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#447 - The Challenge of Our Age, 21-Jun-1995

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 REHW #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: endocrine disrupters; endocrine system;
xenoestrogens; estrogen; hormones; androgens; infertility; fertility;
reproductive health; testicular cancer; sperm count; sperm quality;
hypospadias; cryptorchidism; undescended testicles; birth defects; epa;
william kelce; metabolites; ddt; dde; vinclozolin; pesticides;