PRINCIPLES OF TOXICOLOGY

elements called protamines during later stages of spermatogenesis and protamines are particularly
vulnerable to reactions with ethylene oxide.
These medically related examples indicate the delicate balance between therapeutic or beneficial
uses and potential reproductive toxicity. The powerful alkylating properties of chemotherapy drugs
allow them to work against rapidly dividing cancer cells and the risk of ancillary effects on other cells,
even frank reproductive toxicity, may represent an acceptable tradeoff for the cancer patient. Also, the
safety and benefits of dry, gas sterilization with ethylene oxide are clearly significant. While we can
document the mechanisms of action producing male reproductive toxicity experimentally, there is no
evidence that the ethylene oxide exposures associated with sterilization has produced reproductive
toxicity in men. Again, the toxicology indicates what could happen if the right conditions existed, not
what happens under the typical situations in which the chemicals are encountered.
Many of the compounds of interest in occupational or environmental toxicology require metabolic
activation to produce reproductive effects. The testis has the enzymatic capabilities for oxidative
metabolism, a pathway that frequently produces reactive intermediates. While this activity is low
compared to the liver, it is sufficiently high to produce toxic amounts of metabolites for some
compounds.
Metabolism of common industrial chemicals including the solvents n-hexane and the glycol ethers
appears to contribute to their reproductive toxicity. Some of the phthalates, a chemical class used
extensively as plasticizers and distributed widely in the environment, are also capable of affecting male
reproductive tissues after metabolism. All of these examples are discussed further with regard to the
specific cells they affect and have at least purportedly affected humans. There are also many other
examples of indirect acting male reproductive toxicants where there is at least experimental or
mechanistic information on toxic potential including the intermediate acrylamide and vinyl chloride,
another common industrial intermediate also found in the environment, often as a breakdown product
of dry cleaning solvent.
Cell-type Specific Toxicity
11.1 MALE REPRODUCTIVE TOXICOLOGY 213
Another principle illustrated by examining male reproductive toxicology is the specificity of action on
certain cell types due to the characteristics of the cells or their metabolic potential. For some
reproductive toxicants, there is varying sensitivity among the somatic and germ cell types. While this
may be explained in some cases by the high levels of cell division and activity among the germ cells,
in some cases there appear to be more specific factors involved. Besides the germ cells, there are two
major types of somatic cells in the testis required for spermatogenesis, Sertoli cells and Leydig cells.
Both of these cell types may also be specific targets for some toxicants. In addition, the microvasculature
of the testis can be a specific target and the functional consequences of impaired circulation in
the testis have been described above.
Developing Sperm Cells As germ cells proceed through spermatogenesis, several different terms are
used to distinguish the varying degrees of maturity. At the earliest stages are the spermatogonia,
followed by the spermatocytes, the spermatids, and finally spermatozoa (Figure 11.1). Besides
describing the developmental stage of the germ cells, these distinctions also correspond to some degree
of toxicological specificity as certain stages are targeted by certain compounds. This specificity
generally relates to which stages are the most sensitive to a particular agent. In most cases, as the dose
increases or exposure conditions change, more than one stage can be affected.
One of the occupational episodes that stirred interest in effects on male reproductive function was
reported sterility among workers handling the pesticide dibromochloropropane (DBCP). Subsequent
investigations suggested a toxic effect that would certainly explain sterility. The most significant cell
type damaged by DBCP is probably the spermatogonia. Since these progenitor germ cells are at the
base of spermatogenic cellular expansion, their destruction precludes future cycles of spermatogenesis.
Thus, the expected observation would be a depletion of all the later stages and an inability to recover