introduced into the environment by human activity are capable of disrupting
endocrine system of animals, including fish, wildlife, and humans.
The consequences of such disruption can be profound because of the
crucial role hormones play in controlling development. Because of
the increasing and pervasive contamination of the environment by compounds
capable of such activity, a multidisciplinary group of experts gathered
in retreat at Wingspread, Racine, Wisconsin, 26-28 July 1991 to assess
what is known about the issue. Participants included experts in the
fields of anthropology, ecology, comparative endocrinology, histopathology,
immunology, mammalogy, medicine, law, psychiatry, psychoneuroendocrinology,
reproductive physiology, toxicology, wildlife management, tumor biology,
purposes of the meeting were:
integrate and evaluate findings from the diverse research disciplines
concerning the magnitude of the problem of endocrine disruptors
in the environment;
identify the conclusions that can be drawn with confidence from
existing data; and
establish a research agenda that would clarify uncertainties remaining
in the field
following consensus was reached by participants at the workshop.
are certain of the following:
estimate with confidence that:
large number of man-made chemicals that have been released into
the environment, as well as a few natural ones, have the potential
to disrupt the endocrine system of animals, including humans.
Among these are the persistent, bioaccumulative, organohalogen
compounds that include some pesticides (fungicides, herbicides,
and insecticides) and industrial chemicals, other synthetic products,
and some metals.2
wildlife populations are already affected by these compounds.
The impacts include thyroid dysfunction in birds and fish; decreased
fertility in birds, fish, shellfish, and mammals; decreased hatching
success in birds, fish and turtles; gross birth deformities in
birds, fish, and turtles; metabolic abnormalities in birds, fish,
and mammals; behavioral abnormalities in birds; demasculinization
and feminization of male fish, birds and mammals; defeminization
and masculinization of female fish and birds; and compromised
immune systems in birds and mammals.
pattern for effects vary among species and among compounds. Four
general points can nontheless be made:
chemicals of concern may have entirely different effects on
the embryo, fetus, or perinatal organism than on the adult;
effects are most often manifested in offspring, no in the
timing of exposure in the develping organism is crucial in
determing its character and future portential; and
critical exposure occurs during embryonic development, obvious
manifestations may not occur until maturity.
studies corroborate the abnormal sexual development observed in
the field and provide biological mechanisms to explain the observations
have been affected by compounds of this nature, too. The effects
of DES (diethylstilbestrol), a synthetic therapeutic agent, like
many of the compounds mentioned above, are estrogenic. Daughters
born to mothers who took DES now suffer increased rates of vaginal
clear cell adenocarcinoma, various genital tract abnormalities,
abnormal pregnancies, and some changes in immune responses. Both
sons and daughters exposed in utero experience congenital anomalies
of their reproductive system and reduced fertility. The effects
seen in in utero DES-exposed humans parallel those found in contaminated
wildlife and laboratory animals, suggesting that humans may be
at risk to the same environmental hazards as wildlife.
models predict that:
of the developmental impairments reported in humans today are
seen in adult offspring of parents exposed to synthetic hormone
disruptors (agonists and antagonists) released in the environment.
The concentrations of a number of synthetic sex hormone agonits
and antagonists measured in the US human population today are
well within the range and dosages at which effects are seen in
wildlife populations. In fact, experimental results are being
seen at the low end of current environmental concentrations.
the environmental load of synthetic hormone disruptors is abated
and controlled, large scale dysfunction at the population level
is possible. The scope and potential hazard to wildlife and humans
are great because of the probability of repeated and/or constant
exposure to numerous synthetic chemicals that are known to be
attention is focused on this problem, more parallels in wildlife,
laboratory, and human research will be revealed.
are many uncertainties in our predictions because:
mechanisms by which these compounds have their impact vary, but
they share the general properties of
the effects of natural hormones by recognizing their binding
the effect of these hormones by blocking their interaction
with their physiological binding sites;
directly and indirectly with the hormone in question;
altering the natural pattern of syntheisis of hormones; or
hormone receptor levels.
exogenous (external source) and endogenous (internal source) androgens
(male hormones) and estrogens (female hormones) can alter the
development of brain function.
perturbation of the endocrine system of a developing organism
may alter the development of the that organism: typically these
effects are irreversible. For example, many sex-related characteristics
are determined hormonally during a window of time in the early
stages of development and can be influenced by small changes in
hormone balance. Evidence suggests that sex-related characteristics,
once imprinted, may be irreversible.
effects reported in wildlife should be of concern to humans dependent
upon the same resources, e.g., contaminated fish. Food fish is
a major pathway of exposure for birds. The avian (bird) model
for organochlorine endocrine disruption is the best described
to date. It also provides support for the wildlife/human connection
because of similarities in the development of the avian and mammalian
judgment is that:
nature and extent of the effects of exposure on humans are not
well established. Information is limited concerning the disposition
of these contaminants within humans, especially data on concentrations
of contaminants in embryos. This is compounded by the lack of
measurable endpoints (biologic markers of exposure and effect)
and the lack of multi-generational exposure studies that simulate
there are adequate quantitative data concerning reduction in reproductive
success in wildlife, data are less robust concerning changes in
behavior. The evidence, however, is sufficient to call for immediate
efforts to fill these knowledge gaps.
potencies of many synthetic estrogenic compounds relative to natural
estrogens have not been established. This is important because
contemporary blood concentrations of some of the compounds of
concern exceed those of internally produced estrogens.
improve our predictive capability:
of products for regulatory purposes should be broadened to include
hormonal activity in vivo. There is no substitute for animal studies
for this aspect of testing.
assays for androgenicity and estrogenicity are available for those
compounds that have direct hormonal effects. Regulations should
require screening all new products and by-products for hormonal
activity. If the material tests positive, further testing for
functional teratogenicity (loss of function rather than obvious
gross birth defects) using multigenerational studies should be
required. This should apply to all persistent, bioaccumulative
products released in the past as well.
is urgent to move reproductive effects and functional teratogenicity
to the forefront when evaluating health risks. The cancer paradigm
is insufficient because chemicals can cause severe health effects
other than cancer.
more comprehensive inventory of these compounds is needed as they
move through commerce and are eventually released to the environment.
