By Dr. Stephen Safe
Posted: Saturday, October 1, 1994

ARTICLES
Publication Date: October 1, 1994

Is it true that some pesticides, herbicides and chemicals are wreaking havoc on the reproductive systems of people and animals? Do these environmental estrogens, as they are called, cause breast cancer and endometriosis in women and diminished sperm count and undescended testicles in men and boys? What about the changes in animal health blamed on environmental estrogens — is it true that they're responsible for the low testosterone levels and diminished sperm count noted in Florida's alligators; thyroid problems seen in Great Lakes birds and fish; and immune system abnormalities noted in Atlantic Coast and Mediterranean dolphins?

In this article, we critically examine the evidence, or lack thereof, that certain chemicals with estrogenic activity are responsible for the development of breast cancer in women and male reproductive problems.

What Are Environmental Estrogens?

Environmental estrogens are chemicals that mimic or interfere with the effects of the female hormone estrogen. They do so by binding to the estrogen receptor sites and turning on the chain of events that occur when the hormone estrogen is present.

While women need estrogen for many reasons (to maintain a normal reproductive system, to protect them against heart disease and to retain calcium in their bones), too much can have negative consequences. The growth of some breast cancers, for example, is dependent on estrogen. While men have some naturally occurring estrogen, too much can have feminizing effects, including decreasing sperm production and causing the development of breast tissue.

The most common chemicals that can mimic estrogen include certain organochlorine industrial compounds such as polychlorinated biphenyls (PCBs), various pesticides including DDT (and its metabolites), polychlorinated dibenzo-p-dioxins (PCDDs), and dibenzofurans (PCDFs). In addition to pesticides, these and other estrogenic compounds are used in plastics (including some food wrappings), in paper and pulp production, textiles, hair colorings, spermicides, and detergents.

But, as with any substance, it's the dose that makes the poison — in this case, it's the dose that dictates whether these compounds are truly guilty for the problems noted above. While the chemicals cited are indeed present as environmental contaminants, the question remains: Are amounts significant enough to cause the problems cited? Also in question is: Are the associations cited causal or simply random occurrences?

The Current Furor

The current furor over endocrine-disrupting or estrogenic compounds was highlighted in the BBC program entitled "Assault on the Male — A Horizon Special," shown in North America on the Discovery Channel in the fall of 1994, highlighting the effects of estrogenic compounds on men. To support their claim that male virility is jeopardized by estrogenic compounds, they cited the work of Danish researchers Sharpe and Skakkebaek, who reported in a 1992 British Medical Journal a 50% decline in sperm count from 1938 to 1990 among men from industrialized countries. Sharpe and Skakkebaek subsequently hypothesized in a 1993 Lancet article that falling sperm counts (and other disorders of the male reproductive tract) were caused by in utero exposure to chemicals with estrogenic activity. In another leap of faith, Sharpe and Skakkebaek based their hypothesis on previous studies published in a 1982 American Journal of Obstetrics and Gynecology article by Stillman and colleagues showing that in utero exposure to the highly potent estrogen diethylstilbestrol (DES) can result in impaired reproductive performance in males.

A critical piece of information was missing in the BBC report — the piece of information that totally discredits the claims about decreasing sperm counts and estrogenic compounds: The validity of this hypothesis has been seriously challenged by a reanalysis of the published sperm count data and new sperm count values in the original authors' laboratories. Indeed, Sharpe and Skakkebaek subsequently admitted that the apparent decrease in sperm counts was due to an incorrect reference value utilized for normal sperm concentration. As a result, they concluded that "the original evidence does not support the hypothesis that the sperm count declined significantly between 1938 and 1990." Very telling is the July 2, 1994, British Medical Journal editorial "Falling sperm quality: Fact or Fiction?"

In addition to the BBC special, other major media have pushed the environmental estrogen/reproductive harm connection. Among the most highly publicized was a Journal of the National Cancer Institute study reporting an association between organochlorine pesticides and breast cancer in women. Two additional studies claimed that both PCBs and DDE were significantly elevated in women with breast cancer. Citing these and other studies, USA Today quoted University of Florida zoologist Louis Guillette, who believes estrogens are demasculinizing alligators, as saying, "A guy said, 'I don't see what all this has to do with us,'" Guillette recalls. His response: "It means every man alive today is half the man his grandfather was. And the most important question is: Are our grandsons going to be half the men we are?"

Do Estrogenic Compounds Cause Breast Cancer?

