Endocrine disruptors and combination effects

Endocrine disruptors have been on the agenda in Denmark since the mid 1990s. In 1993 the Danish professor Niels Erik Skakkebæk and Professor Richard Sharpe of Edinburgh launched the 'oestrogen hypothesis', arguing that effects on male reproductive health may be related to environmental effects from oestrogenic compounds/endocrine disruptors during foetal development.

A number of activities were initiated, resulting in 1995 in a Danish Environmental Protection Agency report on male reproductive health and environmental chemicals with oestrogenic effects. This was followed in 1996 by the establishment of a Research Centre for Oestrogenic Substances as part of a strategic four-year environmental research programme.

Since 2001, an annual DKK 3 million has been allocated on the state budget to strengthen the scientific background on the issue of endocrine disruptors. New findings continue to be made and the issue features a continuous focus politically, in the media and in the general population. This has frequently led to new initiatives relating to endocrine disruptors.

The Danish strategy

In September 2002, the Danish Parliament approved a report on endocrine disruptors which established the Danish strategy within this field.

The Danish strategy for endocrine disruptors target three areas:

1. Knowledge building and the development of test methods
2. Action-oriented investigations
3. Regulation

The Danish strategy corresponds closely with the EU strategy for endocrine disruptors, and the primary aim of the Danish efforts is to contribute to the international work on endocrine disruptors mainly within the EU, but also within the UN, the WHO/IPCS, the OECD and in Nordic collaborations.

The Danish strategy is described in more detail in a series of documents, all of which are available on the Danish Parliament website (in Danish):

Report on endocrine disruptors, 2002 (in Danish)

Status of the work on the national strategy, 2003 (pdf)
( http://webarkiv.ft.dk/img20021/udvbilag/lib2/20021_22922/20021_22922.pdf ) (Link virker ikke har skrevet til sagsbehandler)

Status of the work on the national strategy, 2004 (pdf in Danish)

Status of the work on the national strategy, 2007 (pdf in Danish)

Work on endocrine disruptors and combination effects has been reinforced through the adoption of the Chemicals Action Plan I for 2006-2009 and the Chemicals Action Plan II for 2010-2013. A total of DKK 28 million has been allocated to activities in the field of endocrine disruptors and combination effects.

The Chemicals Action Plans include the establishment and operation of a Centre on Endocrine Disruptors, which will build up knowledge to assist the authorities in their preventive work.

Specific projects have been initiated by the center to assess among others: The exposure of pregnant women to endocrine disruptors; combination effects after exposure to endocrine disruptors affecting both the male and female hormone systems; options for the grouping of endocrine disruptors; and the effects of endocrine disruptors in the aquatic environment.

In addition, a special grant of DKK 5 million was allocated in 2010 to assess the exposure of the general Danish population to endocrine disruptors, as well as possible effects late in life of exposure to endocrine disruptors during the foetal stage.

Read more about:
The Chemicals Action Plan I 2006-2009 (in Danish)

The Chemicals Action Plan II 2010-2013 (in Danish)
The Chemicals Action Plan II 2010-2013 (in English)

The Centre on Endocrine disruptors

As part of the efforts to build up knowledge and develop test methods, one focus has been to target and coordinate all activities in order to maximise efficacy.

The status of the development of testing methods and knowledge building is discussed twice a year within the Danish Environmental Protection Agency's hormone network. Here, experts in toxicology, ecotoxicology, epidemiology, endocrinology and paediatrics with experience of experimental studies and clinical experience, and representatives of public bodies exchange knowledge and ideas with the aim of ensuring a coordinated and targeted initiative across disciplines.

This cooperation has proved to be very fruitful and has, for example supported the Danish participation within development of test methods in the EU/OECD and resulted in the regulation of specific endocrine disruptors and initiatives related to combination effects.

Denmark actively contributes to the work within the OECD on the development of testing methods for the identification of endocrine disruptors.

Denmark has been particularly active in contributing to the development of two OECD test methods for screening the endocrine-disrupting properties of substances in laboratory animals (the OECD TG 440 Uterus test and the OECD TG 441 Hershberger test).

Denmark has also taken the lead in the development and adoption of a test for endocrine-disrupting effects in fish (OECD TG 234 Fish Sexual Development Test).

In October 2009, Denmark also hosted an OECD workshop on the activities of Member States relating to the testing, assessment and handling of endocrine disruptors.

Read more about the OECD’s initiatives (at oecd.org)

To promote knowledge-sharing, Danish national workshops on endocrine disruptors were held in 2006, 2008 and 2010. The programmes and presentations from two of the national workshops from 2006 and 2008 are available in Danish.

National workshop on endocrine disruptors 2006 (in Danish)

National workshop on endocrine disruptors 2008 (in Danish)

In 2002, 2005, 2007, 2009 and 2011, international scientific workshops on endocrine disruptors were held at Copenhagen University Hospital.

Action-oriented investigations

The action-oriented investigations included a series of major studies of the Danish aquatic environment following findings in Danish watercourses in 2001 of fish with sexual development abnormalities. The results of these studies showed that the Danish aquatic environment is generally in good condition.

The studies of the Danish aquatic environment can be read here:
"Feminisation of fish - The effect of estrogenic compounds and their fate in sewage treatment plants and nature", Miljøprojekt nr. 729, 2002

"Hormonforstyrrende stoffer og lægemidler i spildevand". Miljøprojekt nr. 799, 2003 (in Danish)

"Survey of Estrogenic Activity in the Danish Aquatic Environment, Part A", Miljøprojekt nr. 977, 2005

"Survey of Estrogenic Activity in the Danish Aquatic Environment, Part B", Miljøprojekt nr. 1007, 2006

Regulation

Endocrine disruptors are in general covered by EU chemicals legislation. However, one of the major barriers to regulation has been the big gaps in the knowledge about this class of substances.

