PRINCIPLES OF TOXICOLOGY - Biology East Borneo

11.2 FEMALE REPRODUCTIVE TOXICOLOGY 223Occupational and environmental exposures that could dysregulate the female endocrine pattern area major topic of current investigation. Dioxins, other polycyclic chlorinated compounds and organochlorineand organophosphate pesticides are all potential compounds of concern. As described in theMale Reproductive Toxicology section, the concern is that many of these compounds have some typeof estrogenic or androgenic activity because they are able to replace the endogenous compounds incellular interactions. The theoretical potential for such compounds to affect female reproductivefunction is clear. However, demonstrating such an effect is extraordinarily difficult, and there are stillno convincing examples of endocrinologically active compounds causing reproductive impairment inwomen through typical occupational or environmental exposures.The endpoints that can generally be observed for women are menstrual interval, fertility as measuredby time to pregnancy, and ability to carry a pregnancy to term. This last potential effect will be discussedin the Developmental Toxicology section. There are such extreme interpersonal differences in menstrualinterval and regularity and so many established causes for missed or delayed menstruation thatassociating any variation with a particular chemical exposure is difficult. Many cultural and occupationalfactors are clearly relevant for affecting time to pregnancy, and difficulty achieving a pregnancywhen desired may affect as much as 25 percent of couples in the United States at times. It is clear thatthis is not always due to female reproductive problems, but this “naturally” occurring backgroundobscures potential toxicologically mediated effects.The high degree of interest in endocrine disruption as a potential mechanism for female reproductivetoxicity is driving extensive investigations of this hypothesis. In the future it should become clearerwhether environmental estrogens and other endocrinologically active compounds can actually reachlevels at which they can produce a significant endocrine disruption and subsequent reproductiveimpairment. Currently, we are left with a potential mechanism for reproductive effects and candidatecompounds that could act through this mechanism, but no clear demonstration of any of the candidatesposing an actual risk through such a mechanism for humans following occupational or environmentalexposures.The potential for exposure to chemicals that could alter endocrine processes and the need to usepharmacological agents known to cause reproductive toxicity opens up controversial occupational andsocietal issues about restricting women’s chemical exposure. What types of data or experimental resultsshould be sufficient to indicate the need to control occupational exposures? When considering whetherwomen should be excluded from certain jobs during certain segments of their reproductive lives,suddenly, the need to get beyond the uncertainties of extrapolating doses and mechanisms of toxicityfrom animal testing becomes crystal clear. The associated issues are as widely disparate as the economicimpacts of possibly needing to move employees in and out of certain jobs or requiring specializedexposure control equipment to the potential for claims of discrimination, should women be excludedfrom opportunities on the basis of concerns they do not believe are relevant for them.Alternatively, when deciding a certain therapy is needed, what constitutes an adequate representationto the patient of the risks to herself or a developing fetus? Clearly, we cannot always discardeffective treatments. The recent return of thalidomide, discussed below as the cause of one of the mostnotorious cases of human developmental toxicity, is a shining example. Thalidomide turns out to be aparticularly effective treatment for patients suffering complications of leprosy or some complicationsof AIDS. It may further be an effective sedative for cancer patients and those suffering autoimmunediseases. These uses expand the patient population where reproductive effects are a possible concern.Effective patient education and carefully planned distribution policies may be relatively straightforwardfor thalidomide, where the toxic timing and dosage is established and the outcomes are readilydocumented, but what is the appropriate balance between protection and restrictiveness for other drugs?Female Reproduction SummaryCompared to the male, there are relatively few female-specific reproductive toxicants that are notrelated to developmental toxicity (Table 11.2). (Developmental toxicants will be covered in thefollowing section.) In part, this is due to the difficulties in analyzing oocyte production and determining