ENDOCRINE DISRUPTORS
Endocrine disruption is a term we hear and read about with increasing frequency. The term has
become synonymous with disorders of reproduction that include hazards to animal and human
health from environmental factors, such as chronic low doses of certain pesticides and other
xenobiotics. Many popular books have been written on the subject, which have caught
the imagination of the American public with their vivid descriptions of hypospadias,
testicular cancer, cryptorchidism, oligospermia, or other bizarre reproductive
happenings. To begin addressing this issue, the Environmental Protection Agency published, in
the October 31, 1996 Federal Register, "Guidelines for Reproductive Toxicity Risk
Assessment." The forty-eight page guideline is not a legal or regulatory document. Nor is it
intended to be a substitute for any EPA regulation. The document sets forth current scientific
thinking and approaches for conducting reproductive toxicity risk assessment. However, even
the EPA acknowledges the scientific weakness of many of the conclusions and that "there is no
definitive evidence that such adverse human health effects have been caused by environmental
chemicals." But though many scientists likewise have questioned the validity of many of the
published findings, all scientists agree that for successful reproduction, "it is critical that the
biologic integrity of the human reproductive system be maintained."
In fact, maintaining this integrity of the human reproductive system, which is triggered by a
sophisticated series of endocrine events, coupled with elements that act upon the reproductive
system, such as nutrition, environment, lifestyle, drug use, and stress may mean definitive
answers will elude us. From this perspective, it might be useful to look at some of the known
causes of reproductive disorders to illustrate the difficulty of isolating any single chemical cause.
Reduced Fertility
Infertility, defined as the failure to conceive after one year of unprotected intercourse, has many
known causes. Some of the known causes of reduced fertility include thyroid malfunction,
scarred fallopian tubes, endometriosis, diabetes, abnormality of the sperm,
undescended testicles, varicose veins in the scrotum, hormonal imbalance, pelvic inflammatory
disease, and many medications, or even from unwise fashion choices.
Impotence
- hormonal--lack of testosterone due to disease, surgery, age, or medication.
- neurological--any injury or disease that interferes with the message sent by the
brain through the nervous pathways to the genital area.
- pharmacological--anti-hypertensive drugs, tranquilizers, sleeping pills, narcotics,
or alcoholic excess.
- psychological--some specific anxiety-producing event, fear of disease, depression,
overwork, fatigue, business worries, etc.
- vascular--arteriosclerosis of the vascular system which blocks the arteries to the
genitals.
Disruption of Menstrual Period
The menstrual cycle is governed by an involved interaction of hormones. The hypothalamus,
which is part of the brain, sends chemicals called releasing factors directly to the pituitary gland;
the pituitary then releases pituitary hormones called gonadotropins, which travel through the
bloodstream to the ovaries, where they cause ovarian follicles to produce estrogen and
progesterone. Attempts at reproduction can go wrong at any stage of this process; as a
result, menstrual irregularity is sometimes caused by the distant hypothalamus, which can be
affected by a multitude of factors, including illness, drug use, drastic weight loss, or stress.
Spontaneous Abortion
Endocrine disorders are only one potential cause of miscarriage and the endocrine are most
frequently associated with corpus luteum insufficiency, polycystic ovary syndrome, diabetes
mellitus, and hypothyroidism or hyperthyroidism. Other causes can be anatomic, genetic,
immunologic, or pharmacological.
A similar recognition was evident at the recent meeting of the International Society of
Regulatory Toxicology and Pharmacology, held January 13-14 in Research Triangle Park.
International Scientists Meet to Discuss Endocrine Issues
According to Dr. C. Jelleff Carr, Secretary of the International Society, a first evaluation of the
session on "Assessing the Risks of Adverse Endocrine Mediated Effects," noted many technical
issues that modify the end findings of all the biological and chemical studies. This was pointed
out again and again by the numerous international speakers and debated by the participants at
the panel discussions that reviewed dose-response issues, human exposure to endocrine-active
chemicals, testing techniques for endocrine-mediated effects, and evaluations of endocrine-risk
characterization.
One speaker pointed out estrogen receptors are basically "atoms in a box," and we seem to live
in a sea of estrogens. Some are weak and some have strong effects. These conclusions were
really a fulfillment of the wise conclusions of many years ago that "we are the victims and/or the
beneficial recipients of normal endocrine functions."
It is clear that many evaluative studies are required if we are to properly evaluate endocrine-
mediated effects. Dr. John Ashby of Zeneca Ltd., Cheshire, England in his "Where Do We Go
From Here?" overview stated we need to examine what is true and what is not in our current
studies. He pointed out, for example, that a chemical can also change the "character" of the
"receptor" and this in turn alters the entire concept of endocrine receptors and disruptors.
