You are here:
A mixture of five phthalate esters inhibits fetal testicular testosterone production in a cummulative manner consistent with their predicted reproductive toxicity in the Sprague Dawley rat
Citation:
HOWDESHELL, K. L., V. S. WILSON, J. R. FURR, C. R. LAMBRIGHT, C. V. RIDER, C. R. BLYSTONE, A. K. HOTCHKISS, AND L. E. GRAY. A mixture of five phthalate esters inhibits fetal testicular testosterone production in a cummulative manner consistent with their predicted reproductive toxicity in the Sprague Dawley rat. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 105(1):153-165, (2008).
Impact/Purpose:
This phthalate mixture study is relevant to human health because multiple phthalate metabolites are detected in the urine of pregnant women, the amniotic fluid of developing fetuses, and in the cord blood of newborns. Furthermore, testosterone is critical for male reproductive tract development in vertebrates, including rats and humans. This study is important to the USEPA because it demonstrates that the reproductive toxicant phthalates, such as DBP - a phthalate for which there is currently an USEPA risk assessment underway, can act in a dose-additive manner and emphasizes the need for a cumulative risk assessment of the phthalates. Our data will also assist the EPA in the execution of, and the National Academy of Science's National Research Council in providing advice for, cumulative risk assessments on the phthalates since this is the first study to provide quantitative potency factors for the adverse effects of phthalates on the fetal male rat and his mother.
Description:
Phthalate diesters are plasticizers to which humans are ubiquitously exposed. Exposure to certain phthalates during sexual differentiation causes reproductive tract malformations in male rats. In the fetal rat, exposure to the phthalates benzylbutyl (BBP), di(n)butyl (DBP), and diethylhexyl (DEHP) decreases testicular testosterone (T) production and insulin-like hormone 3 levels. We characterized the sigmoidal dose response effects of six individual phthalates [BBP, DBP, DEHP, diethyl phthalate (DEP), diisobutyl phthalate (DiBP), and dipentyl phthalate (DPP)] on gestation day (GD) 18 testicular T production following exposure to Sprague Dawley rats on GD8-18. BBP, DBP, DEHP, and DiBP were equipotent (ED50 of 441 27 mg/kg/d), DPP was about 3-fold more potent (ED50=130.9 mg/kg/d) and DEP had no effect on fetal T production. We hypothesized that coadministration of “antiandrogenic” phthalates would reduce T production in a dose-additive fashion since they act via a common mode of toxicity. In a second study, dams were dosed at 100, 80, 60, 40, 20, 10, 5 or 0% of a mixture of BBP, DBP, DEHP, DiBP (300 mg/kg/d per chemical) and DPP (100 mg DPP/kg/d). This mixture ratio was selected such that each phthalate would contribute equally to the reduction in T. As hypothesized, T production was reduced in a dose-additive manner. Several of the individual phthalates and the mixture induced fetal mortality, due to pregnancy loss, in a manner predicted by dose addition. These data demonstrate that individual phthalates with a similar mechanism of action can elicit dose additive effects on fetal T production and pregnancy when administered as a mixture.
