Environmental Health Perspectives Volume
103, Supplement 6, September 1995
[Citation
in PubMed]
Pesticides--How Research Has Succeeded and Failed to Translate Science
into Policy: Endocrinological Effects on Wildlife
Theo Colborn
World Wildlife Fund, Washington, DC
Abstract
Toxicological research became institutionalized in the United States
in response to society's concern about cancer and acute mortality. Driven
by risk assessment, research focused on the need for data development and
the standardization of testing for regulatory and management purposes in
a reactive mode. Although the research community has provided evidence for
over 40 years that a number of pesticides and industrial chemicals have
disruptive effects on the endocrine system, little attention was given to
the evidence when determining the health hazards of synthetic chemicals
because of the fixation on cancer. However, recent findings concerning the
effects of a number of widespread chemicals on the reproductive success
and fertility of wildlife and humans has led to the call for a proactive
approach using investigative research (forensic science). Suggestions are
presented to modernize the research agenda of public health institutions
to meet society's needs to address the problems of exposure to endocrine,
nervous, and immune system disruptors. -- Environ Health Perspect 103(Suppl
5):00-00 (1995)
Key words: pesticides, endocrine disruptors, wildlife, hormones,
differentiation, functionality, multigenerational, multidisciplinary, risk,
policy
This paper was presented at the Symposium on Preventing
Child Exposures to Environmental Hazards: Research and Policy Issues held
18-19 March 1994 in Washington DC.
I am indebted to Rich Liroff and Michael Gilbertson for
the time and consideration they gave to this paper.
This work was done with support from the C.S. Mott Foundation,
The Joyce Foundation, and the W. Alton Jones Foundation.
Address correspondence to Dr. Theo Colborn, Senior Scientist,
Wildlife and Contaminants Program, World Wildlife Fund, 1250 24th Street,
NW, Washington, DC 20037. Telephone (202) 778-9643. Fax (202) 861-8377.
Introduction
For over 40 years the research community provided evidence that a number
of pesticides and industrial chemicals have disruptive effects on the endocrine
system, especially during embryonic development. If the latter is true,
why then has research not been able to translate this message into policy
to prevent chemicals of this nature from entering commerce? This article
will provide an argument that the blame cannot be placed solely on the research
community; some must be placed on the current research agenda of the institutions
dedicated to protect and restore human and wildlife health.
As toxicological research became institutionalized in response to society's
concern about cancer and acute mortality following exposure to pesticides
and industrial chemicals, it became driven by risk assessment. As a result,
research focused on the need for testing (data development) and the standardization
of testing (1). Protocols were established to determine the probability
of a chemical causing cancer, acute mortality, visible birth defects, skin
and eye irritation, and obvious neurotoxicological effects. Even though
wildlife populations were recognized as harbingers of pesticide damage in
humans as early as the 1960s (2), the science was ignored by those
charged with protecting human health. The devastating effects of cancer
so overwhelmed society that the insidious legacy of toxic chemicals being
transferred to our children was overlooked at that time. Despite this, the
fascination with cancer was successful in removing a number of the most
egregious pesticides and industrial chemicals from the market and in preventing
others from becoming introduced in commerce. And by restricting the production
and use of these suspected carcinogens, seriously affected wildlife populations
experienced some relief and rebounded (3).
It was not until the late 1980s, following an intense review and synthesis
of the wildlife literature, that the importance of wildlife health end points
as models for human health was again proposed (4). There was growing
concern arising from the evidence that freshwater, marine, and terrestrial
wildlife populations from widespread geographic regions were still experiencing
reproductive problems. Outright mortality (acute toxicity) was not the case.
Instead, adult animals appeared to be healthy, but their offspring were
plagued with a suite of effects that suggested abnormal development of vital
physiological systems. This led to early death among embryos and offspring
or loss of fertility if they survived to adulthood. Such demographic shifts
are the underlying reason for population instability.
Concern for what these findings might mean for humans prompted the gathering
of 21 scientists from 17 disciplines at the Wingspread Conference Center,
Racine, Wisconsin, in July 1991. The participants shared their knowledge
relevant to "Chemically-Induced Alterations in Sexual Development:
The Wildlife/Human Connection." After presentation of papers, the group
issued a Consensus Statement (5) in which they were :
"...certain that a large number of man-made chemicals had been
released into the environment that were capable of disrupting the endocrine
systems of wildlife and humans," and that
"...if the environmental load of man-made endocrine disruptors
was not abated, widespread dysfunction at the population level would take
place."
