Water Framework Directive (2000/60/EC)1; the REACH2 (Registration, Evaluation, Authorisation and Restriction of Chemical Substances) Regulation (1907/2006); the Plant Protection Products Regulation (1107/2009); and the Biocidal Products Regulation (528/2012). Provisions governing EDCs are also included in the Regulations on Cosmetics (1223/2009)3 and the EC proposals for Medical Devices regulation4.

1 http://ec.europa.eu/health/endocrine_disruptors/docs/wfd_200060ec_directive_en.pdf
2 http://ec.europa.eu/health/endocrine_disruptors/docs/reach_1907_2006_regulation_en.pdf
3 http://ec.europa.eu/health/endocrine_disruptors/docs/cosmetic_1223_2009_regulation_en.pdf
4 http://www.ft.dk/samling/20111/almdel/suu/bilag/225/1085257.pdf


The REACH Regulation is one of the main pieces of legislation addressing EDCs. Under REACH, chemicals classified as Substances of Very High Concern (SVHC) may be subject to authorisation and may not be used unless there is authorisation for specific uses or applications, under strict conditions. Chemicals having endocrine disrupting properties may also be subject to the REACH Authorisation Process if, identified on a case-by case basis, they have a level of concern equivalent to:

  • carcinogens, mutagens, repro-toxins (CMRs); or
  • persistent, bio-accumulative and toxic (PBTs); or
  • very persistent and very bio-accumulative (vPvBs).

Note that the EC has to review ED authorisation under REACH.

There are a variety of ways in which EDCs are referred to across EU legislation, with regard to adversity of effects and causality. As also noted by Stolzenberg et al. (2013), the underlying philosophy of the EU regulatory framework has been predicated on both the identification of hazard (the intrinsic potential of a substance to cause harm) and assessment of risk (the actual probability of harm being caused following exposure to the substance). However, recent changes in EU legislation have marked a shift from risk-based to hazard-based approaches, specifically with regard to the EU Plant Protection Products Regulation (PPPR) and the Biocidal Products Regulation (BPR) (see http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1456663246430&uri=CELEX:32009R1107 and http://eur-lex.europa.eu/legal-content/EN/TXT/?qid=1456663246430&uri=CELEX:32009R1107).

Under the PPPR, a substance with ED properties that may cause adverse effects on non-target organisms cannot be approved as an active substance, safener or synergist unless:

  • exposure is negligible; or
  • it is necessary to control serious plant health danger and alternatives (including non-chemical) are not available (only for a maximum period of 5 years).

[Note: Regulation (EC) No 1107/2009 defines 'safeners' as "substances or preparations which are added to a plant protection product to eliminate or reduce phytotoxic effects of the plant protection product on certain plants"; 'synergists' are "substances or preparations which, while showing no or only weak activity...., can give enhanced activity to the active substance(s) in a plant protection product".
(http://ec.europa.eu/food/plant/pesticides/legislation/docs/qanda_regulation_1107-2009_en.pdf)]

Under the BPR, a substance with ED properties that may cause adverse effects cannot be approved unless:

  • risks are negligible, particularly in closed systems or in conditions excluding human contact and environmental release; or
  • it is essential for human, animal or environmental health; or
  • there would be disproportionate negative impacts on society compared to the risks.

No substance with ED properties can be allowed for use by general public as a biocide.

The need for a Regulatory Definition (Criteria) and associated issues

This shift to regulating EDCs based on hazard and away from being based on risk raises several issues, perhaps most importantly concerning what exactly is meant by the term 'endocrine disrupter'. Several scientific definitions are available, but there is wide acceptance of the WHO/IPCS (2002) definition:

an exogenous substance or mixture that alters function(s) of the endocrine system and consequently causes adverse health effects in an intact organism, or its progeny, or (sub)populations.

However, this is quite broad for legislative application and there are no formal regulatory identification criteria, internationally or at the EU level, for EDCs. The PPPR and BPR empower the EC to establish such criteria for identification of EDCs and there have also been general calls on the Commission by both the European Council and the European Parliament. Furthermore, horizontal criteria (i.e. that can be used across EU legislation) are a key element in the development of a new Community Strategy on Endocrine Disruptors, set out in the EC Working programme in 2012.

There is agreement on many issues concerning EDCs, but diverging views remain on specific points within the scientific community and regulators. These include: whether non-ED effects - e.g. carcinogenicity, mutagenicity, reproductive toxicity - should take regulatory precedence as a 'Lead Dose'; should potency be included, as part of hazard characterisation? If potency were to be included, should it be a 'cut-off' criterion, or part of a weight of evidence approach? Should there be categories of EDCs and, if so, how many?