A closer look at the science simply does not support the claim that estrogenic compounds cause breast cancer. Consider the facts:

* Workers exposed to high levels of PCBs do not exhibit a higher incidence of breast cancer. If you're looking for an association between a substance and a disease, you would study the highest exposed group. In this case, you would go to people exposed to the highest levels of PCBs in the industrial setting. Indeed, there are over 50 years of experience with PCBs in industry. If, as in this case, there is no association between the heavy exposure to PCBs and breast cancer, then there is little doubt that exposures at lower, trace levels (such as would occur through environmental/dietary exposure) are responsible for increasing the number of breast cancer cases.
* DDE and PCBs are not themselves estrogenic compounds; rather it is their metabolites that exhibit only weak estrogenic activity. Further, these metabolites are seldom found in more than trace residues in humans due to their extremely low levels in the environment. But there's more compelling evidence against the hypothesis. A recent prospective study compared serum organochlorine levels in breast cancer patients to levels in women without clinically diagnosed breast cancer. The study found that there was no significant difference between the two groups in serum DDE nor in serum PCB levels.

But the science is even more complicated. One very significant factor the press hasn't addressed in the environmental estrogen stories is the importance of dietary fat. Some studies have linked dietary fat to an increased risk for breast cancer (although other studies have provided compelling evidence to the contrary). The organochlorine compounds bio-concentrate in fatty tissue, and serve as an unofficial marker of overall dietary fat intake. This means that it could actually be dietary fat that's responsible for the increase in breast cancer, not the organochlorine compound. Another possibility is that elevated organochlorine levels may reflect a higher intake of specific foods containing high levels of the compounds in question — and it's actually the food itself that is playing an important role in the development of breast cancer. What's needed is more extensive research in separating these factors.

Another complicating factor the press hasn't included in its alarming accounts is the balance between estrogen and antiestrogen equivalents in the human diet. Just as some compounds act like estrogen, others — anti-estrogenic compounds — impede estrogenic activity. There are two ways that antiestrogenic compounds work. Some are actually weak estrogens that bind to the estrogen receptor. Because they are so weak, they don't induce estrogen activities. But they effectively block the estrogen binding sites, thereby preventing other estrogenic compounds from binding and inducing estrogen activity. The other type of antiestrogenic compound acts in a curious way. Through mechanisms scientists don't fully understand, this other type of compound shuts off the estrogen-induced effects of estrogenic compounds.

In the diet, there are both estrogenic and anti-estrogenic compounds, and there are also naturally occurring vs. man-made (environmental contaminants) compounds of both types. In particular, the major naturally-occurring anti-estrogenic compounds in the diet are found in vegetables containing substances called flavonoids; most vegetables have some, with soy beans being particularly high in them. When it comes to estrogenic compounds, we find that man-made varieties contribute less than 0.001 percent of the total dietary estrogens — the rest are naturally occurring. Another interesting fact: Among man-made chemicals, there are far more anti-estrogenic compounds than estrogenic compounds. Dioxin, for example, inhibits mammary tumor formation and growth in rodents.

Even more compelling evidence comes from follow-up studies with humans exposed to dioxin after an industrial accident in Seveso, Italy. Women exposed to dioxin actually had lower rates of breast and endometrial cancer 15 years after the accident.

Some Parting Thoughts

The possibility that trace levels of environmental contaminants are harming the reproductive systems of humans and animals has been raised in preliminary research and, unfortunately, amplified by an uninformed press. This has caused considerable concern, and is another reason that well-intentioned efforts to protect human health are again misguided.

Chemical-induced effects in highly exposed workers often provide the most compelling evidence for a cause-and-effect relationship, and should be kept foremost in mind when considering the possible effects of that chemical at much lower levels of exposure. Lower dose dietary exposures to possible endocrine-disrupting chemicals must also account for other compounds in the diet that cause the same effects or counteract these endocrine responses — in other words, it is imperative to consider the balance between estrogenic and anti-estrogenic compounds, both naturally occurring and man-made.

Analysis of the data for estrogenic environmental pollutants suggests that we do not live in a "sea of estrogens" — unless they are derived from vegetables — and also that the hypothesized estrogenic "assault" on males and females is more fiction than fact.

Stephen Safe, Ph.D., is Professor of Toxicology in the Department of Veterinary Physiology and Pharmacology at Texas A&M University in College Station, Texas.

(From Priorities, Vol. 6, No. 4)