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Johns Hopkins Bloomberg School of Public HealthCAAT

Abstract for TestSmart -- Endocrine Disruptors

Perspective on Endocrine Screening and Testing

R. A. Becker
American Chemistry Council, Arlington, VA.

Contemporary toxicity testing methods can provide information applicable to hazard identification of hormonally active agents. Many different types of assays are currently available for evaluating the potential of substances to interact with components of the endocrine system and new techniques are being developed, standardized, and validated to improve sensitivity and specificity for those purposes.

Although the steps involved in hazard identification of hormonally active agents are the same as those for other chemical substances, hazard characterization for these agents presents special challenges in that data sets with varying degrees of complexity must be reviewed and evaluated. A tiered, hierarchical approach is recommended to guide development and utilization of screens and tests for hormonally active agents. Such an approach is structured by the type and quality of data provided by the various screens and tests. Validated screening assays are used to identify substances with hormonal activity and prioritize them for more definitive testing. Validated toxicity testing protocols would then be used to identify and characterize adverse effects caused by alterations in endocrine system function. Technical perspectives pertaining to the development, validation and use of specific screens and tests will be discussed in the presentation. Several key principles underlie such a hierarchical approach to screening and testing for hormonally active substances:

  1. Screens should be short-term, quick and inexpensive assays designed to detect specific hormonal activity:
    1. Screening assays should be based on a discreet mode or mechanism of interaction with the endocrine system.
    2. Apical endpoint measurements can be influenced by non-endocrine factors are more appropriate for inclusion in definitive tests.
  2. Longer-term in vivo assays (e.g., multi-generation reproduction studies) should be employed to identify adverse effects using relevant, apical endpoints. Dose-response characterization should also be a goal of such tests.
  3. Hazard identification and risk characterization should rely primarily on the results of definitive tests.

Validated alternatives to animal testing are not presently available for every type of toxicity test. Research to reduce, refine or replace the need for laboratory animals needs to continue. When animal testing is necessary, the use of laboratory animals should follow guidelines for humane treatment and the number of animals minimized to greatest extent practicable without compromising the scientific integrity of the method. Reliance on laboratory animals can be minimized by:

  • Standardizing and validating all new and refined screens and tests - both animal and non-animal
  • International harmonization of guidelines and mutual acceptance of data
  • Tiered testing approaches that use results-based prioritization to focus testing on chemicals of greatest concern, thus reducing the total amount of testing
  • Using hazard and exposure data to prioritize substances for further testing thereby making more efficient use of resources, including laboratory animals
  • Integrating various chemical evaluation initiatives and, when scientifically valid, grouping chemicals with similar characteristics, reducing duplication of testing

Evaluating the results of screens and tests for hormonal activity requires a weight of evidence framework. A weight of evidence evaluation for hormonally active agents begins with an assessment of the relevance, reliability and significance of each individual study in the data set. Then the data from all relevant studies is integrated. This includes the assessment of the overall adequacy and concordance of the data set:

  • higher quality studies are given more weight than lower quality studies;
  • longer-term definitive tests outweigh or supercede screening assays;
  • substances with inadequate data sets may become a high priority for development of additional screening or testing data;
  • where there is a lack of concordance in the overall data set, decisions should be based on the preponderance of available data; in certain cases, additional new screening or testing data using validated methods may need to be developed to resolve conflicting information;
  • substances that have adequate and concordant data sets can proceed to risk assessment and risk management processes as appropriate.

With respect to reporting transparency, it is important to recognize the significance of Good Laboratory Practices (GLPs). Extensive documentation, monitoring, auditing, and quality assurance are integral parts of the GLP process. Therefore, data on individual animals and endpoints that are presented in a GLP report are extremely likely to be accurate, both in terms of their measurement and in the fidelity of the transcription from the original data entry into a notebook or spreadsheet to a report. Although some studies may not be conducted under GLP regulations, the weight given the study should be increased if GLPs have been followed.