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Dose Response Data for Hormonally Active Chemicals: Estrogens, Antiandrogens and Androgens
Citation:
Gray, E. Dose Response Data for Hormonally Active Chemicals: Estrogens, Antiandrogens and Androgens. Presented at EUROTOX 2012, June 18 - 21, 2012.
Impact/Purpose:
The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects of radiation. For noncancer effects the default assumption is generally that noncancer effects generally display threshold rather than LNT responses. More recently, claims have arisen that the chemicals, like endocrine disrupters (EDCS), which can act via high affinity, low capacity nuclear receptors, may display LNT or nonmonotonic low dose responses (NMDRCs): responses that could be missed in multigenerational guideline toxicity testing. This presentation will discuss LNT, threshold and NMDRCs relationships from case studies of chemicals that disrupt reproductive development and function via the Estrogen and Androgen signaling pathways including in vitro and in vivo data.
Description:
The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. For noncancer effects the default assumption is that noncancer effects generally display threshold rather than LNT responses. More recently, claims have arisen that the chemicals, like endocrine disrupters (EDS), which act via high affinity, low capacity nuclear receptors, may display LNT or nonmonotonic low dose responses: responses that could be missed in multigenerational guideline toxicity testing. This presentation will discuss LNT, threshold and nonmonotonic dose response relationships from case studies of chemicals that disrupt reproductive development and function via the ER, AR and AhR pathways and will include in vitro and in vivo multigenerational data. The in vivo studies in this discussion include only robust, well designed, comprehensive studies that administered the chemical via a relevant route(s) of exposure over a broad dose response range, including low dose(s) in the microgram/kg/d range. The chemicals include ethinyl estradiol, estradiol, genistein, bisphenol a, trenbolone, finasteride, flutamide, phthalate esters and 2,3,7,8 TCDD. The objective is to critically evaluate the data from well done studies in this field to address concerns that current multigenerational reproductive test guidelines are missing adverse low dose effects because EDs routinely induce nonmonotonic adverse low dose responses.