EDCs — What’s Happening in the U.S. and Why (SETAC Focused Topic Meeting Day 1)

The range of study scales for endocrine disrupting compounds is mind-boggling.  Although the emerging assay techniques are at the molecular genetics level, it still is essential, from a scientific and regulatory standpoint, to understand what happens to entire organisms or even ecosystems.  The current management scheme still must ask some key questions addressing uncertainties and varied scientific relevancy and interpretability of the required suite of assays.

There are even varying definitions of what endocrine disruption is, although many accept the World Health Organization definition which considers them 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. (WHO, 2012)[1]

For regulatory purposes there is a real challenge to devise a scheme that with reasonable confidence demonstrates the potential for an endocrine disrupting initiating event and an adverse outcome, i.e. cause-effect, especially since the dose to the organism or specific systems is not known.

Much of the presented material and discussion on Day 1 was about this relationship and the approaches of various regulatory bodies to defining and applying it in a systematic management process.  In the case of the European Union, if the chemical has endocrine disrupting potential, based on its inherent properties, the permit to use the chemical in commerce could (would) be withdrawn.  In the case of the U.S. and some other countries, the approach is hierarchical based on a sequence of increasingly refined tests of response to organism exposure and an assessment of risk.  This approach, while inherently appealing, and as one participant noted, accounting for the benefits of use of a chemical, itself is not ideal.

The primary challenges to the EPA’s Endocrine Disruptor Screening Program (EDSP) at the Tier 1 level relate to the expense, time, experimental design versus statistical power, and the fact there is animal testing involved.  If a chemical appears to meet the Weight of Evidence criteria from the Tier 1 assays, it will be subjected to Tier 2 testing to establish dose-response.  The Tier 2 tests are subject to the above issues and also have not been fully validated across the range of endpoints and for a broad variety of taxonomic classes.

Several key points emerge from this challenge – one, how should the chemicals to be subjected to the Tier 1 testing be selected; two, how should the results of the testing be interpreted; three, is there a more efficient scheme, and four, is it possible to avoid using large numbers of test animals in order to obtain adequate confidence in the results?  A related challenge is how to address intergenerational effects when much of the prior regime of chemical testing has been focused on acute and chronic toxic effects on parent organisms or reproductive success as the sole indicator of potential effects on progeny.

Various speakers throughout the first day of the meeting addressed these challenges from various perspectives.  The US regulatory approach is based in Congressional mandates.  EPA estimates there are over 10,000 chemicals potentially to be evaluated.  So, far only a handful have been placed into the Tier 1 testing regime (52 as of mid-2013). It should be noted that EPA themselves wanted to be clear that  “these chemicals or substances should be candidates, at least for screening purposes, under EDSP testing based only on their pesticide registration status and/or because such substances may occur in sources of drinking water to which a substantial population may be exposed.”[2]  The analytical framework that EPA is using addresses three hormonal modes of action – estrogen, androgen, and thyroid, termed EAT for short.  The Tier 1 regime consists of 11 tests, the results of which are rigorously reviewed as a whole (battery approach).

This combination of lines of results is termed weight of evidence (or WOE) and is used to discern what is the overall storyline for a chemical with regard to its potential to interact with the endocrine system.  This approach is one of the most critical elements of the Tier 1 testing, yet the basis for the interpretation to designate a chemical for Tier 2 tests is not fully objective.  Adverse outcome pathways are the sequence of events from a chemical coming into proximity with an organism to the demonstrated undesirable effect with an endocrine mediated mechanism of action.   This structure provides the needed transparent logic and rigor to effect a regulatory response, even if the basis for designation as sufficiently “of concern” based on the Tier 1 battery is not entirely objective.

The next blog installment will compare and contrast what EPA is doing with that of other countries or regions, most notably the European Union.

---

[1] World Health Organization (2012), Global Assessment of the State-of-the-Science of Endocrine Disruptors, Executive Summary, WHO/PCS/EDC/02.2.

[2] Reference: http://www.epa.gov/endo/pubs/prioritysetting/list2facts.htm. Visited February 6, 2014