multidisciplinary group of international
experts gathered for a work session on "Environmental Endocrine-Disrupting
Chemicals: Neural, Endocrine and Behavioral Effects" under the auspices
of the International School of Ethology at the Ettore Majorana Centre
for Scientific Culture in Erice, Sicily, November 5-10, 1995.
need for this work session grew out of evidence accumulated since
the first consensus statement on endocrine disrupting chemicals
was released in October, 1991. This first statement was framed as
a product of a work session on "Chemically-Induced Alterations in
Sexual and Functional Development: The Wildlife/Human Connection".
Research since 1991 has reinforced concerns over the scope of the
problems posed to human health and ecological systems by endocrine-disrupting
evidence is especially worrisome because it underscores the exquisite
sensitivity of the developing nervous system to chemical perturbations
that result in functional abnormalities. Moreover, the consequences
of these perturbations depend upon the stage of development during
which exposure occurs and are expressed in different ways at different
times in life, from birth through to advanced age. This work session
was convened because of the growing concern that failure to confront
the problem could have major economic and societal implications.
in attendance agreed that as scientists we seek only the truth;
we value diversity; we believe global problems require global solutions;
and our goal should be "science without borders and laboratories
without walls" (adapted from: Paul Dirac, Piotr Kapitza, and Antonio
Zichichi, Erice Statement, 1982).
meeting was convened specifically to:
come to agreement in principle concerning the magnitude and geographic
scope of the impact of endocrine disruptors on brain development
review available technologies for ascertaining biologic markers
of exposure to and effects on the nervous system by endocrine
provide strategies for increasing communications and collaboration
among disciplines to optimize resources for future research; and
suggest methods for translating the findings of this work session
into information that is useful for decision makers and the public.
following consensus was reached by participants at the workshop.
We are certain of the following:
We estimate with confidence that:
Endocrine-disrupting chemicals can undermine neurological and
behavioral development and subsequent potential of individuals
exposed in the womb or, in fish, amphibians, reptiles, and birds,
the egg. This loss of potential in humans and wildlife is expressed
as behavioral and physical abnormalities. It may be expressed
as reduced intellectual capacity and social adaptability, as impaired
responsiveness to environmental demands, or in a variety of other
functional guises. Widespread loss of this in nature can change
the character of human societies or destabilize wildlife populations.
Because profound economic and social consequences emerge from
small shifts in functional potential at the population level,
it is imperative to monitor levels of contaminants in humans,
animals, and the environment that are associated with disruption
of the nervous and endocrine systems and reduce their production
Because the endocrine system is sensitive to perturbation, it
is a likely target for disturbance. In contrast to natural hormones
found in animals and plants, some of the components and by-products
of many manufactured organic compounds that interfere with the
endocrine system are persistent and undergo biomagnification in
the food web, which makes them of greater concern as endocrine
endocrine-disrupting chemicals range across all continents and
oceans. They are found in native populations from the Arctic
to the tropics, and, because of their persistence in the body,
can be passed from generation to generation. The seriousness of
the problems is exacerbated by the extremely low levels of hormones
produced naturally by the endocrine system which are needed to
modulate and induce appropriate responses. In contrast, many
endocrine disrupting contaminants, even if less potent than the
natural products, are presented in living tissue at concentrations
millions of times higher that the natural hormones. Wildlife,
laboratory animals, and humans exhibit adverse health effects
at contemporary environmental concentrations of man-made chemicals
that act as endocrine disruptors. New technology has revealed
that some man-made chemicals are present in tissue at concentrations
previously not possible to measure with conventional analytical
methods, but at concentrations which are biologically active.
Gestational exposure to persistent man-made chemicals reflects
the lifetime of exposure of females before they become pregnant.
Hence, the transfer of contaminants to the developing embryo
and fetus during pregnancy and to the newborn during lactation
is not simply a function of recent maternal exposure. For some
egg laying species, the body-burden of the females just prior
to ovulation is the most critical period. For mammals, exposure
to endocrine disruptors occurs during all of prenatal and early
postnatal development because they are stored in the mother.
The developing brain exhibits specific and often narrow windows
during which exposure to endocrine disruptors can produce permanent
changes in its structure and function. The timing of exposure
is crucial during early developmental stages, particularly during
fetal development when a fixed sequence of structural change is
occurring and before protective mechanisms have developed. A
variety of chemical challenges in humans and animals early in
life can lead to profound and irreversible abnornmalities in brain
development at exposure levels that do not produce permanent
effects in adults.
