PRINCIPLES OF TOXICOLOGY

Occupational and environmental exposures that could dysregulate the female endocrine pattern are
a major topic of current investigation. Dioxins, other polycyclic chlorinated compounds and organochlorine
and organophosphate pesticides are all potential compounds of concern. As described in the
Male Reproductive Toxicology section, the concern is that many of these compounds have some type
of estrogenic or androgenic activity because they are able to replace the endogenous compounds in
cellular interactions. The theoretical potential for such compounds to affect female reproductive
function is clear. However, demonstrating such an effect is extraordinarily difficult, and there are still
no convincing examples of endocrinologically active compounds causing reproductive impairment in
women through typical occupational or environmental exposures.
The endpoints that can generally be observed for women are menstrual interval, fertility as measured
by time to pregnancy, and ability to carry a pregnancy to term. This last potential effect will be discussed
in the Developmental Toxicology section. There are such extreme interpersonal differences in menstrual
interval and regularity and so many established causes for missed or delayed menstruation that
associating any variation with a particular chemical exposure is difficult. Many cultural and occupational
factors are clearly relevant for affecting time to pregnancy, and difficulty achieving a pregnancy
when desired may affect as much as 25 percent of couples in the United States at times. It is clear that
this is not always due to female reproductive problems, but this “naturally” occurring background
obscures potential toxicologically mediated effects.
The high degree of interest in endocrine disruption as a potential mechanism for female reproductive
toxicity is driving extensive investigations of this hypothesis. In the future it should become clearer
whether environmental estrogens and other endocrinologically active compounds can actually reach
levels at which they can produce a significant endocrine disruption and subsequent reproductive
impairment. Currently, we are left with a potential mechanism for reproductive effects and candidate
compounds that could act through this mechanism, but no clear demonstration of any of the candidates
posing an actual risk through such a mechanism for humans following occupational or environmental
exposures.
The potential for exposure to chemicals that could alter endocrine processes and the need to use
pharmacological agents known to cause reproductive toxicity opens up controversial occupational and
societal issues about restricting women’s chemical exposure. What types of data or experimental results
should be sufficient to indicate the need to control occupational exposures? When considering whether
women 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 toxicity
from animal testing becomes crystal clear. The associated issues are as widely disparate as the economic
impacts of possibly needing to move employees in and out of certain jobs or requiring specialized
exposure control equipment to the potential for claims of discrimination, should women be excluded
from 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 representation
to the patient of the risks to herself or a developing fetus? Clearly, we cannot always discard
effective treatments. The recent return of thalidomide, discussed below as the cause of one of the most
notorious cases of human developmental toxicity, is a shining example. Thalidomide turns out to be a
particularly effective treatment for patients suffering complications of leprosy or some complications
of AIDS. It may further be an effective sedative for cancer patients and those suffering autoimmune
diseases. These uses expand the patient population where reproductive effects are a possible concern.
Effective patient education and carefully planned distribution policies may be relatively straightforward
for thalidomide, where the toxic timing and dosage is established and the outcomes are readily
documented, but what is the appropriate balance between protection and restrictiveness for other drugs?
Female Reproduction Summary
11.2 FEMALE REPRODUCTIVE TOXICOLOGY 223
Compared to the male, there are relatively few female-specific reproductive toxicants that are not
related to developmental toxicity (Table 11.2). (Developmental toxicants will be covered in the
following section.) In part, this is due to the difficulties in analyzing oocyte production and determining