The candidate, Cynthia Rider, plans to further her scientific development in an academic setting under the mentorship of Dr. David Hinton and Dr. Richard Di Giulio at Duke University during the post-doctoral phase of the program in order to facilitate her transition to an independent position as a tenure-track researcher during the independent phase of the award. Her short term goals include securing funding for her proposed research and developing the skill set needed to successfully operate an independent research laboratory, including: additional technical training, practical laboratory maintenance, mentoring, and teaching. During the mentored phase of the award, her research will involve characterizing the effects of environmentally-relevant endocrine active compounds on a host of endpoints in the aquarium fish, Japanese medaka (Oryzias latipes). This work will provide the foundation for the proposed research to be completed during the independent phase of the award. Her long-term goal is to maintain an active research program in an academic or government environment focusing on the effects of mixtures of endocrine disrupting chemicals using a small vertebrate animal model. The hypothesis to be tested in the proposed research is that compounds that disrupt endocrine signaling via multiple specific mechanisms (estrogenic and antiandrogenic) act in a concentration additive fashion that can be predicted using mixture modeling approaches. First, she will characterize the concentration-response profiles for a select group of endocrine disrupting chemicals. Next, she will use mathematical models of mixture toxicity to predict the combined effects of the mixtures on male reproductive endpoints in medaka. Lastly, she will compare the predicted responses to observed responses generated by exposure of medaka to mixtures of the endocrine active chemicals. The relevance of the proposed research to public health is clear;the investigators are exposed to multiple toxicants and there is epidemiological evidence of endocrine disruption in humans, however, the combined effects of endocrine active chemicals remains obscure. Establishing principles that describe the action of multiple endocrine active chemicals in a vertebrate system will greatly enhance their ability to determine risk associated with exposures to chemical mixtures and therefore, increase their ability to protect the public from potentially harmful combinations.