PRINCIPLES OF TOXICOLOGY - Biology East Borneo

234 REPRODUCTIVE TOXICOLOGYthese reasons, many scientists are convinced that reported sperm count declines are an artifact ofmethodological and analytical flaws of the studies.Many synthetic chemicals have been suggested as potential human endocrine disruptors based uponwidespread human exposure and their hormone-like activity in certain laboratory assays. Various listsof putative endocrine disruptors have been published or otherwise publicized in the media or on theinternet. It is important to recognize that the quality of data supporting inclusion of chemicals on theselists varies considerably, and there is no generally accepted scientific source providing an authoritativelisting at this time. Most lists include chemicals from diverse chemical classes, many of which haveproduced a positive result in at least one of a variety of bioassays and receptor-binding methods devisedto determine the potential interaction of a chemical with the endocrine system. Despite positive resultsin laboratory assays, few chemicals—e.g., those drugs and chemicals already discussed in thissection—have been shown to produce adverse developmental outcomes in exposed humans. Someprominent 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 assessmentsdeveloped for a number of such chemicals (e.g., alkylphenol ethoxylates, phthalate andphenolic plasticizers) indicate little or no potential for adverse effects in humans at environmentallyrelevant exposure levels.Two particular issues have arisen in the controversy over endocrine disruption that deserve specialmention. In 1996, just months before Congress passed the 1996 Food Quality Protection Act, Arnoldand coworkers published a paper in Science that brought national attention to the subject of endocrinedisruption. The report claimed that a combination of synthetic chlorinated pesticides wereone-thousand times more potent than any of the chemicals individually in stimulating an estrogenicresponse. This so-called demonstration of estrogenic synergism was later shown to be in error, and thepublication was retracted more than a year later. Despite its failure to demonstrate synergy, this studyraised a debate within the scientific, regulatory, and regulated communities over the frequency withwhich synergistic interactions are likely to occur and their relevance to human and environmentalhealth. Though the interest in synergy has subsided considerably since the retraction of the Arnoldpublication, a considerable amount of effort is still underway to determine whether such chemicalinteractions 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 dosesof hormonally active agents mask more subtle adverse effects that can only be detected at low dosesusing specialized assay systems? These issues arise from two publications suggesting that very lowdoses of plasticizing agents could produce subtle effects on the developing male reproductive tract notseen 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 ceasethe use of certain plastics in baby bottles and childrens’ toys. Former Surgeon General of the UnitedStates 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 ofhormonally active agents in general, and laboratory studies that purport to demonstrate potentialhormonal activity in particular.• Are positive results in short-term in vivo and in vitro laboratory assays predictive of adversehealth effects in humans?• Can measurements of hormonal potency in laboratory assays be extrapolated to humanpopulations at environmentally relevant exposure levels?