Among their conclusions they also stated that :
"It 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."
They called for changes in testing to include:
"...hormonal activity in vivo," and..."integrated
cooperative research...to develop both wildlife and laboratory models for
extrapolating risks to humans."
In essence the group called for institutionalization of the essential
forensic research (environmental detective work) that integrates multidisciplinary
research in both the field and the laboratory to meet the challenge of a
global environment dusted with man-made chemicals.
Under our present reactive, regulatory system, proof of causality is
essential prior to action. Consequently, it is imperative to determine damage
from pesticides in wildlife and/or humans in the environment, and to return
to the laboratory and recreate this damage. Currently, no federal institution
has the mandate to synthesize the literature available on the noncancer
health effects of pesticides to determine potential damage and then undertake
the necessary environmental detective work to determine if damage is occurring
to wildlife or humans. Instead, the system has been locked into the traditional
risk assessment strategy of testing pesticides on a chemical-by-chemical
basis to determine allowable levels in the environment.
After 50 years of repeated warnings from scientists, the dominance of
cancer as the effect of primary concern in assessing the risks of pesticides
and other synthetic chemicals is being challenged by evidence of the effects
of chemicals on the nervous, immune, endocrine, and reproductive systems
of laboratory animals, wildlife, and humans (6,7). The disease state,
or effect, in this case is measured by loss of function of one or more of
these systems rather than by obvious physical deformities, outright mortality,
or cancer. The bulk of the literature from this new effects research has
focused primarily on the developmental toxicity of three industrial chemicals,
PCBs, dioxins, and furans, and on only a few chlorinated pesticides such
as DDT, its metabolites and analogs. As a result, little is known about
the noncancer health effects of most pesticides and especially herbicides,
the largest portion on a weight basis of pesticides currently in use in
the United States (8).
The Wildlife Message
The scientific community has documented the endocrine disruptive effects
of pesticides for almost 50 years, though little attention has been paid
to the message. For example, in 1950, Burlington and Lindeman (9)
first reported that DDT behaved like the female hormone, estrogen. DDT fed
to newly hatched male chicks prevented them from growing combs and wattles
and from reaching sexual maturity. Shugart (10) and Fox (11)
later reported the occurrence of female-female pairing in colonial nesting
birds carrying elevated levels of DDT and its metabolites and other organochlorine
chemicals. Fry and coworkers (12,13) in the early 1980s reported
that DDT, its metabolites and analogs--kelthane, dicofol, and methoxychlor--caused
male birds to grow oviductal tissue and to be deprived of their dominant
male behavioral characteristics in adulthood. Guillette (14) reported
in 1994 that Lake Apopka, Florida alligators and turtles were suffering
from an estrogenlike effect, probably as a result of exposure to DDE, a
metabolite of dicofol. The male alligators have shortened phalluses (penises),
making them physically incapable of breeding successfully. Slider turtles
sharing nesting mounds with the alligators become either females or intersex,
a blend of both sexes. Functionally normal male turtles are not produced
in the Lake Apopka nests. Except for DDT, the other pesticides--kelthane,
dicofol, and methoxychlor--are still in production and use in the United
States. Despite warnings from the research community, all of the above pesticides,
including DDT, are used on a global scale today.
Over the years researchers have reported a number of other reproductive
problems among wildlife populations in the Northern Hemisphere that reflect
disruption of the endocrine system (Table 1). Disruption was expressed as
changes in functionality across species from terrestrial to marine animals.
Often the effects were not recognized until they reached population proportions.
In most cases the responsibility for the above effects was not assigned
to a single chemical for several reasons: a) because so many chemicals
are present simultaneously in the environment, b) separating effects
is impossible because many chemicals cause similar damage, and c)
complementary laboratory research was not possible because of the high cost
of organic chemical analyses.
