PRINCIPLES OF TOXICOLOGY

are common examples of compounds that decrease libido. Carbon disulfide and chlordecone-exposed
workers also reported decreased libido. It is important to remember, however, that neurological and
psychological factors play a tremendous role in libido and the relative role of chemical-induced
mechanisms for decreasing libido is likely minor. Where there are demonstrable effects that relate to
endocrine balance, it is not surprising to find reported effects on libido. However, where the claimed
effect is simply a report of decreased libido, there is little likelihood of establishing a clear toxicological
basis.
Other factors that can preclude sperm delivery are impotence and inability to ejaculate. These
aspects of reproductive function are centrally controlled, but the autonomic nervous system also plays
a key role in coordinating the physical events. The most common examples of chemical-induced
impotence are some of the adrenergic antihypertensives, methyl DOPA, clonidine and guanethidine,
and the opiates and ethanol. Psychoactive drugs, such as chlorpromazine and diazepam, can also
produce impotence. As with effects on libido, psychological factors are major contributors to impotence.
Clinical findings with humans suggest that the preponderance of reported problems with
impotence are psychological and not related to toxic responses.
Endocrine Feedback and Potential Dysregulation
Some of the key signaling molecules essential for endocrine feedback loops are the steroid hormones
and other protein-based hormones. Since both the absolute levels and the ratio between androgens and
estrogens serve as signals to the hypothalamic-pituitary-gonadal axis, modifications of this balance
can subsequently disrupt endocrine function and result in reproductive effects.
A highly publicized case of occupational exposure leading to reproductive impairment involves the
pesticide chlordecone. Occupationally exposed men appeared to have reductions in fertility. Subsequent
analysis provided a possible mechanism for such effects, as chlordecone turned out to have
estrogenic activity. The endocrine dysregulation produced by elevated estrogenic feedback could
explain the neurotoxic and reproductive effects that have been attributed to chlordecone.
The role of exogenous compounds with estrogenic, anti-estrogenic, and anti-androgenic activity is
a current source of substantial controversy. The extremely potent toxicant dioxin has the potential to
interfere with endocrine balance, and the contribution of this activity to its toxicity is hotly debated.
A variety of pesticides, including DDT, the carbamates, and mirex, are reported to possess endocrine
activity as are some of the polychlorinated biphenyls (PCBs). What is not yet clear is whether
environmental levels of exposure to such compounds can actually produce endocrine-mediated toxic
effects. Most synthetic steroid-like molecules can only displace the actual endogenous compounds in
molecular interactions to a very limited degree. Also, typical exposure levels of the exogenous
compounds are extremely low, and metabolic deactivation before they reach the target tissue further
limits the potential activity. On the other hand, the endocrine system functions with very low effective
concentrations of signal molecules at the target cells. The significance of endocrine-mediated toxicity
in the male reproductive system is not yet clear, however, it is a topic of intense interest and potentially
wide ranging ramifications for the future (see further discussion in Section 11.4).
Male Reproduction Summary
11.1 MALE REPRODUCTIVE TOXICOLOGY 217
There are many industrial and pharmaceutical compounds that are potential male reproductive
toxicants (Table 11.1). Such chemicals may interfere with the development of germ cells directly, or
indirectly, by disrupting the cellular and endocrine factors involved in supporting and regulating
spermatogenesis. The regulatory roles of the neuroendocrine system are also important to the delivery
of sperm. The potential for various compounds to work through a particular toxic mechanism, however,
does not necessarily indicate that there is a relevant human reproductive risk associated with that
mechanism, or even with the compound at all. Mechanistic possibilities and experimental results must
be carefully evaluated in terms of those effects that are actually observed in exposed humans. There