Some specific scientific issues also remain unresolved and include:

  • whether available test methods for EDCs are adequate (i.e. current testing methods are inconsistent and have been criticised for being inadequate and failing to cover all potential effects of EDCs);
  • whether thresholds of adversity exist or can be determined (the outcome of the threshold discussion will have an impact on which regulatory route the chemical ends up in. If regulators decide that EDCs have a threshold of effects, then the adequate control route under REACH is open to the authorisation of EDCs);
  • how to deal with non-monotonic dose responses (NMDRs) and low dose toxicity (i.e. adverse effects at levels far below those currently tested, which challenges basic principles of toxicology);
  • how to deal with mixture effects (i.e. exposure to several EDCs at the same time, which might result in unexpected adverse health effects).

With regard to test protocols, an extensive international development programme has been underway for some time, under the OECD. Taking this into account, the Scientific Committee of the European Food Safety Authority (EFSA) recently provided the following opinion (http://www.efsa.europa.eu/en/efsajournal/doc/3132.pdf).

  • a reasonably complete suite of test methods is (or will soon be) available to identify and characterise the important hazards of EDCs;
  • these methods are, in principle, fit-for-purpose for establishing safe doses/concentrations;
  • consequently, EDCs can be treated like most other substances of concern for human health and the environment and be subject to risk assessment.

With regard to thresholds of adversity, a recent report by the EU Joint Research Centre's Endocrine Disrupters Expert Advisory Group (ED EAG) agreed that they were likely to exist for EDCs, but beyond this they noted a lack of consensus reflecting that found in the wider scientific community.

(see: http://publications.jrc.ec.europa.eu/repository/bitstream/111111111/32062/1/lb-na-26-068-en-n.pdf)


The Commission expects to develop guidance on threshold testing in relation to authorisations, once final EDC criteria have been published.

The interim criteria, Commission Roadmap and consultation

The EC was originally required to propose criteria in 2013, but there was a lack of consensus across EU Member States. In the meantime, the following interim criteria have been adopted:

Pending the adoption of [the] criteria, substances that are or have to be classified, in accordance with the provisions of Regulation (EC) No 1272/2008, as carcinogenic category 2 and toxic for reproduction category 2, shall be considered to have endocrine disrupting properties.

In addition, substances such as those that are or have to be classified, in accordance with the provisions of Regulation (EC) No 1272/2008, as toxic for reproduction category 2 and which have toxic effects on the endocrine organs, may be considered to have such endocrine disrupting properties.

A Roadmap was published by the EC in June 2014, setting out options for criteria and approaches to regulatory decision making.

(http://ec.europa.eu/smart-regulation/impact/planned_ia/docs/2014_env_009_endocrine_disruptors_en.pdf)


Four Options on identification criteria were set out:

Option 1
No Policy Change (baseline). No criteria would be specified, the interim criteria would continue to apply.
Option 2
The WHO/IPCS definition would be applied. Regulation would be purely based on hazard identification.
Option 3
The WHO/IPCS definition would be applied, with categories based on the strength of the evidence. Category I would be classed as endocrine disrupters; Category II as suspected endocrine disrupters and Category III as endocrine active substances.
Option 4
The WHO/IPCS definition would be applied, with the inclusion of potency. This would require hazard identification and characterisation.

A second aspect set out 3 Options for approaches to regulatory decision making:

Option A
No policy change (baseline). The BPR and PPPR provisions on regulatory consequences would be unchanged.
Option B
Introduction of further elements of risk assessment into sectorial legislation. Management measures would remain mainly hazard identification, but with scope to reduce potential socio-economic impacts - e.g. by including an exemption in the PPPR for negligible risk rather than negligible exposure.
Option C
Further socio-economic considerations including risk-benefit analysis, placed into sectorial legislation. This would allow products in situations where an EDC is essential to prevent adverse socio-economic impacts - e.g. by amending the PPPR to allow exemptions where a ban would have a disproportionately negative impact on society.

It is important to note that the criteria the Commission will draw up will apply directly to the PPPR and BPR, but they may have repercussions for other EU legislation containing specific provisions governing endocrine disrupters.

The EC conducted a public consultation on the above options between September 2014 and January 2015.

(See: http://ec.europa.eu/dgs/health_consumer/dgs_consultations/food/consultation_20150116_endocrine-disruptors_en.htm)


Information was requested on:


- assessments according to the 4 criteria options; and
- assessments applying the 3 different regulatory approaches.

Just over 27,000 responses were received from a wide range of society, including medical, agricultural and industry sectors, NGOs, academics and EU and non-EU Authorities. Some 25,000 responses were identical and originated from organised campaigns. All responses were published in February 2015 and an Analysis the following July (see: http://ec.europa.eu/health/endocrine_disruptors/docs/2015_public_consultation_report_en.pdf)

The Analysis concluded that the overall message from respondents was that there was a need for the EU to identify criteria for EDCs; so Option 1, with no specific criteria, was not supported. Beyond that, though, there were divergent views and arguments supporting or rejecting the options on defining the criteria and how EDCs should be regulated. Many respondents raised issues in relation to food safety, the threat that endocrine disrupters might pose to human health and/or environment and the impact of the different options proposed on agriculture, industry, health and environment. In particular, farmers and the agrochemical industry stressed the potential ramifications of setting criteria to identify endocrine disrupters on agriculture. Authorities from non-EU authorities highlighted the potential impact on trade. A risk based approach for regulating endocrine disrupters was proposed by many respondents including farmers, private companies, industrial or trade organisations, or authorities in non-EU countries. Authorities in non-EU countries noted that any decision on endocrine disrupters must respect the principles of the World Trade Organisation.

