Introduction
Convincing evidence exists that a variety of pollutants, some of which
can disrupt endocrine development in wildlife and laboratory animals, is
found in rain water, well water, lakes, and oceans, as well as freshwater,
marine, and terrestrial food products. This paper identifies the need for
a greater awareness about the long-term health consequences associated with
exposure to endocrine-disrupting chemicals during early life. Endocrine-disrupting
effects are not currently considered in assessing risks to humans, domestic
animals, and wildlife. Taking into consideration what is currently known
about chemicals that disrupt the endocrine system, the effects 1) may be
manifested in an entirely different way, and with permanent consequences,
in the early embryo, fetus, and neonate from effects as a result of exposure
only in adulthood; 2) can change the course of development and potential
of offspring, with the outcome depending on the specific developmental period(s)
of exposure; and 3) are often delayed and thus may not be fully or obviously
expressed until the offspring reaches maturity or even middle age, even
though critical exposure occurred during early embryonic, fetal, or neonatal
life.
In mammals as well as all other vertebrates, communication among cells
is required for development to progress normally. Substances produced by
one group of cells can direct the course of development and thus determine
the future functioning of another group of cells (1). For example,
a group of compounds, the steroid hormones produced by the mother's ovaries
and adrenal glands, the placenta, and the fetal gonads and adrenal glands,
has been identified as playing a major role in regulating developmental
processes in many tissues (2). Organogenesis, a particularly vulnerable
stage of development, begins in humans at the end of the second month of
gestation. At this time the course of development of many tissues is regulated
by endogenous steroid hormones along with other endocrine and paracrine
factors (3).
It is now recognized that numerous endocrine-disrupting chemicals have
been released into the environment in large quantities since World War II
(Table 1). Some of these chemicals bind to intracellular receptor proteins
for steroid hormones (4) and evoke hormonal effects in animals (5),
humans (6), and cell culture (7,8). They thus interfere
with the functioning of receptors whose normal role is to mediate the effects
of the endogenous steroid hormones (9). Laboratory experiments have
demonstrated that exposure of fetuses to endocrine-disrupting chemicals
can profoundly disturb organ differentiation (10,11) because
they can act as hormone agonists or antagonists. Organs that appear to be
at particular risk for developmental abnormalities in offspring because
of maternal exposure are those with receptors for gonadal hormones: in female
fetuses this includes the mammary glands, fallopian tubes, uterus, cervix,
and vagina, and in male fetuses it includes the prostate, seminal vesicles,
epididymides, and testes. In both sexes the external genitalia, brain, skeleton,
thyroid, liver, kidney, and immune system are also targets for steroid hormone
action and are thus potential targets for endocrine-disrupting chemicals,
although these chemicals may have multiple modes of action, in addition
to acting as hormone agonists and antagonists, in different target tissues
(11-15).
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A major concern is the profound and permanent effects that exposure to
endocrine disruptors during critical periods in development can have on
the future well-being of wildlife and humans, although chronic exposure
after maturity can also present a health risk. It is generally assumed that
after maturity, exposure to endocrine disruptors does not permanently alter
the functioning of hormone-responsive tissues. However, experimental studies
in animals have shown permanent changes in brain (16) and vaginal
epithelium (17) in females and prostate in males (18) after
administration of estrogenic chemicals in adulthood. The possibility thus
exists that chronic, low-level exposure to estrogenic chemicals in the environment
after maturity can have effects in humans similar to those observed in laboratory
animals administered estrogen (19).
Wildlife
Exposure to endocrine-disrupting chemicals in the environment has been
associated with abnormal thyroid function in birds (20) and fish
(21); decreased fertility in birds (22), fish (23),
shellfish (24), and mammals (25); decreased hatching success
in fish (26), birds (27), and turtles (28); demasculinization
and feminization of male fish (29), birds (30), and mammals
(31); defeminization and masculinization of female fish (32),
gastropods (33), and birds (30); and alteration of immune
function in birds (34) and mammals (35). These deleterious
health effects have been observed in many areas where the presence of multiple
man-made chemicals, such as byproducts of industrial chemical synthesis
(chemical waste) and pesticides (36), has been established. The effects
were not reported before the 1950s and are currently observed in many areas,
such as the Great Lakes in North America. Although much of the data presented
here is from studies conducted in and around the Great Lakes, it is important
to note that the level of contamination in the Great Lakes region is no
greater than some of the other major drainage basins in the United States
(37).
