Testing & Prioritizing Chemicals: Innovative Chemical Prioritization
Congress passed the Food Quality Protection Act and the Safe Drinking Water Act Amendments in 1996 requiring that EPA screen pesticide chemicals for their potential to produce effects similar to those produced by the female hormones (estrogen) in humans and giving EPA the authority to screen certain other chemicals and to include other endocrine effects. Based on recommendations from an Advisory Committee, EPA has expanded the Endocrine Disruption Screening Program (EDSP) to include male hormones (androgens) and the thyroid system, and to include effects on fish and wildlife. There are thousands of chemicals that need to be screened for potential endocrine disruption. The approach to screen these chemicals that has been developed by the EPA uses a battery 11 of in vitro and in vivo tests ("The EDSP Tier 1 Battery"). While these tests do a thorough job of screening chemicals, they are low throughput and high cost (50-100 chemicals per year at a cost of approximately $1 million per chemical). Chemicals that are flagged as potential endocrine disruptors (EDCs) by the Tier 1 tests will then be subjected to an additional, more expensive level of testing, "Tier 2" tests, which are still under development. Resources, time and money are major issues.
Given this limitation, EPA researchers are working with EDSP to develop high-throughput, rapid methods to prioritize chemicals for Tier 1 testing. Chemicals that may have an effect on hormonal systems can often be identified by assessing how they interact with different cells and proteins found in the human body. By looking at EDCs through this mechanistic framework, researchers have developed a number of innovative screening tests to prioritize potential endocrine disrupting chemicals. These tests can be run quickly on a large number of chemicals. These "high-throughput" assays are most fully developed for detecting disruptions in the estrogen signaling pathway. One assay tests to see if a chemical physically attaches to the estrogen receptor, the molecule that initiates the action along this pathway, and which is normally only activated by the natural hormone estrogen. Another assay measures whether cells proliferate in the presence of a chemical. Positive results on these tests suggest that the chemical may mimic the actions of estrogen in the body and lead to endocrine disruption. These high-throughput tests are being performed as part of a larger federal agency collaboration called Toxicity Testing in the 21st century, which aims to evaluate tens of thousands of chemicals for a range of effects, including endocrine disruption.
As part of the EDSP, researchers have also used data from in vitro assays and other tests to create computational tools called QSAR (Quantitative structure–activity relationship) models. A QSAR model can provide a prediction of whether a molecule is likely to have a specific effect based on chemical features such as its molecular structure.
High-throughput tests and QSAR models are both deployed by EPA researchers to assess thousands of chemicals and prioritize them for further testing as part of the EDSP.
Results and Impact
EPA researchers have made the most progress deploying these methods to prioritize chemicals for screening for estrogen activity. Computational tools and data for chemical properties were first used to whittle a list of about 10,000 chemicals down to about 5,000 with chemical properties that are consistent with interacting with the estrogen pathway. About half of these 5,000 chemicals are not readily testable for various practical reasons, for instance it is not possible to readily obtain pure samples of some of these chemicals. EPA researchers have screened the remaining 2,400 of these chemicals using about 20 high-throughput assays. Their preliminary estimates suggest that 5 to 10 percent of these chemicals may mimic the behavior of naturally occurring estrogen. The researchers are on schedule to provide a status report on the use of these tools to help prioritize chemicals for the EDSP in January 2013. After a process of deliberation and peer review, EPA will choose which of these chemicals to move forward into Tier 1 testing.
In addition to evaluating the ability of chemicals to mimic estrogen, EPA researchers are also charged with uncovering a chemical's potential to disrupt two other hormonal systems: the androgen hormones that direct male reproductive development and activities, and thyroid hormones. High-throughput testing to evaluate chemicals for androgen disruption is now underway, whereas high throughput tests and QSARs for thyroid hormones are still under development.