Bacteria can also effect estrogen effectors, with toxaphene, for instance, serving as an example
of a substance that "activates" the effects of estrogens.
In a setting that saw a unanimity by industry and government officials of the ubiquitousness of
problems with the subject of endocrine disruptors, it became obvious to those present that a
screening strategy needs to be developed for endocrine disruptive chemicals, and at the same
time, as Ashby noted, we should be cautious in any agreed upon list of relevant mammalian
toxicities.
It was clear that we are faced by many technical evaluations in developing a basic scientific
strategy. To assist in resolving these concerns the presentations of this meeting will be
published in a forthcoming issue of the Regulatory Toxicology and Pharmacology
Journal. Stay tuned to MTI for further information.
Return To Table of
Contents
GLOSSARY OF TERMS
- Cryptorchidism:a developmental defect in the male in which the testes fail
to descend into the scrotum.
- Endometriosis:the presence of endometrial tissue in abnormal locations,
including the uterine wall, ovaries, or extragenital sites.
- Estrogens:a class of sex hormones associated with the development and
maintenance of secondary female characteristics and control of the cyclical changes in the
reproductive cycle. They also are required for pregnancy maintenance and have an anabolic
effect on protein metabolism and water retention.
- Gynecomastia:excessive development on the male mammary glands.
- Hypospadias:a development anomaly of the penis in which the urethra
opens on the underside of the penis.
- Oligospermia:the steroid hormone secreted by the ovary mainly from the
corpus luteum. It is essential for nidation of the ovum and maintenance of pregnancy; cessation
of its secretion at the end of the menstrual cycle largely determines the time of onset of
menstruation. The hormone, now obtained by synthesis, is used for the management of various
ovarian disorders.
- Xenobiotics:chemical substances that are foreign to the biological system.
They include naturally occurring compounds, drugs, environmental agents, carcinogens,
insecticides, etc.
Return To Table of Contents
Selected Bibliography
- Atterwill,C.K.;Flack,J.D.(1992)Endocrine Toxicology. Cambridge Univ.
Press, Cambridge.
- Carlsen, E.,Giwercman, A., Keiding, N., Skakkeback, N.E. (1992)"Evidence for decreasing
quality of semen during the past 50 years." Br Med J 305:609-613.
- Fisch, H., Goluboff, E.T.,Olson, J.H., Feidshuh,J., Broder, S.J., Barad, D.H. (1996) "Semen
analysis in 1,283 men from the United States over a 25 year period: no decline in fertility." Fertil
Steril 65:1009-1014.
- Paulsen,C.A., Berman, N.G., Wand, C. (1996) "Data from men in greater Seattle area
reveals no downward trend in semen quality: further evidence that deterioration of semen
quality
is not geographically uniform." Fertil Steril 65:1015-1020.
Return To Table of Contents
Medical Foods to be Reviewed
The FDA has asked for comments for a proposed rule in the regulation of medical foods. Citing
an unprecedented growth in the use of medical foods, the enactment of a statutory definition of
the term, and a general uneasiness concerning claims based on what it termed unsound science,
the agency in November announced it was time to re-examine its position on medical foods. In
making its advancednotice for a proposed rule, the FDA announced a period of comment until
February 27. The full noticeof the proposal may be found in the November 29, 1996 Federal
Register (61 FR 60661-60671). Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration,12420 Parklawn Drive, Rm. 1-23, Rockville, MD
20857.
Reduced Sperm Count Bibliography
MTI has a thorough bibliography on infertility and reduced sperm count and their
causes available to our readers. The reviewed publication covers the most recent
meta-analysis studies from a balanced, scientific perspective, as well as the
many known causes of reduced human sperm concentrations. Citations are taken from
a wide range of sources to ensure the most thorough coverage of the medical and
scientific literature.
Toxic Notes
On January 13 -14, 1997, The International Society of Regulatory Toxicology and Pharmacology
met in Research Triangle Park, North Carolina to discuss the many issues involved with
Endocrine Disruptors. SeeInternational Scientists Meet to Discuss Endocrine
Issues in this web site.
MTI Consulting and Expert Witness
Service
In addition to our research information retrieval services, MTI offers a consulting/expert witness
program designed to give you the professional, highly technical assistance you need to meet the
exacting demands of science in the courtroom or in difficult regulatory areas, such as with the
issues of Endocrine Disruptors.
At MTI, we have provided medical and scientific support to some of the top legal firms in the
world as well as small private practices. For more information, consult Expert Witness
Service in this web site.
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