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Ecological Medicine - Essays

Ecological Medicine Phthalate Esters and Endocrine Disruption
By Ted Schettler MD, MPH

The toxicity of phthalate esters is of considerable interest because of their use in many consumer products leading to widespread human exposures and environmental contamination. Of particular concern is their use as plasticizers in medical products and children's toys made of polyvinyl chloride (PVC). Children chewing on PVC toys are exposed to phthalate plasticizers, and patients receiving intravenous, respiratory, or intestinal therapies from PVC products are exposed to varying amounts of the commonly used plasticizer, di-ethyl hexyl phthalate (DEHP). In Europe and in the US, the Health Care Without Harm coalition is concerned about the potential health impacts of phthalate exposures from medical devices and has been closely following the evolution of scientific understanding of mechanisms of toxicity and identification of individuals who are particularly susceptible to toxic effects.

It has been known for many years that some phthalates are testicular and ovarian toxicants. Definitive understanding of all mechanisms of toxicity of phthalates has yet to fully emerge, however. For testicular toxicity, many studies show that developing organisms are much more sensitive than adults are, while studies of impacts on developing ovaries are few. In recent years, considerable interest in endocrine disruptors has emerged. Endocrine disruptors are chemicals that interfere with production, release, transport, metabolism, binding, action, or elimination of natural hormones responsible for homeostasis and essential for normal growth and development. Relatively new data show that, in laboratory tests, some phthalates behave as endocrine disruptors, which seems likely to explain some, but not all, of their toxic effects. Understandably, this line of investigation has generated considerable interest. Legislative bodies and regulatory agencies in the US and Europe have called for a more systematic identification of endocrine disrupting chemicals, and phthalates are among those being studied.

Several lines of evidence show that, at varying concentrations, in cell cultures and animal tests, phthalates disrupt hormone function. First, studiesin rats, following gestational and lactational exposure to dibutyl phthalate (DBP) and DEHP, showed widespread, profound impacts on the male reproductive system in offspring, including abnormalities of the penis, testicles, prostate, epididymis, and vas deferens. These changes are similar to those seen after exposure to the anti-androgen, flutamide. Follow-up studies of DBP, however, showed that the specific pattern of abnormalities was somewhat different from flutamide. These findings show that DEHP and DBP behave as anti-androgens that disrupt androgen-mediated male reproductive tract development, but that DBP acts somewhat different from the androgen-receptor antagonist, flutamide. Further studies are necessary to determine whether or not the DBP or PP on male reproductive tract development are completely independent of the androgen receptor or rather, that they selectively alter normal androgen-receptor function. In either case, each of these phthalates appears to be an endocrine disruptor because of its impact on androgen-mediated development. Whether or not either DEHP or DBP might have any of these effects in humans at lower exposure levels is unknown. Limited studies in animals have not, however, identified a "no-effect" level.

Studies of the effects of some phthalates on developing animal testes have identified a second endocrine disrupting mechanism of toxicity. It is generally agreed that the testicular toxicity of DEHP is largely due to the effect of its metabolite, mono-ethylhexyl phthalate (MEHP), on the Sertoli cells in the testes. Sertoli cells are the "nurse cells" for immature sperm. Sertoli cell damage typically results in decreased sperm production, which may be permanent even if exposure to the toxic agent is discontinued. Normal Sertoli cell development depends on stimulation by follicle stimulating hormone (FSH), produced in the pituitary gland. The FSH receptor is located in the Sertoli cell membrane. FSH interacts with its receptor, triggering a cascade of events within the cell necessary for normal Sertoli cell growth and development. MEHP and other phthalates, including DBP, monobutyl-, monopentyl-, and dipentyl-phthalate, interfere with the cascade of events normally induced by FSH stimulation, resulting in Sertoli cell toxicity.

Details of phthalate interference with FSH action on the Sertoli cell are not yet fully understood. Though there is some evidence that some phthalates, or their metabolites, block the FSH receptor from occupancy by FSH, other downstream events also appear to be disrupted. However, the resultant Sertoli cell toxicity is an example of endocrine disruption since the normal influence of FSH on the Sertoli cell is impaired.

The immature developing organism is particularly sensitive to these testicular effects. Studies in developing rodents show Sertoli cell toxicity after levels of exposure to DEHP or MEHP similar to those experienced by some children after treatment with DEHP-containing medical devices. Of particular concern are some medical treatments of newborn infants where measured DEHP and MEHP levels are actually higher than concentrations that cause toxicity in animal tissues. Of course, if a newborn child sustained permanent damage to his testes during medical treatment with a DEHP-containing medical device, evidence of that damage would not become apparent for years, making it difficult to identify an association between the early life exposure and the subsequent effect.

Granulosa cells of the ovary, responsible for producing estrogen, are also dependent on FSH stimulation for normal function. Studies of DEHP in intact animals and of MEHP in in vitro cell culture systems show toxicity to the granulosa cells, resulting in decreased estrogen production and abnormal estrus cycling in adult females. The implications of these findings for humans exposed to DEHP and MEHP are unknown. Finally, some phthalates have been shown to be weakly estrogenic. In an in vitro recombinant yeast screen assay, the relative estrogenic potency of the tested phthalates descended in the order butyl benzyl phthalate > dibutyl phthalate (DBP) > diisobutyl phthalate > diethyl phthalate > diisononyl phthalate. DEHP showed no estrogenic activity in this assay. Similar results were found in mammalian-based gene expression assays. However, none of the weakly estrogenic phthalates reproducibly increased uterine wet weight or showed estrogenic changes in the vaginal tissues of ovariectomized rats exposed orally once daily for four days to 20-2000 mg/kg. This result implies that pure estrogenic effects are unlikely to be of practical importance in humans at current exposure levels.

In summary, some phthalates behave as anti-androgens and severely disrupt the developing male reproductive system, though details of the mechanism(s) are incompletely understood. Testicular and ovarian toxicity of some phthalates, including DEHP, is, at least in part, the result of interference with FSH function at the level of the Sertoli cell in the testis and the granulosa cell in the ovary. Some phthalates are weakly estrogenic as demonstrated by estrogen receptor binding assays, but in intact animals, do not appear to induce estrogenic effects after fairly large exposures. Humans receiving treatment from some DEHP-containing medical devices are exposed to concentrations of MEHP known to cause Sertoli cell toxicity in animal tests.

Some phthalates, therefore, behave as endocrine disruptors in several different ways, and further research is necessary to clarify mechanistic details.

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