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Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? ###SETAC
Citation:
Gray, E. Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? ###SETAC. Presented at SETAC FOCUSED MEETING ON ENDOCRINE DISTRUPTION, RTP, NC, February 04 - 06, 2014.
Impact/Purpose:
THIS IS AN INVITED PRESENTATION OF A ISSUE OF GREAT INTEREST TO THE SCIENTIFIC COMMUNITY AND GLOBAL REGULATORY AGENCIES. WHAT IS THE SHAPE OF THE DOSE RESPONSE CURVE IN THE LOW DOSE REGION: LINEAR, THRESHOLD OR NONMONOTONIC?
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. Recently, claims have arisen that the endocrine disrupters (EDs), which act via high affinity, low capacity nuclear receptors, commonly induce effects displaying NMDRCs at low doses which would be missed in standard multigenerational toxicity studies. This presentation will discuss LNT, threshold and NMDRCs responses from case studies of chemicals that disrupt reproductive development and function via the androgen and estrogen signaling 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). The chemicals include ethinyl estradiol, estradiol, genistein, bisphenol a, trenbolone, finasteride, flutamide, phthalate esters, selective estrogen receptor modulators and inhibitors of aromatase. The objective is to critically evaluate the reproductive and developmental toxicity 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. My current conclusions are: 1) EDCs appear to induce some LNT effects. 2) NMDRCs are biologically plausible and occur frequently in vitro, but these often occur in vitro at high concentrations of estrogens or androgens that are not relevant in vivo. 3) It appears that NMRDCs are more common 3a) in short- versus long-term exposures and 3b) with upstream, mechanistic events versus downstream phenotypic effects. 4) A few adverse effects of EDs are non-monotonic, but other effects displaying monotonic responses occur at lower dosage levels. 5) A number of robust multigenerational studies of estrogens and antiandrogens have been executed and NMDRCs were uncommon at low dosage levels. 6) Multigenerational Test guidelines can be enhanced on a case-by-case basis to improve the sensitivity to low dose effects of some EDCs. 7) Additional data needs to be examined from robust, multigenerational studies using a broad range of dosage levels for other pathways. This is an abstract of a proposed presentation and does not necessarily reflect EPA policy.