Effects of p-nonylphenol (NP) and diethylstilboestrol (DES) on the alderley park (Alpk) rat: Comparison of mammary gland and uterus sensitivity following oral gavage or implanted mini-pumps

An earlier report by Colerangle and Roy indicated that administration of p- nonylphenol (NP) to Noble rats, via subcutaneously implanted mini-pumps at estimated doses of 53.2 and 0.073 mg kg(-1) day(-1) for 11 days, led to pro liferation of the mammary gland. Those results indicated a ca. 600-fold enh ancement in assay sensitivity to NP over that of the standard 3-day rat ute rotrophic assay. The potential importance of these observations led us to r epeat the experiments in the Noble rat, as described earlier. Although our earlier results confirmed the reported effects of diethylsti Iboestrol (DES ) on the mammary gland of Noble rats, we found no effects with NP. The pres ent report extends our investigations of the effects of NP and DES an the m ammary gland and uterus of other rat strains using both oral dosing and exp osure via mini-pumps. The 3-day oral uterotrophic assay responses to NP were similar for immature Alderly Park (Alpk; Wister-derived) and immature Sprague-Dawley rats, Like wise, oral administration of NP to ovariectomized Alpk rats for 11 days gav e responses of a similar magnitude to those seen in the 3-day immature assa ys and in earlier 3-and 11-day oral assays conducted using Noble rats. Admi nistration of NP via mini-pumps to ovariectomized Alpk rats, at the implant doses employed by Colerangle and Roy, gave a negative uterotrophic respons e. The highest achieved dose levels of NP in the implant experiment (27 mg kg(-1) day(-1)) were lower than in the above assays and the negative respon se was therefore consistent with the previously defined minimum detection l evel for NP in the uterotrophic assay of ca, 40 mg kg(-1) day(-1) day(-1). It is concluded that the uterotrophic activity of NP is independent of the strain of rat, the duration of dosing and the route of exposure. Two mammary gland studies were conducted on NP and DES in the Alpk rat. In the first study (a repeat of the techniques used in earlier studies with th e Noble rat), NP was administered via minipumps (achieved doses of 0.052 an d 37.4 mg kg(-1) day(-3) NP) and produced no effect on mammary gland develo pment, whereas DES gave the expected trophic response. In the second mammar y gland study, NP was administered orally to Alpk rats at 100 mg kg(-1) day (-1) for 11 days (a dose that produced a positive uterotrophic response in ovariectomized rats), In this experiment, DES, and to a lesser extent NP, i ncreased mammary gland differentiation and cell proliferation. The present studies have demonstrated that the rat mammary gland responds predictably t o oestrogenic stimulation but does not show increased sensitivity to oestro gens when compared to the rat uterus. It is also concluded that the minimum detection level for oestrogenic responses of NP in rodents, following oral , dietary and implant routes of exposure, is ca. 40 mg kg(-1) day(-1). Copy right (C) 1999 John Wiley & Sons, Ltd.