This information must be made more accessible. Information such
as this affords the opportunity to reduce exposure through containment
and manipulation of food chains. Rather than separately regulating
contaminants in water, air, and land, regulatory agencies should
focus on the ecosystem as a whole.
the production and use of persistent chemicals has not solved
the exposure problem. New approaches are needed to reduce exposure
to synthetic chemicals already in the environment and prevent
the release of new products with similar characteristics.
on wildlife and laboratory animals as a result of exposure to
these contaminants are of such a profound and insidious nature
that a major research initiative on humans must be undertaken.
scientific and public health communities' general lack of awareness
concerning the presence of hormonally active environmental chemicals,
functional teratogenicity, and the concept of transgenerational
exposure must be addressed. Because functional deficits are not
visible at birth and may not be fully manifested until adulthood,
they are often missed by physician, parents, and regulatory community,
and the causal agent in never identified.
basic research in the field of developmental biology of hormonally
responsive organs is needed. For example, the amount of specific
endogenous hormones required to evoke a normal response must be
established. Specific biologic markers of normal development per
species, organ, and stage of development are needed. With this
information, levels that elicit pathological changes can be established.
cooperative research is needed to develop both wildlife and laboratory
models for estrapolating risks to humans.
selection of a sentinel species at each trophic level in an ecosystem
is needed for observing functional deficits, while at the same
time describing the dynamics of a compound moving through the
endpoints (biologic markers) as a result of exposure to exogenous
endocrine disrupters are needed that include a range of effects
at the molecular, cellular, organismal, and population levels.
Molecular and cellular markers are important for the early monitoring
of dysfunction. Normal levels and patterns of isoenzymes and hormones
should be established.
mammals, exposure assessments are needed based on body burdens
of chemical that describ the concentration of a chemical in an
egg (ovum) which can be extrapolated to a dose of chemical to
the embryo, fetus, newborn, and adult. Hazard evaluations are
needed that repeat in the laboratory what is being seen in the
field. Subsequently, a gradient of doses for particular responses
must be determined in the laboratory and then compared with exposure
levels in wildlife populations.
descriptive field research is needed to explain the annual influx
to areas of know pollution of migratory species that appear to
maintain stable populations in spite of the relative vulnerability
of their offspring.
reevaluation of the in utero DES-exposed population is required
for a number of reasons. First, because the unregulated, large
volume releases of synthetic chemicals coincide with the use of
DES, the results of the original DES studies may have been confounded
by widespread exposure to other synthetic endocrine disruptors.
Second, exposure to a hormone during fetal life may elevate responsiveness
to the hormone during later life. As a reuslt, the first wave
of of individuals exposed to DES in utero is just reaching the
age where various cancers (vaginal, endometrial, breast, and prostatic)
may start appearing if the individuals are at a greater risk because
of perinatal exposure to estrogen-like compounds. A threshold
for DES adverse effects is needed. Even the lowest recorded dose
has given rise to vaginal adenocarcinoma. DES exposure of fetal
humans may provide the most-severe-effect model in the investigation
of the less potent effects from environmental estrogens. Thus,
the biological endpoints determined in in utero DES-exposed
offspring will lead the investigation in humans following possible
effects of endocrine disruptors on longer-lived humans may not
be as easily discerned as in shorter-lived laboratory or wildlife
species. Therefore, early detection methods are needed to determine
if human reproductive capability is declining. This is important
from an individual level, as well as at the population level,
because infertility is a subject of great concern and has psychological
and economic impacts. Methods are now available to determine fertility
rates in humans. New methods should involve more use of liver-enzyme-system
activity screening, sperm counts, analyses of developmental abnormalities,
and examination of histopathological lesions. These should be
accompanied by more and better biomarkers of social and behavioral
development, the use of multigenerational histories of individuals
and their progeny, and congener-specific chemical analyses of
reproductive tissues and products, including breast milk.
Bern, H et al. 1992. Statement from
the work session on chemically-induced alterations in sexual development:
the wildlife/human connection. pp 1-8 in Chemically-Induced
Alterations in Sexual and Functional Development: The Wildlife/Human
Connection. eds T Colborn and C Clement, Princeton Scientific
Publishing Co., NJ, U.S. [Return.]
Chemicals known to disrupt the endocrine system include: DDT and
its degradation products, DEHP (di)2-ethylhexyl)phthalate), dicofol,
HCB (hexachlorobenzene), kelthane, kepone, lindane and other hexachlorocyclohexane
congeners, methoxy-chlor, octachlorostyrene, synthetic pyrethroids,triazine
herbicides, EBDC fungicides, cetain PCB congeners, 2,3,7,8-TCDD
and other dioxins, 2,3,7,8-TCDF and other furans, cadmium, lead,
mercury, tributyltin and other organo-tin compounds, alkyl phenols
(non-biodegradable detergents and anti-oxidants present in modified
polystyrene and PVC's), styrene dimers and trimers, soy products,
and laboratory animal and pet food products. [Return.]