United States
Environmental Protection
Agency
U.S. EPA Region 5
Chicago. IL 60604
EPA-905/R-97-019
November 1997
EPA Proceedings of the 1997
Great La'-^s
Endocrine Disrupters
Symposium
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FOREWORD
The 1997 Great Lakes Endocrine Disrupters Symposium (GLEDS) was held at the Ambassador West
Hotel in Chicago, Illinois, on July 14, 1997. The U.S. Environmental Protection Agency (EPA) Region 5
sponsored the 1-day symposium. The conference goal was to create a forum about endocrine disrupters
for Great Lakes stakeholders, including concerned citizens, state and local government employees, tribal
representatives, research scientists, industrial groups, regional academicians, environmental groups, and
EPA regional staff. All opinions expressed in this report are those of the GLEDS speakers and do not
necessarily reflect the opinions of EPA.
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CONTACT INFORMATION
If you have questions about GLEDS, please contact any of the EPA Region 5 staff members listed below.
Colleen Olsberg
U.S. EPA Region 5 (DRP-8J)
Waste, Pesticides, and Toxics Division
77 West Jackson Boulevard
Chicago, IL 60604
(312)353-4686
Amy Pelka
U.S. EPA Region 5 (B-19J)
Office of Strategic Environmental Analysis
77 West Jackson Boulevard
Chicago, IL 60604
(312)886-9858
Lara Pullen
U.S. EPA Region 5 (WA-16J)
Water Division
77 West Jackson Boulevard
Chicago, IL 60604
(312)886-0138
Mark Johnson
U.S. EPA Region 5 (SRF-5J)
Superfund Division
77 West Jackson Boulevard
Chicago, IL 60604
(312)353-9298
Howard Zar
U.S. EPA Region 5 (T-17J)
Great Lakes National Program Office
77 West Jackson Boulevard
Chicago, IL 60604
(312)886-1491
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ACKNOWLEDGMENTS
EPA Region 5 would like to thank the Toxics Reduction Team, the Office of Strategic Environmental
Analysis (OSEA), and Michele Anthony for their support in organizing GLEDS.
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ENDOCRINE DISRUPTERS: A SCIENTIFIC OVERVIEW
Dr. Anthony F. Maciorowski and Mr. Gary Timm
U.S. Environmental Protection Agency
This session provided a broad scientific overview of issues related to endocrine disrupters. The
presentation provided background information on endocrine and hormone functions; gave examples of
environmental, epidemiological, and experimental evidence for endocrine disruption in wildlife and
humans; discussed several scientific uncertainties; and described research and regulatory initiatives
currently being pursued by the U.S. Environmental Protection Agency (EPA) and other federal agencies.
The endocrine system is a series of glands that controls reproduction, development, behavior, and
homeostasis (maintenance) by secreting hormones. Hormones elicit responses from target tissues
through interactions with intracellular or membrane-bound receptors. Specific binding of a natural
hormone to its receptor is a critical step in hormone function. Separate receptor sites for estrogenic,
androgenic, thyroid, and other hormone-mediated activities exist. Approximately 50 major vertebrate
hormones are currently known.
There exists a plausible hypothesis that chemicals in the environment may affect endocrine function.
These chemicals are called endocrine disrupters (ED) or endocrine disrupting chemicals (EDC) and
include organic chemicals, such as polychlorinated biphenyls (PCB) and DDT, and inorganic chemicals,
such as mercury and tin. EDs have two primary definitions. Researchers define an ED as an exogenous
agent that interferes with the synthesis, secretion, transport, binding, action, or elimination of natural
hormones in the body that are responsible for homeostasis, reproduction, development, and behavior.
From a regulatory perspective, an ED is an exogenous substance that changes endocrine function and
causes adverse effects at the level of the organism, its progeny, and subpopulations of organisms. ED
mechanisms alter hormonal functions, such as synthesis, storage, release, transport, clearance, receptor
recognition, and post-receptor activation.
Environmental, epidemiological, and experimental evidence supports the hypothesis that EDs exist. Dr.