Mechanisms of Action: Complicating the Risk Paradigm
Taking advantage of high-technology (analytical chemistry, sophisticated
microscopy, supercomputers, sensitive analytical assays), scientists are
recording changes that take place at the molecular and cellular levels under
both normal conditions in the presence of internally produced chemicals
(hormones, neurotransmitters, growth factors, and inhibiting substances)
and under abnormal conditions in the presence of toxic chemicals (pesticides
and industrial chemicals) (7). Scientists have repeatedly documented
the scrambling of normal hormonal signals by pesticides in vivo and
in vitro (15). This mechanism-of-action approach has provided
answers to how certain toxic chemicals affect various tissues, organs, and
systems and how chemicals affect whole organisms. However, considering the
number of chemicals widely released in the environment today, it is improbable
the mechanisms of action of all the chemicals in use will be determined.
The results of extensive research on the effects of diethylstilbestrol
(DES), a synthetic estrogenic pharmaceutical administered to several million
women between 1948 and 1971, parallel effects reported in wildlife and humans
as a result of exposure to PCBs, dioxin, and DDT (16). Many of the
disruptive effects of DES have been documented in laboratory rat and mouse
embryos and thus provide an excellent model for the effects of other estrogenlike
compounds on humans and wildlife (17). The literature on DES, like
that on PCBs, dioxins, and DDT, indicates that it affects developing organisms
differently than mature organisms. Furthermore, the functional deficits
in animals and humans as a result of exposure in the womb can occur at much
lower concentrations than those required to illicit similar changes in adults
(18-20). And most important, only one exposure, called a "hit,"
at a critical window of time during sexual differentiation can change the
course of sexual development of the exposed individual (18-20).
It is during differentiation that construction of the vital physiological
systems and programming of the pituitary/hypothalamic region of the brain
takes place. It is also at this time that endocrine disruptors may be the
most threatening, leading to endocrine, immune, and nervous systems that
are architecturally unsound and hypothalami that do not respond to normal
hormonal and neurotransmitter messages in the usual manner throughout life
(19). The insidious nature of these effects makes the induced modifications
difficult to discern, since in most cases they are expressed in the offspring
of the individuals who were exposed, not in the exposed parents.
The endocrine system holds the key to fertility. For some sensitive populations
the message is clear: avoidance and prevention are the only options for
survival. Meanwhile, as decision makers wait for tolerance levels, dose-response
curves, threshold levels, and unequivocal cause-effect linkages in order
to regulate on a chemical-by-chemical basis, evidence that more and more
synthetic chemicals are being passed from mother to offspring continues
to surface (21,22). Top predator, long-lived wildlife populations
are suffering declines. Evidence of human damage as the result of generational
transfer of synthetic chemicals is accumulating.
Extrapolating to Humans
There is evidence that many man-made chemicals can invade the pristine
environment of the womb (23,24). Defying the paradigm that the placenta
is impenetrable to exogenous compounds, the chemicals readily cross the
placenta and brain barrier as they are passed from the mother to her developing
baby. In addition, in the case of estrogen-like compounds, if they do not
bind to the estrogen-binding protein in human maternal blood that protects
the fetus from a large part of maternally produced estrogen during gestation
(25), their toxicity will be enhanced (7).
Using the laboratory animal as a model, the disruptive effects associated
with exposure to developmental toxicants in the womb can range from mild
to extreme, reflecting gradations of loss of potential. The effects are
not necessarily expressed as a clinically relevant disease state. Furthermore,
in many cases the effects are irreversible (7,16). There are an infinite
number of windows of time during embryonic and the early postnatal period
(7,16) when disruption can take place, each leading to potentially
different changes in an individual's course of development and behavior.
Response to exposure is unpredictable because the process of development
is so delicate and complex. Consequently, a simple, standardized descriptor
of damage can never be generated. For long-lived humans, the effects may
never be traced to a specific exposure event because the effects can arise
twenty years or more later--the disconnection between exposure and effect
is too great. Ultimately, exposure of this nature leads to loss of potential
at the individual level. At the population level, hoever, the effects could
have vast social and economic impacts (26).
The full impact of exposure to chemicals on humans may just be coming
to light. Because the effects are not expressed as physical disfigurements
at birth, they do not appear in public health birth records. Often it is
a generation or more before they are recognized. For example, loss of fertility
that includes reduced sperm count associated with exposure to estrogens
(27), shortened penises at puberty associated with exposure to PCBs
and furans (28), cognitive and motor loss associated with exposure
to PCBs (29), and aberrant immune responses associated with exposure
to diethylstil-bestrol (30,31) have all been documented in humans
to be a result of their exposure in the womb. None of the above were predictable
at birth using current clinical examination procedures. And none are described
as single diseases or syndromes associated with exposure to one chemical
or a class of chemicals.
