By Sean Henahan, Access Excellence

NEW ORLEANS (6/12/96)- The combination of two chemicals commonly found in insecticides and pesticides produces estrogenic effects that are one thousand times more powerful than either individual chemical alone, according to scientists at the Tulane-Xavier Center for Bioenvironmental Research .

Many synthetic chemicals and some natural plant hormones are estrogenic. These so-called environmental estrogens include numerous types of insecticides and pesticides (endosulfan, atrazine, DDT), industrial chemicals (polychlorinated biphenyls (PCBs), dioxins), pharmaceuticals (Cimetidine, DES), and plastic enhancers (phthalates, bisphenol A).

The Tulane scientists conducted studies using a yeast estrogen system containing human estrogen receptors and the estrogenic compounds endosulfan, dieldrin and toxaphene. When alone, the chemicals only slightly inhibited natural binding of estradiol - a natural estrogen hormone. When combined, however, mixtures of two of these weak environmental estrogens kept higher amounts of estradiol from binding and were 1,000 times more potent than any of the chemicals alone.

"I think it's clear now that at least at one level, we can no longer just assume that these are weak estrogens. We have to try and understand what happens when you mix them together," said University of Florida zoologist Louis Guillette, a collaborator with the New Orleans center. "The mixtures we're studying suggest that the potency of these compounds are now within the range of natural estrogens, and thus there is room for concern."

Estrogenic compounds can mimic the effects of the estrogen hormone, interfere with the body's endocrine system, which is responsible for normal development, bone growth and reproduction.

Guillette has been researching environmental estrogens for years, believing they could be responsible for dropping population levels and reproductive abnormalities in wildlife in some Florida waters, especially alligators in Lake Apopka, near Orlando.

Guillette found female and male alligators with abnormally high levels of estrogen and discovered the Lake Apopka male alligators had low levels of testosterone, poorly developed testes and significantly smaller penises.

"We knew these alligators had problems, we knew that there were chemicals in the eggs and we hypothesized that those chemicals were in fact causing the problems in the alligators," Guillette said. "But we did not have the underlying molecular basis to explain that."

"We have identified a molecular mechanism that explains how a mixture of chemicals synergistically activates the endocrine system, allowing low doses of weak environmental chemicals to combine and create a much higher response than each single chemical," says John McLachlan, director of the CBR and a member of the Tulane University research team. "In these cases, one plus one doesn't necessarily make two, it can make 10."

In addition to the alligators in Florida, fish in England and seagulls in California exposed to high doses of estrogenic contaminants have shown adverse reproductive and developmental effects such as abnormal genitalia, lower fertility and bizarre mating behavior.

The risk to human health, however, remains unclear since environmental estrogens are less potent than natural estrogens and humans are usually exposed to lower levels than those encountered in wildlife and laboratory studies. Even so, some researchers attribute human health problems such as falling sperm counts, reproductive cancers and low fertility to estrogenic compounds. The findings of the Tulane scientists may shed more light on how environmental estrogens impact human health, says McLachlan.

It is thought that one hormone reacts with one receptor site in the endocrine system to produce a required response. But the finding that two environmental chemicals synergistically trigger an intended action suggests that the receptor may bind the estrogenic compounds at two sites.

"It seems that combining chemicals increases their estrogenic activity to between 1/15 and 1/500 of a natural estrogen called estradiol, instead of the 1/50 to 1/10,000 when a chemical acts alone," says Steven Arnold, assistant professor at Tulane/Xavier CBR. "This scenario suggests that environmental chemicals may be active in low amounts, like those found in the natural environment, because of their synergistic effect."

Several recent studies have pointed in this direction. In 1993, McLachlan and researchers at the University of Texas reversed the sex of developing male turtles by painting eggs with natural estrogens, with PCBs and with a mixture of low concentrations of two kinds of PCBs. The sex of turtle eggs is determined by incubation temperatures, so even though the eggs were held at male-determining temperatures, the estrogen and the synthetic chemicals acted like the female hormone estrogen and influenced the embryos' development. The PCB mixture sex-reversed the turtles at much lower concentrations than the PCBs alone, proving the mixtures are more powerful than the individual PCBs.

The new research appeared in the June 7, 1996 issue of Science.

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