PRINCIPLES OF TOXICOLOGY

234 REPRODUCTIVE TOXICOLOGY
these reasons, many scientists are convinced that reported sperm count declines are an artifact of
methodological and analytical flaws of the studies.
Many synthetic chemicals have been suggested as potential human endocrine disruptors based upon
widespread human exposure and their hormone-like activity in certain laboratory assays. Various lists
of putative endocrine disruptors have been published or otherwise publicized in the media or on the
internet. It is important to recognize that the quality of data supporting inclusion of chemicals on these
lists varies considerably, and there is no generally accepted scientific source providing an authoritative
listing at this time. Most lists include chemicals from diverse chemical classes, many of which have
produced a positive result in at least one of a variety of bioassays and receptor-binding methods devised
to determine the potential interaction of a chemical with the endocrine system. Despite positive results
in laboratory assays, few chemicals—e.g., those drugs and chemicals already discussed in this
section—have been shown to produce adverse developmental outcomes in exposed humans. Some
prominent examples of chemicals listed as endocrine disruptors include organochlorine pesticides
(e.g., toxaphane, methoxychlor, chlordecone, DDT and metabolites), alkylphenol ethoxylates
(detergents or dispersing agents in household cleaners), PAHs (combustion products) dioxins
(TCDD), co-planar PCBs, phthalate and phenolic plasticizers (e.g., benzyl butyl phthalate,
di-n-butyl phthalate, bisphenol A). However, more definitive laboratory studies and risk assessments
developed for a number of such chemicals (e.g., alkylphenol ethoxylates, phthalate and
phenolic plasticizers) indicate little or no potential for adverse effects in humans at environmentally
relevant exposure levels.
Two particular issues have arisen in the controversy over endocrine disruption that deserve special
mention. In 1996, just months before Congress passed the 1996 Food Quality Protection Act, Arnold
and coworkers published a paper in Science that brought national attention to the subject of endocrine
disruption. The report claimed that a combination of synthetic chlorinated pesticides were
one-thousand times more potent than any of the chemicals individually in stimulating an estrogenic
response. This so-called demonstration of estrogenic synergism was later shown to be in error, and the
publication was retracted more than a year later. Despite its failure to demonstrate synergy, this study
raised a debate within the scientific, regulatory, and regulated communities over the frequency with
which synergistic interactions are likely to occur and their relevance to human and environmental
health. Though the interest in synergy has subsided considerably since the retraction of the Arnold
publication, a considerable amount of effort is still underway to determine whether such chemical
interactions are important considerations for risk assessment.
The second issue of debate involves the dose-response function for endocrine active agents. First,
is there a threshold for endocrine-mediated adverse effects and second, do toxic effects of high doses
of hormonally active agents mask more subtle adverse effects that can only be detected at low doses
using specialized assay systems? These issues arise from two publications suggesting that very low
doses of plasticizing agents could produce subtle effects on the developing male reproductive tract not
seen at higher doses, possibly because subtle effects are masked by more overt toxicity at higher doses.
Neither study has been replicated, despite attempts that employed more comprehensive study designs.
Nonetheless, the issue has lead to an outcry from consumer and environmental activist groups to cease
the use of certain plastics in baby bottles and childrens’ toys. Former Surgeon General of the United
States Dr. C. Everett Koop has responded, calling this reaction irresponsible.
In summary, a number of critical questions have been raised with respect to the identification of
hormonally active agents in general, and laboratory studies that purport to demonstrate potential
hormonal activity in particular.
• Are positive results in short-term in vivo and in vitro laboratory assays predictive of adverse
health effects in humans?
• Can measurements of hormonal potency in laboratory assays be extrapolated to human
populations at environmentally relevant exposure levels?