21st Century on the horizon for endocrine disruptor screening?

Rachel Shaffer is a research assistant. Jennifer McPartland, Ph.D., is a Health Scientist.

BPA, DDT, PCBs, PBDEs, phthalates, PFOA … Forgive the alphabet soup, but chances are you’ve heard of at least some of these endocrine-disrupting chemicals (EDCs), which have been the subject of a lot of public and media attention in the last several years. Research has begun to uncover the ways in which these chemicals can interact with the body’s hormone – or endocrine – system to disrupt various natural biological processes, including metabolism, the reproductive system, and development of the brain and nervous systems.

While the endocrine-disrupting properties of the chemicals named above have been confirmed, scientists suspect there may be many more such chemicals in our environment, in the products we use, and in our bodies.  How can we identify them?

Legislation enacted in 1996 required the U.S. Environmental Protection Agency (EPA) to develop a screening program to identify potential EDCs.  More than 10 years later, EPA finally launched the Endocrine Disruptor Screening Program (EDSP).  Testing is being conducted in two phases, or “tiers.”  In “Tier 1,” a screening battery of validated in vivo and in vitro assays is used to identify chemicals with potential to interfere with the endocrine system. Chemicals flagged in the first tier of testing are then subject to “Tier 2” testing intended to determine the specific effect and the lowest dose at which it occurs. (We should note this program is very controversial and the subject of ongoing debate, but that is not the subject of this post.)

EPA has identified an estimated 9,700 chemicals to be screened – a very daunting task given the time- and resource-intensive nature of the testing battery EPA has established.  Might there be a way to expedite the identification and testing of the more problematic chemicals? A study published earlier this year in Environmental Health Perspectives (EHP) investigates a possible approach: using in vitro high-throughput (HT) assays developed through EPA’s ToxCast and Tox21 programs to target and prioritize chemicals for further testing under the EDSP. While use of these assays poses its own challenges, might it at least help in determining an appropriate testing sequence? 

Incorporating in vitro HT assays into EDSP is the centerpiece of EPA’s Endocrine Disruptor Screening Program for the 21st Century (EDSP21), which aims to take advantage of advancements in chemical testing to “more quickly and cost-effectively complete chemical assessments.”

The EHP study referenced above focused on the initial phase of the EDSP and investigated whether available HT assays could sufficiently identify potential endocrine disruptors so as to prioritize chemicals for Tier 1 testing.

The results were mixed.  For certain types of endocrine disrupting effects – those related to estrogenic and androgenic activity – the authors reported that the HT assays were fairly predictive, reaching the same conclusion for 90% of the chemicals as did the standardized tests EPA used as a benchmark.  By contrast, assays for other types of endocrine disrupting effects – including those related to thyroid function – performed quite poorly, “correctly” categorizing only 50-60% of chemicals.         

What accounts for this stark difference? The explanation may lie in the manner by which chemicals perturb different parts of the endocrine system.  Many of the chemicals known to disrupt normal estrogen and androgen activity do so by binding to the same cell receptors that estrogen and androgen bind to.  The current battery of HT assays is fairly effective in detecting this activity.  On the other hand, chemicals that interfere with the thyroid system, for example, act in many different ways, and the existing HT assays are unable to adequately detect these other types of interferences.

This shortcoming reflects a broader challenge facing the use of this new approach to toxicity testing. If we are to have complete confidence in the results of these new techniques, then the assays used need to cover the full biological response landscape. In other words, they must be able to detect disruptions in any of the hundreds of biochemical processes that take place in our bodies (for more on this limitation, see this EDF primer page).   If not, then the tests may miss an effect (in the situation just described, an endocrine-disrupting effect) of a chemical not because there isn’t one, but merely because an assay for the specific effect has not yet been developed. 

In the long term, such limitations may be addressed through research that yields new assays that increase coverage. In the interim, however, transparency and full disclosure about the capacity of these approaches are crucial. The authors of the EHP study did a good job in communicating clearly about the pros and cons of this potential application of HT assays to the EDSP:  based on the results, they concluded these assays can be used to effectively and efficiently prioritize estrogenic and androgenic chemicals, but not other types of EDCs.

A new era for EDSP is peeking around the corner.  In fact, EPA is holding a meeting on the development and application of EDSP21 this week. Further incorporating these 21st century methods provides the potential to improve this chemical screening program, but, as demonstrated by this study, full transparency about the gaps and limitations is essential.

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