Thyroid hormones are essential for normal brain functions throughout
life. Interference with thyroid hormone function during development
leads to abnormalities in brain and behavioral development. The
eventual results of moderate to severe alterations of thyroid
hormone concentrations, particularly during fetal life, are motor
dysfunction of varying severity including cerebral palsy, mental
retardation, learning disability, attention deficit hyperactivity
disorder, hydrocephalus, seizures and other permanent neurological
abnormalities. Similarly, exposure to man-made chemicals during
early development can impair motor function, spatial perception,
learning, memory, auditory development, fine motor coordination,
balance, and attentional processes; in severe cases, mental retardation
Sexual development of the brain is under the influence of estrogenic
(female) and androgenic (male) hormones. Not all endocrine disruptors
are estrogenic or anti-estrogenic. For example, new date reveal
that DDE, a breakdown product of DDT, found in almost all living
tissue, is an anti-androgen in mammals. Man-made chemicals that
interfere with sex hormones have the potential to disturb normal
brain sexual development. Wildlife studies of gulls, terns, fishes,
whales porpoises, alligators and turtles link environmental contaminants
with disturbances in sex hormone production and/or action. These
effects have been associated with exposure to sewage and industrial
effluents, pesticides, ambient ocean and freshwater contamination,
and the aquatic food web.
Commonalties across species in the hormonal mechanisms controlling
brain development and function mean that adverse effects observed
in wildlife and in laboratory animals may also occur in humans,
although specific effects may differ from species to species.
Most important, the same man-made chemicals that have shown these
effects in mechanistic studies in laboratory animals also have
a high exposure potential for humans.
The full range of substances interfering with natural endocrine
modulation of neural and behavioral development cannot be entirely
defined at present. However, compounds shown to have endocrine
effects include dioxins, PCBs, phenolics, phthalates, and many
pesticides. Any compounds mimicking or antagonizing actions
of, or altering levels of, neurotransmitters, hormones, and growth
factors in the developing brain are potentially in this group.
There are many uncertainties in our understanding because:
pregnant woman in the world has endocrine disruptors in her body
that are transferred to the fetus. She also has measurable
concentrations of endocrine disruptors in her milk that are transferred
to the infant.
There may not be definable thresholds for responses to endocrine
disruptors. In addition, for naturally occurring hormones, too
much can be as severe a problem as too little. Consequently, simple
(monotonic) dose-response curves for toxicity do not necessarily
apply to the effects of endocrine disruptors.
Because certain PCBs and dioxins are known to impair normal
thyroid function, we suspect that they contribute to learning
disabilities, including attention deficit hyperactivity disorder
and perhaps other neurological abnormalities. In addition,
many pesticides affect thyroid function and, therefore, may have
Some endocrine disruptors or their breakdown products are nearly
equipotent to natural hormones. Even weak endocrine disruptors
may exert potent effects because they can bypass the natural protection
of blood binding proteins for endogenous hormones. Some disruptors
also have a substantially longer biological half-life than naturally
produced hormones because they are not readily metabolized, and
as a result are stored in the body and accumulate to concentrations
of concern. Some man-made chemicals that appear non-toxic are
converted by the liver to more toxic compounds. Also, compounds
that are not toxic in the mother may be toxic to her developing
embryo, fetus or newborn. The exquisite vulnerability of the fetal
brain to methylmercury and lead are prime examples of this principle.
Functional deficits are not as easily measured as physical anomalies
or clinical disease, in part because they are typically expressed
as continuous measures, such as IQ, rather than the number of
cases in a population. Consequently, conventional population surveys
may overlook the extent of such deficits. Moreover, because such
surveys tend to express their findings as shifts in mean values
even when they are based on appropriate measures, they tend to
obscure influences on the more susceptible members of the population.
Large amounts of man-made chemicals capable of disrupting the
endocrine and nervous systems are sold to, or produced and used
in, third world countries that lack the resources or technology
to properly monitor and control exposure levels. Insufficient
and improper training in handling chemicals and ignorance of concerning
health effects and monitoring strategies leads to the likelihood
of very high levels of exposure.
