Impact/Purpose:

This project is a multidisciplinary approach to address a number of uncertainties in the risk assessment of chemicals that alter serum TH concentrations. The project attempts to describe the quantitative and qualitative relationships between the short-term screens and endpoints of concern, such as the potential for developmental neurotoxicity. In addition, the project attempts to develop biomarkers for thyroid responsiveness that will provide for the development of screens that will allow for a better understanding of the dose-response relationship for adverse effects.

Results will provide for a better understanding of the dose-response relationships between alterations in THs in short-term screens and adverse developmental outcomes. In addition, data will allow risk assessors to make more informed decisions concerning exposure to multiple chemicals with potential to disrupt THs and on issues related to species-to-species extrapolation. This information will be critical in the interpretation of data from short-term screens for TH disruptors.

Description:

A wide range of chemicals with diverse structures act as thyrotoxicants. Broadly defined, thyrotoxicants are chemicals that alter the structure or function of the thyroid gland, alter regulatory enzymes associated with thyroid hormones (THs), or change circulating or tissue concentrations of THs. These structurally diverse chemicals act through a variety of mechanisms. One uncertainty in our understanding of the toxicity of chemicals that alter TH concentrations is the dose response relationship between alterations in TH concentrations and developmental toxicities. While some chemicals decrease both T3 and T4, other chemicals predominately decrease T4. It is uncertain whether these classes of chemicals will result in the same spectrum of developmental toxicities or whether these two classes of chemicals will induce unique spectrums of developmental toxicities. The specific aims of this project are: 1) To develop predictive animal models for thyroid hormone disrupting chemicals using a short-term dosing assay. 2) To determine the relationship between alterations in serum THs and developmental neurotoxicity using prototype thyrotoxicants. 3) To develop sensitive tissue biomarkers for thyroid responsiveness and examine the effects of different classes of thyrotoxicants on these biomarkers. 4) To develop improved experimental models for extrapolation of endocrine effects between species. 5) To determine whether mixtures of thyrotoxicants are additive or synergistic.

Record Details: