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DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY
Citation:
Gray Jr., L E., C J. Wolf, J. R. Furr, M. G. Price, C R. Lambright, V S. Wilson, AND J S. Ostby. DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY. Presented at Society of Toxicology, Nashville, TN, March 17-21, 2002.
Description:
DOSE-RESPONSE BEHAVIOR OF ANDROGENIC AND ANTIANDROGENIC CHEMICALS: IMPLICATIONS FOR LOW-DOSE EXTRAPOLATION AND CUMULATIVE TOXICITY. LE Gray Jr, C Wolf, J Furr, M Price, C Lambright, VS Wilson and J Ostby. USEPA, ORD, NHEERL, EB, RTD, RTP, NC, USA.
Dose-response behavior of androgenic and antiandrogenic chemicals: Implications for low-dose extrapolation and cumulative toxicity. Concern has arisen regarding the shape of the dose response curves in the low dose range for EDCs. Although it is generally assumed that noncancer effects, including those induced by EDCs, display a threshold, several scientists have questioned the validity of this assumption. In regards to cumulative risk, it is generally assumed that dose-additivity prevails for chemicals that act via a common mechanism of action. TEF (Toxic Equivalent Factor) approach for mixtures is a valid if the dose-response curves for all the chemicals are parallel. This presentation will examine the dose-response behavior of several androgenic and antiandrogenic chemicals. In vitro, antiandrogenic chemicals (i.e. hydroxyflutamide, M2 a vinclozolin metabolite) can display antiandrogenic activity at low concentrations and agonist activity at high concentrations. U- or inverted U-shaped dose response curves have been described in vivo for AR agonists. In addition, many AR-mediated in vivo and in vitro effects do not display an obvious threshold. Furthermore, the dose-response curves for antiandrogenic developmental effects produced by vinclozolin (V) administration reveals that the responses to this AR antagonist do not display a common shape or ED50. When V and procymidone (P, an AR antagonist) are coadministered, the effects all appear dose-additive, suggesting that a single TEF could be used to assess cumulative toxicity. While cumulative developmental effects also were observed with coadministration of an AR antagonist (procymidone) and an inhibitor of fetal testosterone synthesis (di-n-butyl phthalate), it is evident that single TEF will not suffice because the relative potencies of these two chemicals varies from tissue to tissue. Our data indicate that cumulative adverse effects can be observed after coadministration of chemicals that affect the differentiation of the reproductive tract, regardless of the mechanism of action. Disclaimer: This is an abstract of a proposed presentation and does not necessarily reflect USEPA policy.