In 2002, the World Health Organisation (WHO) International Programme on Chemical Safety (IPCS) defined an endocrine disruptor as “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.” Endocrine disruption is currently a complex issue in chemical regulation with a marked conflict between EU policies and the rest of the world.
Certain global regulatory agencies do not consider endocrine disruption to be an endpoint in itself, but rather a mode, or mechanism of action leading to other outcomes, for example, carcinogenicity, reproductive toxicity, or developmental effects. Evidence of endocrine disruption may nevertheless influence the prioritization of a chemical for further testing, and the results may lead to regulatory action if adverse effects are found. The whole process is risk based however, meaning that potential exposure is also considered. These agencies include, but are not limited to, the US Environmental Protection Agency (EPA), Canadian Pest Management Regulatory Agency (PMRA), and Australian Pesticides and Veterinary Medicines Authority (APVMA).
The risk assessment view contrasts with that of the European and Brazilian legislation for agrochemicals and biocides, where endocrine disruptors are not permitted. Under REACH however, endocrine disruptors may still be available, but with restrictions. Still under debate in the EU is the interpretation of what legally constitutes endocrine disruption, and whether any dose of a weakly hormonally active substance is potentially adverse. Consequently, the regulatory environment for chemicals which might show these properties can be particularly challenging to navigate and involves both mammalian and ecotoxicological consideration.
EPA’s Endocrine Disruption Screening Program (EDSP)
Enactment of the 1996 Food Quality Protection Act and 1996 Safe Drinking Water Act Amendments required the US EPA to “…develop a screening program using appropriate validated test systems and other scientifically relevant information…” to examine the endocrine disrupting properties of pesticides and “any other substances that may be found in sources of drinking water … if a substantial population may be exposed.”
EPA responded by initiating the EDSP to identify potential endocrine disruptors using a two-tiered approach. The Tier 1 screening assays are designed to identify whether substances have the potential to interact with the estrogen, androgen or thyroid (EAT) hormonal pathways. The weight of the evidence from the Tier 1 screening determines whether it will be necessary to conduct additional Tier 2 testing. Tier 2 testing includes longer term, definitive studies intended to identify any adverse health effects and to establish dose-response relationships that may result from endocrine bioactivity identified from Tier 1 screening. Thus far, 52 pesticides have been screened under EDSP Tier 1 at a cost of approximately $1 million per test substance; 18 of these compounds were identified for further Tier 2 testing. EPA has also released a list of further chemicals to undergo Tier 1 screening in the near future, a combination of pesticide active ingredients and drinking water contaminants. For these compounds and others, the EPA anticipates allowing alternative approaches using validated high throughput assays and computational models in lieu of some Tier 1 screening assays.
The EU’s Endocrine Disruptor Exclusion Criteria
The European Plant Protection Products (EC 1107/2009) and Biocides (EU 528/2012) Regulations both include endocrine disruption as an exclusion criterion; i.e. substances that are endocrine disruptors cannot be approved under these Regulations. The EU REACH Regulation requires that endocrine disruptors progress to the stage of “authorisation” as Substances of Very High Concern (SVHC).
However, these Regulations are unclear as to which properties of a chemical might qualify it as an “endocrine disruptor”, or how substances with mild properties or low potency will be addressed. These criteria are still being decided, with a decision unlikely before 2017. It seems probable that a chemical with evidence for both an endocrine effect, and adversity linked to that effect, will be vulnerable. In the meantime, classification as “C2R2” (Carcinogenicity Cat. 2 AND Reproductive toxicity Cat.2 under CLP or GHS), or classification as R2 in conjunction with “toxic effects on endocrine organs”, are the interim criteria for endocrine disruption. The EU does not presently require any of the US EDSP studies on a routine basis, but relies initially on detailed and well-performed subchronic and multigeneration study designs. However, findings in the EDSP – even if conducted for US legislation - will be relevant in the EU, and may become necessary to elucidate findings for certain chemicals. While the EDSP currently investigates only the androgen, estrogen and thyroid systems, the EU exclusion criteria may be applied more widely than these pathways.
Broader International Ramifications
In Canada, regulations under the Canadian Environmental Protection Act (CEPA) and the Pest Control Products Act (PCPA) are being considered, but are still in the development stage. Under the EXTEND 2010 program in Japan, and in China, environmental monitoring and testing and assessment are being undertaken to evaluate endocrine disruptors. Brazilian legislation prohibits endocrine disruptors as pesticides. Obvious, significant differences currently exist in how regulatory authorities worldwide consider the issue of endocrine disruption. On one side, some agencies are using an exposure-based evaluation of potential risks from endocrine disruption, which contrasts with the hazard-based exclusion criteria being considered in Europe and Brazil. Regardless, being labeled as a potential endocrine disruptor in the EU or the US will result in increased regulatory pressure, market deselection, and/or restrictions.
How Exponent Can Help
Exponent is exceptionally well qualified to offer creative solutions to complex endocrine disruption problems. Exponent scientists have been recognized leaders in endocrine disruption, mammalian and wildlife science and policy. Our consultants have served on committees of the National Academy of Science, International Life Science Institute (ILSI), or government, including the Endocrine Disruption Screening and Testing Advisory Committee. We have been invited participants at workshops, conferences, and other scientific forums both in the EU, the U.S. and abroad. Scientists of Exponent’s Centers for Chemical Regulation & Food Safety, Toxicology and Mechanistic Biology, and Ecological and Biological Sciences Practice have teamed up to design, advise and place bespoke studies and strategies (for example, investigating potential secondary mechanisms) as well as EDSP protocols.
Our experience has been applied to a wide variety of molecules, including BPA, phthalates, pesticides, industrial (HPV) chemicals, and pesticide inert ingredients. Case studies are given below.
Our endocrine disruption consultation adapts to our clients’ requirement and can include:
- Vulnerability assessment for potential endocrine disruption issues in the US and EU including evaluation of sub-chronic, reproductive or developmental toxicity data, published literature, and publicly-available high throughput screening data, to assess potential to trigger or satisfy EDSP testing requirements or EU exclusion criteria.
- Critical assessment of published chemical-specific literature compared to GLP study data.
- EU REACH, Agrochemicals, and Biocides testing and registration strategy.
- Development of EDSP Tier 1 and Tier 2 testing strategies, preparation and submission of mammalian and wildlife Other Scientifically Relevant Information (OSRI), Tier 1 Weight of Evidence analysis including necessity for Tier 2 testing, testing waivers or submissions for supplemental testing to address Tier 2 testing.
- Design, placement and monitoring of studies including including EDSP Tier 1 and Tier 2.
- Representation to EPA, EU, and international regulatory authorities.
- US and EU testing strategies to explore possible non-relevance of apparent endocrine-related findings. Where appropriate, these strategies are discussed and refined with regulatory authorities to ensure the program fulfils the specific regulatory need.
- Determination of adverse outcome pathways (AOPs)
- Consortia organization and management.