Researchers from Guelph University report a 100% prevalence of thyroid
enlargement in 2-4-year-old salmon in the Great Lakes. Moreover, in some
Great Lakes salmon stocks, there is an extremely high prevalence of precocious
sexual maturation in males (40-80% depending on the year), poor egg survival
(<15%), and low egg thyroid hormone content (23). Multiple abnormalities,
including behavioral changes, reproductive loss, and early mortality in
offspring have been documented in bird species that feed on Great Lakes
fish (38). Reproductive loss and early mortality have also been observed
in offspring of confined mink that were fed Great Lakes fish (39).
The devastating effect of DDT on embryonic survival in bald eagles due
to eggshell thinning and cracking has been known for some time (40).
DDT was introduced on a large scale into the environment in the early 1940s.
Restrictions on the use of DDT since 1972 have been only partially successful
in reducing levels in the Great Lakes (36). Monitoring nesting sites
along the Great Lakes shoreline indicates that while eggshell thinning has
abated, embryonic and chick survival is not adequate to maintain stable
populations. Recruitment is from inland populations that responded to the
restrictions on DDT and other chemicals and that do not depend on contaminated
fish in the Great Lakes as a primary food source. However, adult bald eagles
that migrate to the shoreline have difficulty producing viable offspring
after consuming fish and other food from the Great Lakes for 2 or more years
(36). The shoreline has thus become a "black hole" for
bald eagles that migrate from successful inland populations. Abandoned eggs
hold as much as 10 times the critical concentration of DDT below which stable
populations of bald eagles can be maintained (41). In addition to
DDT, bald eagles carry elevated concentrations of other compounds that are
known endocrine disruptors, such as chlordane, dieldrin, and polychlorinated
biphenyls (PCBs) (41). Similar findings have been reported for bald
eagles nesting along the Columbia River in Washington State (42).
There are several explanations for the continued elevated concentrations
of endocrine-disrupting chemicals in wildlife tissues and the associated
instability in wildlife populations, despite the fact that some of the chemicals
have been regulated. First, many pesticides, such as DDT, are still manufactured
abroad and used extensively in developing countries where there are limited
safeguards or monitoring of use. There is now evidence that DDT, PCBs, and
other chemicals that readily vaporize are being transported long distances
over the globe via the atmosphere (43,44). For example, it
is estimated that 90% of the PCBs entering Lake Superior, the largest of
the Great Lakes, is derived from the atmosphere (36). Second, some
chemicals are very persistent: DDT has a half-life of 57.5 years in temperate
soils (45). PCBs were introduced in 1929, and production ceased in
the United States in 1972. Many PCB residues which are endocrine disrupting
and/or developmental toxicants have not been properly stored and are already
dispersed in the environment. PCBs will be around over geologic time (46).
Effects of pollutants on the reproductive system, in addition to the
well-documented reduction in eggshell thickness, became apparent in the
late 1970s when histopathological examination of herring-gull embryos and
newly hatched chicks collected in Lake Ontario revealed oviducts and gonads
resembling ovaries in male birds and abnormal development of the oviductal
system in female birds (38). Follow-up laboratory studies using DDT
and other pesticides which remain in wide use today (dicofol, kelthane,
and methoxychlor) produced the same results in kestrels, western gulls,
and California gulls (30,47). Today, adult female herring
gulls have been observed tending double clutches in their nests in unstable
populations (38). Elevated concentrations of DDT, its metabolite,
DDE, PCBs, and other organochlorine residues have been found in eggs from
these populations (48). It has not been determined whether half of
the birds that are pairing are genotypic males that had been feminized during
embryonic development by environmental chemicals with estrogenic activity
or whether they were all genotypic females showing abnormal behavior. Recent
laboratory experiments with small mammals corroborate many of the anomalies
cited above, although the effects vary among species and among chemicals
(5).
The DES Syndrome: A Model for Exposure to Estrogenic Chemicals in
the Environment
Diethylstilbestrol (DES) is a synthetic estrogen that was used by physicians
to prevent spontaneous abortions in women from 1948 until 1971, when its
use for this purpose was banned. DES-exposed humans thus serve as a model
for exposure during early life to any estrogenic chemical, including pollutants
in the environment that are estrogen agonists. The primary model for determining
estrogenic activity of a chemical is the stimulation of mitotic activity
in the tissues of the female genital tract in early ontogeny, during puberty,
and in the adult (49), although estrogen also affects other tissues
in females and males (2,19). Daughters whose mothers took
DES (about 1 million or more between 1960 and 1970) suffer reproductive
organ dysfunction, abnormal pregnancies, a reduction in fertility, immune
system disorders, and periods of depression (50,51). As young
adults these women also suffer increased rates of vaginal clear-cell adenocarcinomas
(52); this is a reproductive tract cancer found in women beginning
in their fifties, but it is rare in women in their twenties (50,51).
