Malignant Mimicry
False estrogens may cause cancer and lower sperm counts
SCIENTIFIC AMERICAN September 1993 pg. 34 Pollutants resembling crucial human hormones may be short-circuiting some of the body's most important control mechanisms. The substances that worry researchers most are the usual suspects fingered in pollution reports: polychlorinated biphenyls (PCBs), dioxins, DDT and some petroleum by-products, among others.
To varying degrees, all of these chemicals can mimic the effects of estvogens on cells. Some recent work has turned up hints that a lifetime's subtle overexposure to such potent physiological signals could be responsible for cancers, birth defects and reproductive problems.
In a report scheduled to appear in Environmental Health Perspectives, for example, Devra Lee Davis of the Department of Health and Human Services and her colleagues conjecture that PCBs and similar compounds might be causing many cases of breast cancer. Davis, who has previously made controversial assertions about rising cancer rates, notes that most of the known genetic risk factors for breast cancer influence the body's estrogen metabolism.
Many of the suspect compounds have that same effect or have an affinity for the receptors on cells that normally bind to estrogens. The chemicals might therefore increase a woman's life-time exposure to estrogens. Because some cells in the breast respond to estrogens by multiplying, the chemicals could trigger rapid, inappropriate cell divisions like those in tumors.
Women may not be the only victims of estrogenic pollutants. This past May in the Lancet, Richard M. Sharpe of the University of Edinburgh and Niels E. Skakkebaek of the University of Copenhagen hypothesized that environmental estrogens might be damaging men's reproductive systems. "When I was going to medical school [in the 1960s]," Skakkebaek recalls, "more than 60 million sperm per milliliter was normal. And then it was changed to 40, and some years ago the World Health Organization set a line of 20 million."
Skakkebaek and his Danish colleagues have found evidence that those shifting standards reflect a shocking nose dive in sperm counts during the past half century. They looked at 61 papers on male fertility published between 1938 and 1990, covering data on almost 15,000 men from around the world. According to their analysis, the mean sperm count had declined from 133 million per milliliter in 1940 to only 66 million per milliliter in 1990. Moreover, the volume of semeo in a single ejacu- lation had also fallen from 3.40 to 2.75 milliliters. Those figures suggest that, on average, men now produce less than half as many sperm as did men 50 years ago.
At the same time, other abnormalities of the male reproductive tract have increased. Skakkebaek says rates of testicular cancer in Europe and the U.S. have risen between twofold and fourfold. Many urologists also believe undescended testicles and other male reproductive abnormalities have become more common, although the diagnosis and reporting of these conditions are less thorough. "I think these data are less substantiated, but there is a trend," Skakkebaek remark.
He and Sharpe argue that chemicals with affinities for estrogen receptors* on cells could cause all these phenomena. Animal studies have shown that if male fetuses are exposed to high doses of estrogens, they may develop with many female characteristics. Lower doses may alter the differentiation and multiplication of the germ cells that eventually give ri{e to sperm, the researchers note.
Hormonal meddling during this sensitive stage of development could also predispose some testicular cells to become cancerous. Research previously published by Skakkebaek's laboratory has suggested that cellular abnormalities associated with testicular cancer may originate during fetal life. "And the semen quality of men with testicular cancer is reduced," Skakkebaek observes. "So there is evidence that estrogens can cause all these changes. The question is whether what we are seeing is caused by estrogens."
If pollutants are acting as estrogens, their effects may parallel those of the notorious drup diethylstilbesterol (DES). This powerful estrogen was prescribed to millions of women for more than 20 years beginning in the 1940s to prevent miscarriages. Use of the drug ended with the discovery that the daughters of DES mothers are unusually likely to develop a rare form of vaginal cancer. Later studies showed that they also often have reproductive and urologic abnormalities that impair their fertility. Many sons of DES mothers suffer from related problems, including undescended testicles, deformities of the penis and low sperm counts.
Some researchers fear that the sons have an elevated incidence of testicular cancer as well, although that issue is still under scrutiny. The women who took DES face a one third higher risk of breast cancer.
John A. McLachlan, director of intramural rescarch at the National Institute of Environmeotal Health Sciences, has studied the effects of DES and other estrogenic chemicals for two decades. Experience with DES, he says, shows that "what may look like a perfectly functioning organ may have developmental abnormalities at the molecular or chemical Ievel that appear only later in life."
Whether pollutants with weaker estrogenic effects than DES can have similar effects at environmental concentrations remains to be seen. Conducting those tests may prove difficult. McLachlan notes that "some of the environmental chemicals that have estrogenic activity also seem to have a long half-life and can bio-accumulate" in the body's fat.
One group, he explains, looked at the effects of kepone, an insecticide that is only weakly estrogenic. At first, female rats exposed to parts-per-billion levels of kepone showed no effects, but after about nine weeks of exposure the chemical reached po- tent levels, and the animals' reproductive systems locked into a perpetual ovulatory state.
The World Wildlife fund has gathered evidence that some seagulls, fish and other creatures in polluted areas exhibit abnormal reproductive behavior or physiology. Nevertheless, it is by no means certain that the health consequences in humans are caused by mimicry of estrogen.
Karl T. Kelsey of the Harvard School of Public Health points out that "although PCBs and DDT metabolites have been shown to have estrogen-like activity, other compounds such as birth-control pills that have orders of magnitude more activity have not been definitively associated with breast cancer. So it's hard to understand how these compounds could be active when those others are not." Unfortunately, the estrogen pathway is just one of many that toxicologists will need to explore in search of the answers. * * *
Promoters
LAW OF TOXIC TORTS, Litigation/Defense/Insurance, by Michael Dore Clark Boardman §26.08[3] pg26-12.8
Advances in the field of environmental carcinogenesis suggest that certain materials may be promoters - i.e., substances which, while not carcinogenic themselves, interact with other substances in an organism 28 to cause a carcinogenic effect.
What substances may be promoters, and whay the mechanism of action for this phenomenon of scientific debate. 29 Since, at least theoretically, such promoters can make even low level exposures to toxic substances extremely significant, the development of receptor/promoter theories promises to be a fertile for scientific advances relevant to the toxic tort area. * * *
8/10/96
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