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---June 22, 1995---
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In the past 60 days, two important British scientific journals have published editorials calling for more research into environmental chemicals that may be harming the reproductive health and sexual development of men throughout the industrialized world. NATURE (the equivalent of SCIENCE magazine in the U.S.) said on June 15th, "The case for research to be conducted urgently is overwhelming." [1] The medical journal, LANCET (approximately equivalent to the NEW ENGLAND JOURNAL OF MEDICINE in this country) was much more explicit, making the following points: [2]

** Industrial chemicals that mimic sex hormones (or xeno-estrogens, as they are sometimes called) "may be responsible for a massive decrease in male sperm counts and semen quality since 1940," LANCET said.

** "Female infertility is the subject of intense research and an unfailing source of headlines for the popular press. Male reproductive health has not been studied nearly so thoroughly, and little attention was paid to a series of observations indicating that the frequency with which a male factor is responsible for a couple's infertility has increased in recent years from about 10% to 25%," LANCET said.

** "Numerous compounds in daily industrial, agricultural, or domestic use have oestrogenic effects [oestrogen is the British spelling of estrogen], but the endocrine effects of the tens of thousands of man-made chemicals with which we come into daily contact have been studied in only a few instances, and then by accident rather than design.... For most chemical pollutants we do not know whether they are oestrogenic or not, what their effects are singly or together, or even the degree of our exposure.... They will remain in the environment for generations, and even small amounts of such contaminants can lead to the accumulation of considerable quantities in animal and human tissues," LANCET said.

** "It is the mother's lifetime exposure [prior to pregnancy] that determines the fetal dose, not just her exposure during pregnancy," LANCET said.

Both these journals called for urgent research to learn more about the male reproductive system, the chemicals that we encounter in our daily lives, and the effects those chemicals may have, singly or in combination, on male reproductive health.

The research task is formidable, to say the least. It is well-known that sexual differentiation (the point at which males become males and females become females in the womb) is initiated by the presence of the Y chromosome, which sets in motion male development; absence of the Y chromosome sets in motion female development. After initiation by the Y chromosome (or absence of it), all further steps are controlled by chemicals called hormones --estrogens are the "female" hormones and androgens are the "male" hormones. But the development of gender, with all its physical and behavioral aspects, depends upon both estrogens and androgens in both males and females; it is the balance of these chemicals, in combination, that produces normal differentiation and development. [3] All females contain some androgens, and all males contain some estrogens; it is the balance of the two types of chemicals that is important.

Over the past 30 years, it has been discovered that many industrial chemicals mimic estrogens. (See RHWN #263, #264, #343, #365, #372, #377, #446.) An "estrogen hypothesis" has been proposed to explain why each year more men in the industrialized world are getting cancer of the testicles, birth defects affecting the penis, lowered sperm count, lowered sperm quality, and undescended testicles. The estrogen hypothesis suggests that all of these effects can be traced to one cause: industrial chemicals mimicking hormones, affecting male children while they are still in the womb. [4]

However, in the last two years, a different set of concerns has been raised: some chemicals that don't mimic estrogens can still interfere with sexual differentiation and development in laboratory animals; they do it by interfering with the action of androgens (male hormones). Since it is the BALANCE of estrogens and androgens that creates one gender or another, anti-androgens can interfere with male development as effectively as excessive estrogens can. In NATURE June 15, William Kelce, a researcher at U.S. Environmental Protection Agency (EPA) reported that a breakdown byproduct ("metabolite") of the pesticide DDT (called p,p'-DDE, and pronounced "p, p-prime D D E") is a powerful anti-androgen. [5] Anti-androgen drugs (developed as therapy for human prostate cancer), when given to animals before and shortly after birth, can cause reproductive tract disorders, including small penis, hypospadias, [6]and undescended testicles. Thus it is important to learn that a DDT metabolite is a powerful anti-androgen. DDT has been banned in this country, but many countries still allow its use, including its use on food products that are imported into the U.S. [7]Furthermore, despite the ban, many ecosystems in the U.S. remain heavily contaminated from past DDT use.