Maciorowski presented several examples of this evidence. In the Great Lakes, enlarged thyroid glands in
salmon and herring gulls have been linked to PCB contamination. Several EDs have been blamed for
cross-bill deformities, supernormal clutching, and decreased hatchling success in Great Lakes birds. In
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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Florida, DDT has contributed to decreased hatchling success in alligators and turtles, demasculinization
of alligators, and feminization of turtles. Researchers in the United Kingdom have observed
feminization offish caused by estradiol and masculinization of female dog-whelk snails by tributyl tin.
Human epidemiological evidence of endocrine disruption has been suggested in women with increased
vaginal carcinomas, cervical cancers, and endometriosis. Increased genital malformation, declining
sperm count and quality, and increasing prostate and testicular cancers have also been observed in men.
In Taiwan, diminished penis size was observed in a population of boys exposed to PCBs in utero. PCBs
have also been linked to neurological dysfunction in children.
Dr. Maciorowski also described several studies that have raised questions regarding the link between
EDCs and effects in humans. For example, the incidence of breast cancer is on the rise; however,
epidemiological studies present conflicting findings about whether EDs are among the causes of breast
cancer. A meta analysis of 61 case studies by Carlsen et al. in 1992 revealed a 50 percent decline in
sperm count and volume as a result of exposure to EDs. However, these results have been challenged by
studies in the United States and Finland that report no decline in sperm counts. A study of men exposed
in utero to diethylstilbestrol, a suspected ED, reports no change in fertility despite urinary anomalies.
Experimental studies reveal that exposure to kepone, DDT, and methoxychlor causes endocrine
disrupting effects, such as masculinization of female rats. Atrazine and choroquine disrupt the estrous
cycle. Hypospadias, vaginal pouches, and reduced sperm production occurred in the male progeny of
female rats given vinclozolin while pregnant. Dioxin caused impaired testosterone synthesis, delayed
testis descent, impaired spermatogenesis, and feminized behavior in rats. Alligator eggs painted with
DDT produced 20 percent female hatchlings, 40 percent males, and 40 percent exhibiting both male and
female characteristics. While acknowledging the importance of these animal studies, Dr. Maciorowski
stressed a need to test more appropriate animal surrogates for predicting risk to humans.
Uncertainties generated by conflicting studies and lack of data make the ED issue scientifically
controversial. Many questions arise, including the following:
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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• What amount of chemical exposure is necessary to cause adverse effects?
• What is the shape of the dose-response curve?
• What levels are humans and wildlife exposed to?
• Do breast and testicular cancer result from exposure to EDCs?
• Are wildlife effects isolated, high-exposure incidents or the results of a broader
environmental contamination problem?
• Do EDCs act synergistically?
• Are our test protocols adequate?
• What chemicals can be considered EDCs?
Domestic and international research initiatives and workshops are emerging in an attempt to resolve
these uncertainties. The federal government is involved major research activities, including federal
interagency research coordination through EPA's Office of Science and Technology Policy. EPA has
also funded a National Academy of Sciences review of ED issues. Currently, EPA has a $10 million
budget for researching EDs. EPA is cooperating with the United Nations Environmental Program in
coordinating ED-related international research. In addition, an international scientific assessment of EDs
will be coordinated by the Intergovernment Program on Chemical Safety, which is part of the World
Health Organization.
Screening and testing workshops are being conducted by stakeholders, including the Chemical
Manufacturers Association, World Wildlife Fund, and Endocrine Disrupter Screening and Testing
Advisory Committee (EDSTAC). Workshops include the European Workshop on the Impact of
Endocrine Disrupters on Human Health and Wildlife and the Endocrine Modulator Wildlife Assessment
and Testing Workshop. International harmonization of screening and testing for product registration has
received strong support.
In 1997, EPA issued a "Special Report on Environmental Endocrine Disruption: An Effects Assessment
and Analysis," after an agency-wide colloquium on EDs that convened in 1994. The report provides an
overview on the state of the science regarding this issue and states the interim position of EPA's Science
Policy Council, which is the only EPA policy statement on EDs to date. The report is available at
website address http://www.epa.gov/endocrine.
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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The future of ED research is uncertain. Scientific and policy debates on ED research are occurring
simultaneously. With time, scientific issues will be resolved through research. However, as a result of
public pressure, policy issues will likely be decided before ail scientific questions are resolved.
