Comparative activities of p-nonylphenol and diethylstilbestrol in noble rat mammary gland and uterotrophic assays

Colerangle and Roy (1996, Endocrine 4, 115-122) have described the apparent ability of both diethylstilbestrol (DES) and p-nonylphenol (NP) to cause e xtensive cell proliferation and lobular development in the mammary glands o f young adult Noble rats. The chemicals were administered over 11 days via subcutaneously implanted minipumps, The dose level of DES used (0.076 mg/kg /day) was about 70 times higher than its minimum detection level in rodent uterotrophic and reproductive toxicology studies. In contrast, the lowest a ctive dose level of NP (0.073 mg/kg/day) in the Noble rat mammary gland stu dy was about 600 times lower than its minimum detection level in rat uterot rophic and multigeneration studies. The apparent enhanced sensitivity of th e Noble rat mammary gland to the estrogenic activity of NP was considered w orthy of further study. Ovariectomized Noble rat uterotrophic assays with NP (minimum detection lev el similar to 40 mg/kg/day, 3 or 11 days, oral gavage) revealed similar ass ay sensitivity to that observed for earlier immature and ovariectomized Ald erley Park (AP) rat uterotrophic assays of this chemical. The response of t he ovariectomized Noble rat uterotrophic assay to DES and estradiol was als o as expected from earlier immature AP rat assays. It is concluded that the general sensitivity to estrogens of the Noble rat and the AP rat is simila r. A repeat of the Noble rat mammary gland study with DES (11 x 0.076 mg/kg/da y) and NP (11 x either 0.073 or 53.2 mg/kg/day), as originally reported by Colerangle and Roy (1996), revealed a strong positive response to DES and n o response to NP. It is concluded that the minimum detection level of NP as a weakly estrogenic material in the rat should be based on the results of rat uterotrophic and multigeneration studies and therefore be set at simila r to 40 mg/kg/day. It is also concluded that induced S-phase in the rodent mammary gland is best monitored using BRDU, as opposed to PCNA staining, an d that use of subcutaneously implanted minipumps/pellets is inappropriate f or risk/ hazard assessment studies of chemicals already established as estr ogenic in vitro and in vivo, as are NP and DES. (C) 1999 Academic Press.