A major concern is that when women exposed in utero to estrogenic
chemicals (DES and/or environmental pollutants that are estrogen agonists)
reach the age at which the incidence of reproductive organ cancers normally
increases, they will show a much higher incidence of cancer than unexposed
individuals.
There is a substantial literature documenting the detrimental effects
of exposure to DES during the critical period of organ differentiation in
experimental studies using rodents. Animal models corroborate clinical studies
in humans. For example, dysplastic changes in the rodent prostate (53)
are comparable to those seen in stillborn male offspring of women treated
with DES (54). In female mice, DES exposure during early life leads
to permanent cornification of the vaginal epithelium, which may be independent
of effects on the brain-pituitary-ovarian axis (50,55,56).
Significant impairment of immune function (particularly the T-cell system)
has also been reported after exposure to DES during early life (57)
as well as an increase in autoimmune diseases in women (58). These
outcomes were typically not noticeable at birth and often not detected before
maturity. For example, treatment of male rats with DES during the first
month after birth [accessory reproductive organs are still developing (2)]
did not result in observable malignancies at 6-9 months of age, but by 20
months (old age), squamous cell cancer was detected with involvement of
the dorsolateral prostate (59). In female mice treated during early
life with DES, an increase in sensitivity of mammary glands to carcinogens
has been reported (60).
A variety of agricultural and industrial chemicals produced today (either
within or outside the United States) are capable of binding to intracellular
estrogen receptors either directly, such as o,p´-DDT
(61), or after in situ conversion to an active metabolite.
For example, the pesticide methoxychlor (62) is demethylated in
situ to a more estrogenic bisphenolic compound (63). Pesticides
such as o,p´-DDT, chlordecone (6), and components
of plastics, such as nonylphenol (7), mimic the action of endogenous
estrogens (and exogenous DES) both in laboratory animal models as well as
in estrogen-sensitive cells in culture (8). A number of conditions
in wildlife (reviewed earlier) parallel those reported in laboratory animals
and humans exposed to DES during development.
It is worth noting that the estrogenicity of chlordecone was first detected
in people working at a pesticide-producing plant (64), and although
many effects of estrogenic chemicals may be primarily due to exposure during
in utero development, chronic exposure throughout adulthood is also
a concern. For example, in studies with male dogs, which show prostatic
hyperplasia during aging, the disease only developed in castrated males
treated with both androgen and estrogen, not androgen alone (18).
Exposure of adult men to estrogen has been implicated in the etiology of
prostate hyperplasia (19,65). Both prostate cancer and benign
prostatic hyperplasia in men and cancers of estrogen-responsive tissues
in women (vaginal, cervical, endometrial, and breast) represent major medical
problems faced by older people.
It is now suspected that increases in the incidence of numerous pathologies
in men and women may be related to exposure to pesticides and other endocrine-disrupting
chemicals that can mimic DES and are thus estrogen agonists. The clinical
and experimental findings with DES show that consideration must be given
to the following facts: 1) an increase in breast and prostatic cancer in
the United States occurred between 1969 and 1986 (66), 2) a 400%
increase in ectopic pregnancies occurred in the United States between 1970
and 1987 (67), 3) a doubling of the incidence of cryptorchidism occurred
in the United Kingdom between 1970 and 1987 (68,69), and 4)
an approximate 50% decrease in sperm count worldwide over the last 50 years
(70).These trends may be a reflection of the increase from estrogenic
pollutants in the environment. It has been suggested that the decrease in
sperm count in men is the result of exposure during the fetal period of
testicular differentiation to pollutants that have estrogenic activity (71).
For example, an association between reduced sperm motility and PCBs in men
with fertility problems has been reported (72); some PCBs are directly
estrogenic while others become estrogenic after in vivo conversion,
although the binding affinity of estrogen receptors for estrogenic PCBs
is lower than that for estradiol-17ß (4).
Characterization of Endocrine-Disrupting Chemicals
Literally thousands of synthetic compounds, a number of which are endocrine
disruptors, have been released in the environment, generating concern about
their additive and synergistic effects. Also, many of the endocrine disruptors
are persistent, lipophilic, and have low vapor pressures, which facilitates
their widespread dispersal.
