PRINCIPLES OF TOXICOLOGY

11.4 CURRENT RESEARCH CONCERNS 233
The basis for presuming that exposure to hormonally active agents can lead to significant risks is
mechanistically sound and clearly operates in certain high-dose situations, such as the birth control
pills and other therapeutic uses of synthetic hormones such as DES. However, there are well-understood
biological reasons to expect that the characteristics of the endocrine response differ under dramatically
different levels of stimulation (i.e., dose). Since doses of DES prescribed during the first three months
of pregnancy are equivalent to more than 150 years worth of a woman’s natural estrogen production,
this example is probably not relevant to potential risks from low levels of weakly estrogenic
environmental contaminants. It is important to recognize that the potency of “environmental estrogens”
typically range from hundreds to millions of times less than estradiol itself. Although there are
factors that might tend to reduce these potency differences, such as binding to serum proteins, these
factors are insufficient to answer the serious questions raised as to whether synthetic chemicals could
affect endocrine signaling in humans at realistic exposure levels.
Other putative developmental effects of hormonally active agents in humans derive from environmental
exposures, some of which occurred in accidental, high-dose poisoning incidents. Prenatal and
postnatal exposure to PCBs and polychlorinated dibenzofurans (PCDFs) in high-dose accidental
poisonings from contaminated rice oil in Yusho, Japan and Yucheng, Taiwan have resulted in various
developmental defects. The syndrome of effects includes low birth weight, dark pigmentation of the
skin and mucous membranes, gingival hyperplasia, exophthalmic edematous eyes, dentition at birth,
abnormal calcification of the skull, rocker bottom heel, and low birth weight. Most of the affected
infants were found to be shorter and had less total lean mass and soft-tissue mass. Follow-up studies
on poisoned individuals suggest neurobehavioral effects and cognitive deficits. Gross developmental
defects have not been observed in populations exposed at lower levels, but proponents of the endocrine
disruptor hypothesis point out that typical body burdens of PCB’s and dioxins are relatively close to
the levels measured in epidemiological study groups where adverse effects on IQ and neuromuscular
development have been reported. Nonetheless, these body burdens of PCBs have not been shown to
cause any specific adverse effects, and the overall epidemiological evidence is equivocal and does not
support a causal association between typical body burdens of PCBs and adverse developmental
outcomes.
Another highly publicized putative consequence of endocrine disruption in humans is reduced
sperm counts in men living in industrialized nations. Increasing background levels of a variety of
persistent, estrogenic environmental chemicals have been identified as a potential cause. This theory
has some mechanistic plausibility because sperm production is controlled by androgen levels, and
some effects of androgens can be antagonized by estrogens. This theory also has some high-dose
precedent from DES, a potent estrogenic compound that may have reduced sperm counts among males
exposed to therapeutic levels in utero. However, several of the studies that report declining sperm
counts have been criticized for methodological flaws, failing to account for alternative factors, and
biases in data collection. The statistical tests used and the proper interpretation of the tests have also
been called into question. Based on these difficulties and criticisms, many scientists question whether
sperm counts have actually declined in men from industrialized nations.
It is important to recognize that suggested reduction in sperm numbers is not the type of readily
apparent pathological condition observed in DBCP manufacturers (discussed above under Male
Reproductive Toxicology). The sperm count decline suggested by some authors (up to around 50
percent) would not be expected to correspond to a general fertility reduction because of the large excess
of sperm that are produced by most men.
Numerous methodological difficulties arise in evaluating sperm counts from different laboratories
over a long time frame, and hence, the degree of change that is purportedly related to environmental
exposures may be too subtle to be easily measured. Collection and preparation methods have varied
over the years, and differing criteria have been used to categorize typical, or “normal” sperm counts.
Different studies have handled samples from possibly infertile patients differently, some studies
including and others excluding them according to differing criteria. These differences in methodology
have confounded attempts to combine the results into a larger database for integrated analysis. For