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High Throughput Pre-Screening (HTPS) and Quantitative Structure Activity Relationships (QSAR)

EPA investigated the use of High Throughput Pre-Screening (HTPS) and Quantitative Structure Activity Relationships (QSARs) to develop hormonal or biological activity information. These techniques might allow EPA to quickly screen thousands of chemicals at low cost without requiring animal testing.

High Throughput Pre-Screening

During the course of its deliberations, the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) realized that, with the exception of food-use and consumer pesticides with regulatory mandates requiring prenatal developmental and two-generation reproductive toxicity testing, substantial endocrine effects data were lacking for most chemical substances. This poses a problem in the priority setting process: In the absence of biological effects data, EPA will set the priority of a chemical on the basis of exposure data alone.

To address the problem of having little or no data on endocrine effects for the majority of chemicals that will be sorted for Tier 1 Screening, EDSTAC recommended that EPA use HTPS to aid in priority setting and screening of chemicals. High throughput screening technology is used extensively in the pharmaceutical and agrochemical industries to identify chemicals that have commercial potential or that may have desirable or undesirable biological effects. HTPS is an automated cell-based test system capable of detecting estrogen and androgen receptor interactions on thousands of chemicals. These automated processes involve a number of preparatory operations, some of which are also associated with traditional screening approaches, such as sample preparation (weighing and dissolving in the appropriate medium), screening, and the reading of screening results. However, in the case of HTPS, the process of placing the samples into a microliter plate, the sampling process itself, and the reading of sampling results, are all automated. Since all processes are automated and can be programmed to run continuously, it is possible for large numbers of samples to be assayed in a relatively short period of time using this technology.

EPA proposed that high throughput screening technology could be employed as a prioritization tool if demonstrated as a feasible method- hence the term "prescreening"- for the endocrine disruptor screening and testing program. HTPS results, although limited in the scope of information they generate, would be useful in identifying chemicals that have an affinity for the estrogen, androgen, or thyroid hormone receptor. This information could be used in conjunction with other exposure- and effects-related information to determine the priority by which chemicals should be advanced to the screening and testing tiers of the program. However, HTPS results would not be sufficient to make a definitive determination about whether a chemical does or does not have endocrine disrupting properties. This is the function of Tier 2 Testing.

EPA completed an HTPS feasibility study in 2000. Unfortunately, the results of the study showed that the HTPS technology and assay systems are not yet sufficiently developed for regulatory purposes. EPA is still considering this technology for certain uses but also has been investigating using QSAR analysis as a feasible and effective alternative.

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Quantitative Structure Activity Relationships

QSAR analysis uses computer simulations to estimate how a chemical behaves based on its structure. EPA would use QSAR models to predict the likelihood of a chemical binding with estrogen and androgen receptors. This prediction is based on a number of factors, the most important being how well the molecular structure of a certain chemical fits into the molecular structure of the estrogen and androgen receptors. This fit, or capability to bind, is usually referred to as the binding affinity of the chemical and is compared with the binding affinity of the natural hormone. For example, a chemical with a "square" structure trying to fit into a receptor with a "round" structure of a smaller size would likely have a low binding affinity.

Chemicals can affect the endocrine system in a number of ways other than through receptor binding; thus QSAR analyses provide limited information on the potential for a chemical to interfere with the endocrine system. Currently, QSAR analyses are not yet sufficiently developed for regulatory purposes. EPA is still considering applying this technology when reliable, repeatable models are developed.

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