The guinea pig exhibits cyclic and luteal similarities to the human, a feature not present in other small experimental animals such as rats, mice, or rabbits. Studies were undertaken to investigate the in vivo effects of three persistent environmental xenobiotics (nonylphenol, 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene [p,p'-DDE], and pentachlorophenol) on the microanatomy of the adult female guinea pig reproductive system. The effects brought about by these compounds (40 mg/kg/day) were compared to those caused by the synthetic estrogen diethylstilbestrol (DES; 50 microg/kg/day). Adult female guinea pigs, intact and castrated, were treated with 14 daily subcutaneous (s.c.) doses of one of these agents. The 50% decline in the weight of the tract that occurred following castration, was prevented by administration of nonylphenol, p,p'-DDE, and DES, but not of pentachlorophenol. Nonylphenol produced weak estrogenic stimulation of the tract of intact animals and maintained a relatively normal histologic appearance in castrated animals. Focal mucinous metaplasia of the endometrium, however, was observed in both groups. Treatment of intact and castrated animals with p,p'-DDE resulted in cystic hyperplasia and mucinous metaplasia of the endometrium, hyperplasia of the cervical epithelium, estrogenic stimulation of the vagina, and dilation of the rete ovarii. Treatment of intact or castrated animals with DES resulted in effects that were qualitatively similar to those caused by p,p'-DDE. The appearance of the vaginal epithelium, however, was abnormal and the rete ovarii were less dilated. Pentachlorophenol had minimal effect on the histology of the tract of castrated or intact animals. These data support our hypothesis that some environmental toxicants can substitute for estradiol in regulating the microanatomy of the female reproductive tract. They indicate the potential of these compounds to act as endocrine disrupting agents.