It is common to find PCBs, dioxins, DDT, and a number of other organochlorine
pesticides together in human breast milk and adipose tissue (73,74).
Of concern for humans, domestic animals, and wildlife are the likely additive
effects due to exposure to these and other endocrine-disrupting chemicals
either together or at different times in life. For example, possible exposure
to multiple estrogenic chemicals may be related to the fact that not all
offspring of DES-exposed mothers show abnormalities. Although genetic factors
may partially account for this outcome, it is also possible that the most
affected individuals are those whose mothers were exposed to endocrine-disrupting
environmental pollutants with estrogenic activity before or during treatment
with DES. Many of the effects of endocrine disruptors that have been reported
in wildlife are associated with the presence of a toxic contaminant in the
mother due to exposure before egg production in birds and fish or pregnancy
and lactation in mammals.
Evidence already exists that a number of organochlorine chemicals (such
as dioxin, PCBs, and DDT) has reached concentrations in aquatic food sources
that can lead to substantial functional deficits in animals that consume
this food. Male rats fed Lake Ontario fish showed hyperreactivity to stress,
and offspring of females fed Lake Ontario fish during pregnancy also expressed
the same hyperreactive condition, although the offspring were never fed
fish (75). In addition, offspring of women who ate two to three Lake
Michigan fish a month for at least 6 years preceding their pregnancies were
slightly preterm, had lower birth weight, smaller skull circumference, and
cognitive, motor (hypotonicity and hyporeflexivity), and behavioral deficits
at birth compared with offspring whose mothers did not eat fish (76).
The effects were associated with the mothers' lifetime experience of eating
fish, not just what they ate during pregnancy. These findings emphasize
the importance of exposure of females to contaminants before pregnancy in
terms of effects on their offspring.
Subsequent studies of the above cohort beginning at 6-7 months revealed
delays in psychomotor development and poorer visual recognition compared
with controls (77). When examined at 4 years of age, the children
of women who had eaten fish in this study exhibited short-term memory problems,
and 17 of the children became intractable and refused to cooperate during
testing; they were the children of the mothers with the highest PCB concentrations
(measured in their breast milk) in the study (78). The childrens'
intractable behavior appears to be analogous to the behavior of the rats
fed Lake Ontario fish. In another study using the infants of mothers who
ate Lake Michigan fish and infants of mothers exposed to a PCB "farm
incident," both cohorts experienced growth retardation and neurological
effects which were related in a dose-dependent manner to umbilical cord
serum PCB concentrations (reflecting the levels in fetal blood) (79).
It remains to be determined whether the neurotoxic effects mentioned above
are mediated through the endocrine system. It is recognized that endocrine-disrupting
chemicals may act via multiple mechanisms, some of which may only operate
during specific developmental periods (11,80,81).
Based on current breast milk concentrations nationwide, it is estimated
that at least 5% and possibly more of the babies born in the United States
are exposed to quantities of PCBs sufficient to cause neurological effects
(82). These findings provide evidence that contemporary PCB exposure
is above "any regulatory guideline" (82: 247). The possible
immunological and endocrinological consequences remain to be determined
in these cohorts. A major concern is that some of these consequences may
not become apparent until young adulthood or even middle age.
Accumulation of pollutants increases the probability of repeated or constant
exposure but, as the literature on dioxin shows, administration at only
one time in development, rather than the more likely chronic exposure, can
profoundly affect the embryo, fetus, or perinatal infant. Ample evidence
exists from both in vivo and in vitro studies that dioxin
can antagonize the action of estrogen in some estrogen target cells (83,84),
although this effect does not appear to be due to dioxin binding to estrogen
receptors (11). The fact that dioxin is antiestrogenic is important
because the conversion of androgen to estrogen in some target cells plays
a critical role in masculinization (2). For example, a series of
studies describing the dose-related inhibition (dose range: 0.064-1.0 µg/kg/
body weight to the dam) of masculinization and persistence of feminine traits
in male rat offspring whose dams were fed one meal of dioxin during pregnancy
at a critical period during sexual differentiation illustrates the vulnerability
of the male rat fetus in utero to administration of only one low
dose of dioxin to the dam. In these studies the effects were not fully manifested
until the rats reached adulthood (85-87). These effects would
be expected from either chronic, low-dose exposure to dioxin before pregnancy
or to a single exposure during a critical time in pregnancy.