Therefore, the research task requires us to know not only which chemicals mimic estrogens, but also which chemicals interfere with androgens. For example, a common pesticide, Vinclozolin, was recently discovered to be a powerful anti-androgen. [8] Dosing a pregnant female rat with Vinclozolin at a level that caused no toxicity in the mother, gave rise to baby male rats which all appeared to be female at birth. The newborn male rats developed nipples (which, in rats, only females normally have), and they all had the hypospadias birth defect, [6]and undescended testicles. Furthermore, they were all sterile, unable to produce enough sperm to inseminate a female. In the U.S. today, Vinclozolin is legal for use on cucumbers, grapes, lettuce, onions, bell peppers, raspberries, strawberries, tomatoes, and Belgian endive. [9] It is sold under the following trade names: Ronilan, Ornalin, Curalan, and Vorlan. It is also one of the ingredients in the following mixtures: Hitrun, Konker, Ronilan M, Ronilan T combi, Silbos, and Fungo-50. EPA has no published plans for banning Vinclozolin.

Note that in the cases of both DDT and Vinclozolin, the chemical itself has certain gender-bending properties, but the breakdown byproducts (metabolites) have even more powerful anti-androgenic properties. For example, the M1 metabolite of Vinclozolin is 100 times more powerful than Vinclozolin itself. Therefore, researchers will need to study not only the main chemicals but all of their important metabolites. In the case of Vinclozolin, there are at least 2 important metabolites. Obviously, the need to, first, identify and, second, test, metabolites greatly increases the size and scope of the research task.

The problem of chemical combinations is even more difficult. Several prominent researchers calling for urgent work on gender-benders have suggested that combinations of chemicals might be important. For example, we quoted the editorial from LANCET April 15: "For most chemical pollutants we do not know whether they are oestrogenic or not, what their effects are singly OR TOGETHER, or even the degree of our exposure...."

Suppose we wanted to study only the possible 2-chemical combinations among the commonest 500 industrial chemicals. To do this, we would have to run 124,749 different experiments (let's call it 125,000). [10] To study all the different 3-chemical combinations among the 500 would require 20.7 million experiments--an impossible task. Even testing all 3-chemical combinations among only 100 chemicals would require 161,700 experiments. Testing combinations is a burden.

If we were worried about 500 chemicals, each with one metabolite, for a total of 1000 chemicals, and we wanted to study all possible 2-chemical combinations, we'd have to run 499,500 (just shy of half a million) experiments; to learn about all the different 3-chemical combinations of these 1000, we'd have to run 166 million experiments--simply out of the question.

Running even 125,000 experiments (all 2-chemical combinations of the top 500 chemicals) would require quite a different attitude than public health officials presently exhibit toward these problems. Many dozens of competent laboratories would have to get involved. Hundreds of researchers and technicians would have to be trained (or re-trained). Much current research would have to be abandoned. If each experiment cost only $100,000, then 125,000 experiments would cost $12.5 billion and 499,500 experiments would cost $50 billion.

Finally, recent research on dioxin reveals that, at dose levels not toxic to the mother, both male and female offspring of dioxin-exposed pregnant rats and hamsters have their sexual development stunted. [11]In females, the external genitalia were malformed; in males, testicles were reduced in weight, and sperm count was reduced by more than 50%. These effects were not caused by estrogen-mimicking, nor by an anti-androgen mechanism. Some entirely different mechanism, not understood, allows dioxin to interfere with sexual development of mammals at extremely low levels of exposure. Are there other chemicals like dioxin in this regard? It seems a fair question.

For scientists all these research questions may seem interesting, if not actually doable. But for the public, a different question seems paramount: how can we avoid exposure to dioxin and to all the other gender-benders found in pesticides, detergents, paints, plastics, and so on? After they are made and released into the environment, there is no avoiding them. Therefore, we must prevent their manufacture in the first place. This is the life-and-death challenge of our age.
                                                                         --Peter Montague
[1] Anonymous, "Masculinity at risk [editorial]", NATURE Vol. 375 (June 15, 1995), pg. 522.

