GlobalChem: Challenges for endocrine disruption regulation

27 February 2014 11:15  [Source: ICB]

Scientific challenges and policy decisions lie ahead for endocrine disruption regulatory actions in the US and EU

From the first days in 1996 when endocrine disruption made headlines after the publication of the book Our Stolen Future and from a research paper published in Science reporting an extraordinary degree of synergy by reputed endocrine disruptors (EDCs), the issue has been a hot bed of scientific challenges and policy debates.

With much fanfare, the reports were soon followed by enactment of legislation in 1996 by the US Congress that created the Endocrine Disruption Screening Program (EDSP).

Copyright: Alamy

Five years later, however, the NIH Office of Scientific Integrity determined there was scientific misconduct with the synergy research reported in Science by the intentional falsification of the research data. Nearly 20 years later, scientific issues and policy debates continue to pervade endocrine disruption regulatory activities.

A risk-based approach underpins the EDSP in the US for both pesticides and commodity/consumer chemicals, drawing on the authority provided by the Food Quality Protection Act 1996 and the Safe Drinking Water Act Amendments 1996.

On the other hand, European endocrine disruption legislation for plant protection products, the core chemical safety legislation in the EU dealing with pesticides, is founded on a hazard-based approach, for which controls are imposed due to the intrinsic properties of a substance.

In 2002 the World Health Organization (WHO) and the International Programme on Chemical Safety (IPCS) refined the Weybridge definition. The WHO-IPCS 2002 definition is the most widely accepted: “An endocrine disrupter is 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.”

Despite widespread agreement on this definition, debate continues on how to assess and manage risks from EDCs – not just among regulators, politicians, NGOs but also among scientists.

The EPA’s risk-based evaluation programme consists of two tiers. Under the programme, prioritised chemicals are put through a Tier 1 battery consisting of 11 screens to identify substances which have the potential to interact with oestrogen, androgen or thyroid hormone systems. Those found to have interaction, based on a weight of evidence determination, would then undergo certain Tier 2 tests to determine whether they cause any adverse effects and to establish a dose-response relationship for any of these effects. The Tier 2 test results provide the information needed for integrating with exposure data to derive risk determinations.

The first list of chemicals for Tier 1 screening finalised in 2009, comprised both pesticide active ingredients and high production volume (HPV) chemicals used for pesticide inerts. The chemicals were chosen because of their high level of exposure through four pathways of food, drinking water, residential use and occupational exposure.

In total, 52 substances underwent the Tier 1 screening battery, and EPA is currently evaluating the results. EPA is expected to release its conclusions for these 52 chemicals in mid- to late 2014. Therefore, Tier 2 testing on those substances found to interact with the oestrogen, androgen or thyroid system has not begun.

A second list of chemicals for Tier 1 screening was issued last year and consists of 109 chemicals. These substances were prioritised based on Safe Drinking Water Act criteria (ie occurring in sources of drinking water to which a substantial population may be exposed). Currently, the Office of Management and Budget is reviewing EPA’s Information Collection Request for the second list of EDSP chemicals; this approval must be granted before EPA may issue test orders to initiate Tier 1 screening of List 2 substances.

Spurred by a critique from the EPA Office of Inspector General (OIG), EPA has developed a comprehensive management plan for the EDSP with clear goals and objectives. EDSP screening is an expensive and animal intensive programme, costing companies $750,000-$1m for the Tier 1 screening alone, and both industry and NGOs have pushed EPA to improve the programme based on lessons learned from List 1 before launching List 2 screening.

EPA has responded by holding four meetings of its Science Advisory Panel in 2013 seeking review and recommendations for improving prioritisation, Tier 1 screening, Tier 2 testing and EPA’s evaluation framework for reviewing Tier 1 results. EPA is currently reviewing these recommendations.

Meanwhile the European Commission failed late last year to meet a deadline for issuing scientific criteria to identify EDCs under existing EU legislation. The regulatory deadline is set by the plant protection directive and the biocides directive. The approach taken by the EC will likely set a precedent for other regulatory programs in the EU, such as Reach.

In late 2013, the Commission decided to conduct an impact assessment based on an analysis of costs and benefits of their implementation, before finalising the regulatory criteria.

Scientific issues and policy choices are driving the EU debate. The EU executive has faced a challenge, as it has become clear that there are competing schools of thought on approaches to identifying endocrine disruptors and implementing that approach horizontally within the different legislation.

A European Commission meeting of scientific experts in October chaired by Anne Glover, its chief scientific adviser, reached what the Commission believed to be, “substantial agreement” on a number of issues and identified other areas of uncertainty, according to the minutes of the meeting. One of the most significant of these was the matter of dosage-response thresholds. While certain participants stated “there is a high likelihood that thresholds regarding EDCs exist and behaviour of EDCs can be predicted based on mechanisms,” which is in line with the principles underlying the US EDSP, other participants claimed that thresholds cannot exist for EDCs when endogenous oestrogens and androgens are already active in the hormone system.

The Commission’s hazard-based approach has been criticised by both the European and US scientists in a number of commentaries in scientific journals. Industry has also weighed in: “All regulation should be limited solely to those substances which can cause harm under realistic use conditions,” said the German chemical association (VCI) in a position paper on EDC regulation issued last year.

In evaluating the initial proposal from DG 
Environment, ACC also stated that the categorisation concept was essentially a hazard-based approach. “Under this categorisation proposal, the EU would treat all substances shown to interact with the endocrine system as sources of potential harm, without determining whether they present risk of actual harm,” says Emily Tipaldo, ACC’s director of regulatory and technical affairs.

“To actualise the IPCS definition in a ­regulatory programme requires consideration of both potency and exposure” states Rick ­Becker, a senior toxicologist with ACC. “The proposed categorisation approach by DG ­Environment is not grounded in well-­established scientific principles of toxicology and safety evaluation.”

In February 2013, a report was released by the WHO and the United Nations Environment Programme entitled “State of the Science of Endocrine Disrupting Chemicals – 2012”. The report is billed as an update of the IPCS (2002) comprehensive review, focused on providing “the global status of scientific knowledge on exposure to and effects of EDCs [endocrine disrupting chemicals.” Citing the report, the WHO states that “the latest science shows that communities across the globe are being exposed to EDCs, and their associated risks.”

But again there is disagreement. In its initial review of the report, ACC agreed with the need to better understand how chemical exposures might impact the endocrine system to cause adverse health effects, but criticised the report for not following best practices of systematic evidence-based review. Specifically, ACC criticised the authors of the report for not employing objective criteria for determining data quality and study reliability, and for abandoning the approach used in the 2002 WHO/IPCS State of the Science report for weight of evidence and substituting judgment of the authors for evaluating cause and effect.

ACC, together with Cefic, ECPA, CLI, CLA and CLCanada, recently commissioned an in-depth expert review of the WHO-UNEP report. This review has been published in the peer reviewed journal Regulatory Toxicology and Pharmacology; it is publicly available as an open access article, at

The analysis shows that the report failed to use a systematic process for assessing causation, attributed trends in human disease incidence or prevalence to endocrine disruption without evidence of their known causes or discussion of other possible causative factors. In addition, the analysis highlighted the fact that the report had little discussion of dose-response and potency, which are key determinants for causing toxicity and adverse effects, including endocrine disruption.

Author: Sean Milmo

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