Dioxin accumulates in human tissue and is generally found in all tissues
of people living in developed countries (88). However, only the toxic
congeners of the dioxin family complex bioaccumulate in human breast milk
(88). Similarly, these chemicals have also been found in follicular
fluid obtained during in vitro fertilization procedures in women
(89). Although direct correlations have not yet been reported between
reproductive success and the presence of xenobiotics in the follicle, these
substances could disrupt oocyte development (19,90,91).
Many endocrine-disrupting chemicals have been reported in the reproductive
tissues of men and women (74). These lipid-soluble compounds appear
to sequester in all fatty tissue in the body, so that organs and tissues
with higher fat content hold more of the compounds on a wet weight basis
(73). Little is known about the concentrations in embryos and fetuses
other than they appear to be similar to those in mothers (73,92).
Of considerable concern is bioaccumulation of organochlorine chemicals in
breast milk due to its high lipid content, which leads to a much higher
concentration in breast milk than in maternal blood (73). It is well
documented that the infant is exposed to higher concentrations of many of
these chemicals during breastfeeding than at any other time in its life
(74).
Consideration should also be given to the fact that man-made chemicals,
such as DES, which bind to estrogen receptors in cells, do not bind to estrogen-binding
plasma proteins (93). One function of estrogen-binding plasma proteins,
such as sex-steroid binding globulin in humans, is to restrict entry of
endogenous estrogen into cells (94). As a result of this affinity,
only a small fraction of the total endogenous estrogen in blood is able
to pass into cells. This is particularly important during pregnancy when
the concentration of estrogen-binding plasma proteins increases dramatically
(2,95). It is possible that estrogenlike chemicals may show
low or no binding affinity to estrogen-binding plasma proteins. These chemicals
may be able to freely enter cells (similar to DES), which would greatly
increase their biological activity relative to similar blood concentrations
of endogenous estrogen, most of which is inhibited from entering cells.
This would contribute to the in vivo effectiveness of these pollutants,
many of which show lower binding affinity to estrogen receptors than the
most potent endogenous estrogen, estradiol-17ß (4). Environmental
pollutants with estrogenic activity are less potent agonists for the induction
of proliferation of breast cancer cells in vitro (8).
Summary
The deleterious effects of endocrine-disrupting chemicals in the environment
on the reproductive success of wildlife populations have been documented;
this is not an isolated problem, and today many wildlife populations are
at risk. At present, no coherent policy has been articulated to remedy this
problem. This is due in part to the lack of knowledge concerning which of
the many chemicals present in the environment are responsible for endocrine-disrupting
effects. Regulatory agencies should recognize that the current endpoints
of most tests to assess the risk of pesticides and other pollutants (carcinogenicity,
acute toxicity, and immediate mutagenicity) have led to the misconception
that these chemicals do not pose a threat to the health of wildlife, domestic
animals, or humans. Although the effects of mutagens can be seen immediately
in terms of gross abnormalities, the consequences of fetal exposure to endocrine-disrupting
chemicals would likely not be recognized until young adulthood, at which
time abnormalities, particularly relating to the function of the reproductive
system, become apparent.
Because endocrine-disrupting chemicals are in most cases neither mutagens
nor acute toxicants at ambient concentrations, they may be released without
proper caution into the environment. This may be partially remedied by screening
for hormone agonistic and antagonistic activity using hormone-responsive
cells in culture; this procedure identifies compounds that are endocrine
disruptors because they are hormonally active (8). Although this
procedure cannot rule out chemicals devoid of hormonal activity that may
disrupt development through other mechanisms, it can at least rule out compounds
like DDT, chlordecone, alkylphenols, and some PCBs, which are estrogen agonists.
It is also essential to continue to examine transgenerational effects in
animal studies because some pollutants require metabolism in vivo
to exert hormonal effects and because neurobehavioral and other developmental
effects cannot be addressed with in vitro models (96,97).
Wildlife species have provided the model for maternal transfer of environmental
endocrine-disrupting chemicals with their resulting suite of effects in
offspring; experiments with laboratory animals have confirmed the findings.
In humans, the DES model is clear and traceable. However, for clinicians
and public health authorities, the implications of these findings regarding
man-made endocrine disruptors present in air, water, and food for human
health is just coming to light. Transgenerational exposure, hormonal activity,
functionality, and delayed expression of effects must be addressed when
determining the hazards of exposure to persistent chemicals already in the
environment and of new chemicals that might be released in the future.
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