[2] Anonymous, "Male reproductive health and environmental oestrogens [editorial]," LANCET Vol. 345, No. 8955 (April 15, 1995), pgs. 933-935.

[3] See Frederick S. vom Saal and others, "Sexual Differentiation in Mammals," in Theo Colborn and Coralie Clement, editors, CHEMICALLY-INDUCED ALTERATIONS IN SEXUAL AND FUNCTIONAL DEVELOPMENT: THE WILDLIFE/HUMAN CONNECTION [Advances in Modern Environmental Toxicology Vol. XXI] (Princeton, N.J.: Princeton Scientific Publishing Co., 1992), pgs. 17-83; and in the same volume, see Leon Earl Gray, Jr., "Chemical-Induced Alterations of Sexual Differentiation: A Review of Effects in Humans and Rodents," pgs. 203-230.

[4] For example, see Niels E. Skakkebaek and Niels Keiding, "Changes in semen and the testis," BRITISH MEDICAL JOURNAL Vol. 309 (November 19, 1994), pgs. 1316-1317.

[5] William R. Kelce and others, "Persistent DDT metabolite p,p'-DDE is a potent androgen receptor antagonist," NATURE Vol. 375 (June 15, 1995), pgs. 581-585. Our thanks to Peter deFur and Mechelle Evans of the Environmental Defense Fund (EDF) for providing us with a copy of this article.

[6] As a male grows inside the womb, the penis develops a urinary channel called the urethra; with the birth defect called hypospadias, the urinary channel is not closed but remains open for a certain distance on the underside of the penis, and this has to be corrected surgically after birth. The hypospadias birth defect is thought to be increasing in frequency; see A. Giwercman and N.E. Skakkebaek, "The human testis--an organ at risk?" INTERNATIONAL JOURNAL OF ANDROLOGY Vol. 15 (1992), pgs. 373-375.

[7] Richard M. Sharpe, "Another DDT connection," NATURE Vol. 375 (June 15, 1995), pgs. 538-539.

[8] William R. Kelce and others, "Environmental Hormone Disruptors: Evidence That Vinclozolin Developmental Toxicity is Mediated by Antiandrogenic Metabolites," TOXICOLOGY AND APPLIED PHARMACOLOGY Vol. 126 (1994), pgs. 276-285. And: L. Earl Gray, Jr., and others, "Developmental Effects of an Environmental Antiandrogen: The Fungicide Vinclozolin Alters Sex Differentiation of the Male Rat," TOXICOLOGY AND APPLIED PHARMACOLOGY Vol. 129 (1994), pgs. 46-52.

[9] See 40 CFR [Code of Federal Regulations] Chapter 1 (7-1-94 edition), section 180.380.

[10] The formula for calculating how many different subcollections of size k can be formed from a collection of n different chemicals is (n!)/((k!)*((n-k)!)) when n! means n factorial and * means "multiplied by". See, for example, Michael Orkin and Richard Drogin, VITAL STATISTICS (New York: McGraw-Hill, 1975), pg. 285.

[11] L.E. Gray, Jr., and others, "Exposure to TCDD during Development Permanently Alters Reproductive Function in Male Long Evans Rats and Hamsters: Reduced Ejaculated and Epididymal Sperm Numbers and Sex Accessory Gland Weights in Offspring with Normal Androgenic Status," TOXICOLOGY AND APPLIED PHARMACOLOGY Vol. 131 (1995), pgs. 108-118.

Descriptor terms: nature; lancet; endocrine disruptors; endocrine system; xenoestrogens; estrogen; hormones; androgens; infertility; fertility; reproductive health; testicular cancer; sperm count; sperm density; sperm quality; hypospadias; cryptorchidism; undescended testicles; birth defects; epa; william kelce; metabolites; ddt; dde; p,p'-dde; vinclozolin; pesticides;

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