Dr. Anthony Maciorowski is Senior Technical Advisor with the EPA Office of Prevention, Pesticides,
and Toxic Substances. He is helping with the development of EDSTAC, a multistakeholder federal
advisory committee, to devise a screening and testing strategy for EDCs in response to the Food Quality
Protection Act and the Safe Drinking Water Act.
Mr. Gary Timm is Senior Technical Advisor with the EPA Chemical Control Division of the Office of
Pollution Prevention and Toxics. He is also involved in the development of EDSTAC.
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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THE STATE OF THE SCIENCE: AN ENVIRONMENTAL GROUP PERSPECTIVE
Dr. Ted Schettler
Physicians for Social Responsibility
This presentation provided a perspective on endocrine disrupters from a representative of the
environmental community. Dr. Schettler presented an overview of endocrine disrupters (ED); gave a
historical perspective on EDs; reviewed evidence showing the health effects of EDs; and urged for more
research in certain areas related to this issue. He encouraged refinement of traditional study methods to
identify adverse effects at the cell, organism, community, population, and species levels.
Investigators began studying the estrogenic activity of compounds as early as the 1930s. One of the
compounds tested is now called bisphenol-A, which was shown to have estrogenic effects. BisphenoI-A
is now a major component of a variety of consumer products, including polycarbonate plastics, epoxy
resins, and flame retardants.
DDT was recognized to have estrogenic effects in chickens since 1950. Although DDT is now banned
from domestic use, the United States exported 1 ton of DDT per day for overseas use in 1996.
Diethylstilbestrol (DES) was given to millions of pregnant women tor more than 20 years before
researchers recognized its adverse effects in children exposed to DES in utero.
Timing, duration, and amount of exposure are all important in determining the outcome of exposure to
endocrine disrupting chemicals (EDC). Windows of vulnerability exist during fetal development during
which small exposures to EDs may have profound effects not observed in adults. For example, slight
fluctuations in steroid hormone levels in mice during fetal development influenced genital morphology,
the timing of puberty, sexual attractiveness, sexual behavior, aggressiveness, and activity level of
offspring.
Wildlife and human epidemiological evidence demonstrates important health effects resulting from
exposure to EDs at current environmental levels. Wildlife studies have shown a relationship between
exposure and abnormal thyroid function, sex alteration, poor hatching success, decreased fertility and
growth, and altered behavior. The occurrence of breast, testicular, and prostate cancer have increased,
and plausible hypotheses link these illnesses to earlier exposures to EDCs. A common deficiency that
All opinions expressed in this report ait those of the GLEDS speakers and do not necessarily reflect the opinions of EPA. [
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runs through many studies is a lack of accurate exposure assessment and accurate analysis of exposure to
mixtures of contaminants. Our understanding of ED mechanisms and dose-response relationships is still
very incomplete.
To improve understanding of the issue, considerable research is necessary. However, when scientific
evidence is weighed, it is important to recognize that the limits of science influence both the questions
asked and how well studies are designed. Laboratory studies may help researchers decide whether a
chemical attaches to a hormone receptor, causes sperm count decline, or causes diminished reproductive
success. Reproducible and valid methods exist to answer these questions. However, free-ranging
wildlife and human populations living in diverse environments present difficult study problems.
The list of known EDCs varies in length depending on individual interpretations of study evidence.
Approximately 40 pesticides are on the list, including herbicides, insecticides, and fungicides, many of
which are widely used commercially. The list also includes several industrial chemicals such as alkyl
phenols and phthalates, which are produced in large quantities around the world. Dioxins and furans are
produced as unwanted byproducts of industrial activities such as medical and municipal waste
incineration, paper bleaching, fuel combustion, and polyvinyl chloride manufacturing. Polychlorinated
biphenyls (PCB), now banned from production in the United States, were used as insulators in electrical
equipment and as a coating on the inside of grain silos, Organochlorines bioconcentrate high in the food
chain, persist for decades in the environment, and are transported globally. Significant exposures to
these substances will continue indefinitely without definitive, coordinated global action.