Our judgment is that:
No one is exposure-free, thus confounding studies to determine
what is normal. Everyone is exposed at any single time and throughout
life to large numbers of manmade chemicals. Relatively few of
the manmade chemicals found in human tissue have been identified.
Lack of funding has seriously constrained testing these chemicals
for their potential to disrupt natural systems.
Sensitive parameters, including neurological abnormalities, behavioral
and neuropsychiatric disorders, and neuroanatomical, neurochemical,
and neurophysiologic endpoints need to be investigated. Most important,
criteria at the population level need to include the social and
economic costs of impairment because the true costs to society
of such problems can be significant, e.g., the costs of a 5 point
IQ loss across a population. Investigation of potential toxicity
typically includes laboratory, population and field studies, clinical
reports, and accident reports. However, developmental neurotoxicants
produce a spectrum of effects that are not typically evaluated.
such as the progression and latency of behavioral and neurological
changes. In addition, alternation of other systems can produce
subsequent cognitive, behavioral, and neurological dysfunction;
i.e. diseases of other organ systems that influence the brain;
non-CNS drugs; other foreign substances such as air pollutants;
and immune system involvements that alter behavior.
Trade secret laws afford industry confidentiality, depriving the
consumer and public health authorities of the right to know the
components of commercial products so they can be tested.
The benefits of reduced health care costs could be substantial
if exposure to endocrine-disrupting chemicals were reduced.
A trivial amount of governmental resources is devoted to monitoring
environmental chemicals and health effects. The public is unaware
of this and believes that they are adequately protected. The message
that endocrine disruptors are present in the environment and have
the potential to affect many people over a lifespan has not effectively
reached the general public, the scientific community, regulators,
or policy makers. Although this message is difficult to reduce
to simple statements without over- or understating the problem,
the potential risks to human health are so widespread and far-reaching
that any policy based on continued ignorance of the facts would
The outcome of exposure is inadequately addressed when based just
on population averages. Instead, risk should be based on the range
of responses within a population -- that is, the total distribution.
The magnitude of the problem can be better determined by knowing
the distribution of responses to endocrine disruptors by individuals
within subsets of the population most at risk, such as pregnant
women, developing embryos, fetuses, and newborns, teens, the aged,
the ill or those with pre-existing endocrine disorders. The magnitude
of the risks also depends upon the endpoint under consideration.
For example, a variety of motor, sensory, behavioral, and cognitive
functions, endpoints which are more sensitive than cancer, must
be considered when assessing neurological function. This holds
for wildlife and domestic animals, as well as human populations.
Wildlife have been effective models for understanding endocrine
disruption at the molecular, cellular, individual, population,
and ecosystem levels. Future research to examine diverse wildlife
species at all levels of biological organization must be broadened
and adequately supported.
Those responsible for producing man-made chemicals must assure
product safety beyond a reasonable doubt. Manufacturers should
be required to release the names of all chemicals used in their
products with the appropriate evidence that the products pose
no developmental health hazard.
Current panels of scientists who determine the distribution of
public research funds often have a narrow scope of expertise and
are thus ill-equipped to review the kind of interdisciplinary
research that is necessary in this field. Funding institutions
should be encouraged to increase the scope of representation on
review panels and to develop more appropriate mechanisms for interdisciplinary
reviews. Governmental agencies should also increase funding for
multidisciplinary extramural projects for surveillance of wildlife
and human populations where neurological damage is suspected and
follow any leads with laboratory research. In addition, populations
of animals consuming the contaminated foods also eaten by humans
should be studied for developmental health effects. It is important
to observe a variety of vertebrate species through multigenerational
Strategies for increasing interdisciplinary communication and
collaborations to optimize resources and future research are needed.
Studies should be designed more economically to include the sharing
of material among many collaborators. Interdisciplinary teams
should explore neurological and other types of damage at all levels
of biological organization from molecular through biochemical,
physiological, and behavioral.
A concerted effort should be undertaken to deliver this consensus
statement to the public, key decision makers, and the media. In
addition, specially designed messages should be developed for
family physicians and others responsible for public health who
are often unaware of the possible role of occupational and environmental
chemical pollutants as agents underlying or constituting risk
factors for "primary" human diseases. Physicians must be trained
in medical school about often latent effects of pollutants on
human development and health. This training is currently inadequate.
A coordinated speakers bureau and on-line systems such as a site
on the World Wide Web for endocrine-disruptors should be established.