Lack of (anti-) androgenic or estrogenic effects of three pyrethroids (esfenvalerate, fenvalerate, and permethrin) in the Hershberger and uterotrophic assays

Abstract

Synthetic pyrethroids are among the most common pesticides and insecticides currently in use worldwide. Recently, chemicals classified as synthetic pyrethroids are suspected as being endocrine disrupting chemicals. However, no study has been conducted to assess their potential hormonal activities using in vivo test specifically focused on endocrine disruption. In the present study, we evaluated the interaction of three pyrethroids (esfenvalerate, fenvalerate, and permethrin) with androgen receptor (AR)- and estrogen receptor (ER)-mediated mechanisms using in vivo short-term assays. While internationally standardized protocols for the Hershberger and uterotrophic assays have not yet been fully developed, both are widely used and are being considered by OECD as short-term screening assays for hormonal activity. A 5-day Hershberger assay using castrated male rats measures agonistic and androgenic ability of the test chemicals to AR of several accessory glands/tissues (the ventral prostate, dorsolateral prostate, seminal vesicles with coagulating glands, and levator ani plus bulbocavernosus muscles). Esfenvalerate (5, 10, or 20 mg/kg/day), fenvalerate (20, 40, or 80 mg/kg/day), or permethrin (25, 50, or 75 mg/kg/day) was administered by oral gavage for 5 days to castrated male Crj:CD(SD)IGS rats (1 week after the castration, 11 weeks of age) with or without coadministration of 0.25 mg/kg/day testosterone propionate (subcutaneous injection on the dorsal surface). The highest dose levels tested for each chemical were considered the maximum level that could be used without causing excessive systemic toxicity. None of esfenvalerate, fenvalerate, and permethrin showed any androgenic or antiandrogenic effects. Reference control of p,p'-DDE and methyltestosterone (100 mg/kg/day) provided significant effects in this assay protocol. Potential effects of these pyrethroids mediated through the ER were evaluated by means of 3-day uterotrophic assay using ovariectomized Crj:CD(SD)IGS rats (2 weeks after the ovariectomy, 8 weeks of age). No increase in weight of uterus (wet or blotted) was observed following oral exposure to esfenvalerate (5, 10, or 20 mg/kg/day), fenvalerate (20, 40, or 80 mg/kg/day), or permethrin (37.5, 75, or 150 mg/kg/day), respectively. Again, the highest dose levels tested for each chemical were considered the maximum level that could be used without causing excessive systemic toxicity. Reference controls consisting of ethynyl estradiol (0.03 mg/kg/day) and methoxychlor (125 mg/kg/day) both showed a significant effect in this assay protocol. It is concluded that, based on the results of these two reliable in vivo assays, none of esfenvalerate, fenvalerate, or permethrin exhibit any potential to cause adverse (anti-) androgenic or estrogenic effects at dose levels below that of those causing excessive systemic toxicity.