Human studies should consider the functional deficits reported in wildlife
resulting from transgenerational exposure. Also, consideration should be
given to the extent of constrained potential in children that includes behavioral,
cognitive, social, immunological, and endocrinological end points. This
is a daunting task because of the widespread use and distribution of pesticides
and industrial chemicals.
Discussion
A veneer of long-lived, man-made chemicals now covers the earth from
the Arctic to the Antarctic (32). Concentrations of these chemicals
that include a number of organochlorine pesticides are now at levels associated
with population declines of marine, freshwater, and terrestrial animals
and with functional deficits in human offspring (33). It is impossible
to predict the effect of the addition of a single new chemical to this veneer,
let alone the addition of several hundred or more new chemicals a year that
are introduced into commerce. It is doubtful that unequivocal cause-and-effect
relationships will ever be made for the wildlife population declines and
the human loss of potential mentioned above because so many chemicals are
involved, many of which have never been identified analytically.
Unlike many of the developmental toxicants that are unintentionally produced,
pesticides are produced and released to the environment intentionally. This
provides opportunities to control further release of pesticidal compounds
currently in use until they are proven safe and to prevent the release of
new substitutes that may pose similar or greater threats. However, under
the current regulatory system, to accomplish this, a case has to be made
that the chemicals are, indeed, harmful. This can only be accomplished with
quantitative evidence of damage. Unfortunately, the research agenda in the
United States today is not organized to support science of this nature.
Most of the current wildlife toxicology research comes as a result of serendipitous
observations by scientists engaged in unrelated fields of studies or from
reactive science to severe damage in areas heavily contaminated. Most human
studies have also been reactions to concern over high-dose exposure.
Currently no government institution is dedicated solely to promoting
innovative, multidisciplinary research on transgenerationally transmitted
loss of function. This will require multilevel (gene to ecosystem) research
that addresses real-world pollution problems. Real-life exposure and effect
studies should be encouraged using free-ranging wildlife as models for human
exposure and effects. This will require extensive activities in the field,
followed in the laboratory with replication of the damage found in the field,
and should lead to identification of the most sensitive end point(s) (the
lower limits of effect) on offspring using a multigenerational model.
To assure that the research agenda is modernized to meet society's current
needs, a review process must be created for research proposals and it must
be geared to support the cutting edge research necessary to keep ahead of
the technologies producing new and more powerful pesticides. This must be
a multidisciplinary review process separate from current practices in use
in federal institutions today.
In addition to the institutionalization of ecotoxicological research,
there are other research needs for:
* Development of inexpensive, short-term screening techniques to test
new and old products for endocrine, nervous, and immune system disruptive
capacity;
* Acceleration of testing of banned and restricted products that still
pose a threats to humans and wildlife because of their persistence and presence
in human tissue;
* Industry to test all new products, their metabolites, intermediates,
and by-products for a) multigenerational immune, endocrine, reproductive,
and nervous system effects in at least three animal species and b)
their environmental fate in all media; and
* Industry to provide the chemical analytical protocol to monitor its
new products in the environment after they have been released.
In light of the new evidence about the endocrinological effects of PCBs,
dioxins, furans, DDT and its analogs, and a growing list of pesticides and
other chemicals used in commerce, it is prudent that society make a concerted
effort to reexamine the endocrinological effects of a) all pesticides
in use, b) any new pesticides that come on the market, and c)
those that have been banned and restricted but still persist in the environment.
Many of the latter chemicals have proved to be very persistent and are still
present in the U.S. environment at dangerous levels (34,35). In addition,
their use has not been discontinued overseas, and in some instances they
are being used in greater intensities overseas than ever used in the United
States.
Conclusion
Institutions will continue to fail to translate into policy the impacts
of developmental toxicants on wildlife and humans if they remain locked
in current modes of testing and continue to function in a reactionary manner.
Testing must be broadened to include real-world experiences for both wildlife
and humans. Until institutions shift to a preventive mode and incorporate
these forensic studies in their agendas, little will change. It is also
imperative that the cumulative results of the new testing be systematically
reviewed and synthesized. And most important, the results of these syntheses
must become accepted components of the decision-making process.
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