There is no internationally recognised definition of an endocrine disrupting chemical, and no criteria have yet been established to qualify a substance as an endocrine disruptor. This is partly because until recently no internationally recognised test methods have been available to predict endocrine-disrupting properties.

The first test methods have now been adopted by the OECD. Denmark has actively participated in development of these methods, and the work within OECD to prepare guidance for the authorities and industry on the use of these test methods for the assessment of endocrine-disruptors.

Endocrine disruptors are covered by REACH Art. 57(f), i.e. substances of very high concern (SVHC) that are candidates for regulation through authorisation. A specific assessment of the individual substance is required to determine whether it is covered by this article in REACH and this is naturally difficult as long as the criteria for endocrine disruptors are not clear.

The new pesticide regulation also requires that criteria for classifying pesticides as endocrine disruptors – and therefore prohibiting their use – be established by December 2013.

Work is thus underway within the EU to establish criteria for the identification of endocrine disruptors. Denmark work for a set of criteria applicable across all relevant legislative areas, but provide for a differentiated handling of identified endocrine disruptors depending on the requirements within the individual areas of use. Denmark has therefore presented a proposal for criteria as a contribution to the EU process.

Read the Danish proposal for criteria for endocrine disruptors submitted to the EU

Awaiting the establishment of criteria for identifying endocrine disruptors, efforts have been put into obtaining documentation for the endocrine-disrupting properties of specific substances, primarily with the aim of EU regulation. Denmark's strategy is to strive for strict regulatory measures when scientific documentation is available to indicate that a specific exposure constitutes a risk.

A typical example of a strict regulatory measure would be a ban on the use of the substance in general, or in specific products. Where a reasonable suspicion of risk exists, the aims would be 'soft' regulatory measures to help reduce exposure to endocrine disruptors in everyday life. This might for example involve voluntary agreements with industry associations or distributors, or the provision of information to the general population.

In order to enable the general population and industry to reduce exposure of humans and the environment to suspected endocrine-disrupting chemicals, Category 1 substances on the EU's list of potential endocrine disruptors are included in the Danish List of Undesirable Substances if they are used in high quantities in Denmark.

A number of information campaigns have also been carried out with the aim of reducing the population's exposure to endocrine disruptors .

In order to coordinate the handling of endocrine disruptors throughout legislative areas, cross-ministerial meetings are held twice a year involving delegates from the Danish Environmental Protection Agency (responsible for industrial chemicals, consumer products, cosmetics, indoor climate, pesticides and biocides), the Danish Veterinary and Food Administration (responsible for pollutants and additives in food products and food packaging materials), the Danish Medicines Agency (responsible for pharmaceuticals and medical equipment), the National Board of Health (responsible for the general health of the population, including semen quality monitoring), the Danish Working Environment Authority (responsible for the working environment) and the Danish Enterprise and Construction Authority (responsible for construction materials).

Among other things, the Danish efforts within the field have resulted in regulations governing specific phthalates, parabens and fungicides for use in greenhouses.

Many substances are suspected of being endocrine disruptors, but it has proven difficult to regulate these substances as it cannot be demonstrated that they constitute a risk for humans and the environment in themselves at the low doses to which we are exposed on a daily basis. However, we are exposed to many substances in low concentrations every day; combination effects must therefore also be taken into consideration.

Combination effects

During the past 5-10 years, Danish and other research has shown that combinations of endocrine disruptors in low concentrations can give rise to severe health effects in mammals, even if the same substances acting individually in the same concentrations would not have any effect. Denmark therefore wishes combination effects to be included in EU legislation.

In 2009, Denmark hosted an international Expert workshop on combination effects. The conclusion from this workshop was that, although we still have large gaps in our knowledge, we have in recent years learned enough about the combination effects of endocrine disruptors to make their consideration in risk assessments of endocrine disruptors both possible and advisable.
Download the report here

As a result of the conclusions of the expert workshop, which also specified a method for taking combination effects into account, the Danish Environmental Protection Agency undertook a study of the total exposure to endocrine disruptors of two-year-old children. The study showed that the exposure of two-year-olds to endocrine disruptors gave cause for concern and this resulted in an information campaign on how to reduce exposure to endocrine disruptors in day-to-day life.
Read more about the study and the campaign here

The expert report and the Danish Environmental Protection Agency's report on the total daily exposure of two-year-old children to combinations of endocrine disruptors led Denmark to raise the issue of combination effects at EU level. The initiative resulted in the Council (environment) adopting Council conclusions on the combination effects of chemicals . As a follow-up to the Council's conclusions, the European Commission has begun to investigate whether, and if so, how, existing legislation takes combination effects into consideration, as well as to prepare a proposal for incorporating combination effects into relevant legislation in the future.

As part of the work relating to combination effects, the European Commission also commissioned a report on the 'state-of-the-science' on combination effects. This report has been assessed by the European Commission's three scientific committees (draft opinion has been in public hearing) .

In 2010, Denmark held the chairmanship of the Nordic Council of Ministers; endocrine disruptors and combination effects were given high priority.

The ministers for the environment of the Nordic countries reached agreement on a joint Nordic action in relation to the EU work on the development of criteria for endocrine disruptors and the regulation of combination effects.

In this context, three Nordic workshops were held on the subject of endocrine disruptors, with the aim of building up expertise within the authorities in the Nordic countries.

Reports from the three workshops can be downloaded from the Nordic Council of Ministers' website:

Endocrine disruptors - consumer protection by soft regulatory measures

Endocrine disruptors - developing criteria

Endocrine disruptors - combination effects

In January 2012, Denmark takes over the Presidency of the Council of the European Union. One of the Danish priorities during the Presidency is a focus on combination effects and endocrine disruptors.