How things stand at present - the Impact Assessment and likely timetable

Defining regulatory criteria for EDCs will have significant impacts and this, in addition to the range of views as expressed in the consultation and the lack of legally-binding criteria in third countries, led the Commission to undertake an Impact Assessment (IA) in line with its standard procedure (See: http://ec.europa.eu/health/endocrine_disruptors/impact_assessment/index_en.htm). The IA is intended to gain a better understanding of the potential impacts on health, environment, agriculture, trade and socio-economy in general. Impacts are expected to be particularly significant for plant protection products, where the decision making is mainly based on hazard, but less so in other sectorial legislation (e.g. biocidal products). The IA is not intended as a full evaluation, so it cannot pre-empt any regulatory conclusions. As a basis for the IA, the EC's Joint Research Centre (JRC) developed a screening methodology. This is being applied by an external, independent contractor to around 600 chemicals covering the PPPR, BPR, REACH, the Cosmetics Products Regulation and the WFD. The full IA will draw on a variety of information sources, including regulatory assessment reports, a range of databases and targeted literature searches. There will also be input from the public consultation and stakeholder conferences.

The chemical screening began in May 2015 and had been expected to be completed by the end of February 2016 with the assessment of impacts on agriculture/trade, health/environment, Small and Medium Enterprises (SMEs) and industry and administration due by the end of June 2016. This meant that the final IA was expected to be available at the end of September 2016. However, although some Member States feel the EC should take care over the development of the criteria, there has been criticism of the overall time being taken. After a judgement in the EU General Court at the end of 2015, which was followed by a debate in the EU Parliament in February 2016, the deadline has been shortened and the criteria are now due to be presented by the summer of 2016.

Conclusions

The issue of how to regulate EDCs remains a high priority in the EU and there is a need for agreed criteria to support legislative approaches. However, the lack of 'political' and scientific consensus in key areas has made the development of such criteria more difficult than might have been originally supposed. There will continue to be several outstanding issues even when the Commission's proposals are published, not least how the EU regulatory approach will work alongside those of other jurisdictions, such as Japan, the USA, Canada and Australia, which apply risk-based assessments to EDCs.

Japanese

References

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Bateman, K.S., Stentiford, G.D., Feist, S.W., 2004. A ranking system for the evaluation of intersex condition in European flounder (Platichthys flesus). Environ. Toxicol. Chem. 23, 2831-2836.

Bortone, S.A., Cody, R.P., 1999. Morphological masculinization in poeciliid females from a paper mill effluent receiving tributary of the St. Johns River, Florida, USA. Bull. Environ. Contam. Toxicol. 63, 150-156.

Cody, R.P., Bortone, S.A., 1997. Masculinization of mosquitofish as an indicator of exposure to kraft mill effluent. Bull. Environ. Contam. Toxicol. 58, 429-436.

Gibbs, P.E., Bryan, G.W. 1996. TBT-induced imposex in neogastropod snails: masculinization to mass extinction. In: Tributyltin: Case study of an environmental contaminant. Ed S.J. de Mora, Cambridge University Press, Cambridge, pp. 212-236.

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Bio for Michael Roberts and Christina Lye

Dr. Roberts has Doctoral, Master and Bachelor degrees in environmental biology.
He worked previously at the UK Department for Environment, Food and Rural Affairs (Defra), bridging science with policy development for the sustainable management of chemicals, specifically with regard to potential hormone disrupting chemicals and metals in the environment.
He was closely involved as a Defra representative in the UK-Japan Research Collaboration on Endocrine Disrupters in the Aquatic Environment. He was also the UK National Co-ordinator (Environment) for the OECD Chemicals Test Guidelines Programme.
Since leaving Defra in January 2016, Dr. Roberts has become an independent consultant.
He enjoys playing golf (although not to a very high standard!) and reading history.


Dr. Lye is Head of Operations and oversees business and services across Enviresearch. She also heads the Risk Assessment team.
With over 25 years of experience of environmental risk assessment and management from working in government, industry, academia and consultancy, she has gained extensive specialist knowledge in the areas of ecotoxicology, in particular chemicals that are suspected to be endocrine disrupters).
Dr. Lye has published a number of peer reviewed scientific papers in the field of endocrine disrupting chemicals and has acted as a consultant to the UK regulatory authorities (DEFRA) on several of their work programmes. She has also acted as a consultant to OECD in their development of the test guidelines and programmes.
Dr. Lye holds a PhD degree in Biology from the University of Newcastle, UK and an MSc in Microbial Ecology from University of Stockholm, Sweden.
During her spare time Christina is active in the local community, enjoys keeping fit and is a regular yoga practitioner and fitness boot camper.