Research needs to address several biological complexities, including interactions among the endocrine,
neurological, and immune systems; interactions among genetic, environmental, and social factors;
particularly susceptible species, subpopulations, and individuals; and multiple, real-world background
exposures. Existing study methods are insufficient to examine these complexities. Historic
concentration on dioxins, PCBs, and DDT has produced a large volume of literature relating to their
toxicity. However, even with these chemicals, large gaps still exist in our understanding of the
mechanisms of action. Most other compounds, some of which have widespread commercial use
throughout the world, have been studied much less or not at all.
All oplnioni expreixd In Mi report tn ihote of the OLEDS tpciktrt and do not nectuarily reflect the oplnloni of EPA,
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Dr. Ted Schettler 'a a staff physician at the East Boston Neighborhood Health Center in Boston,
Massachusetts. Since 1991, he has been affiliated with the group Physicians for Social Responsibility as
a member of the Steering Committee of its Greater Boston chapter, and he is the Co-Chair of the
Committee on Human Health and the Environment in New England.
All opinion! cxprewd In thii report in ihott of the QLEDS ipcakera and do not neecutrlly reflect the opinion! of EPA.
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AN INDUSTRY PERSPECTIVE
Dr. Thomas Gardiner
Chemical Manufacturers Association
This presentation provided an industry perspective on endocrine disrupters (ED). It discussed the need
for scientific criteria to define the term "endocrine disrupter" and to determine a chemical's potential to
cause adverse health effects or environmental effects; explained the importance of using a risk-based
approach to assess adverse effects on human health and wildlife; urged the inclusion of the essential
elements of hazard, exposure, and potency in risk characterization; described research efforts of the
Chemical Manufacturers Association (CMA) and other chemical and related industry groups; and
explained industry participation in advising EPA on appropriate screens and tests for EDs.
CMA is currently spending $4 million over 3 years on ED research. Data gaps that industries and the
U.S. Environmental Protection Agency (EPA) have identified and questions being addressed to
understand the ED issue include the following:
• What are the criteria for a chemical to be considered an ED?
• To what EDs are humans and wildlife exposed?
• Who are the sensitive individuals?
• Do endocrine-active chemicals adversely affect the fetus?
• What are the mechanisms of ED action?
• What are the effects of ED mixtures — additivity, inhibition, or synergism?
• Are current testing protocols adequate, and if not, how can chemicals be screened?
• What is the shape of the dose-response curve?
Several relevant concepts and terminology were presented to provide a better understanding of the term
"endocrine disruption." Environmental estrogen is a manufactured chemical in the environment that
mimics natural estrogen. An endocrine modulator (EM) is a hormonally-active chemical that affects the
endocrine system but that may not produce an adverse effect. Naturally occurring EMs, or
phytoestrogens, include chemicals naturally present in many fruits, vegetables, and grains, including
cabbage, peas, potatoes, plums, limes, peanuts, sunflower oil, rice, barley, and oats. These foods can be
hormonally active if intake is high but can also protect against heart disease and some cancers. Certain
I All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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drugs are manmade EMs designed to mimic hormones for medical purposes (for example, insulin and
birth control pills). Some industrial chemicals also constitute manmade EMs. Large amounts of a few
particular EMs have caused adverse effects by disrupting the endocrine system. The key issue is whether
exposure to small amounts of EMs can be harmful.
Efforts have been made to identify EM substances and understand the potential for human exposure to
them in the environment. Suspected EMs have been identified in test-tube experiments. However, the
ability to predict harm from exposure to EMs remains uncertain. Hormonal activity does not necessarily
mean that an EM causes adverse health effects, but may indicate a need for more definitive testing.
EDs adversely affect endocrine function in an intact organism or its offspring. Risks associated with
exposure to EDs depend partly on the potency of the EDs and partly on how exposure occurs. ED issues
that should be considered as part of ongoing research efforts include (1) defining hazards or adverse
effects, (2) understanding potency or the amount necessary to result in an adverse effect, and (3) duration
of exposure resulting in a significant risk. For example, in a risk assessment involving diethylstilbestrol
(DES), reproductive problems in offspring and increased breast cancer in mothers were obvious adverse
effects. But DES potency was much greater than that of the body's own estrogen, and DES was
prescribed at high doses for pregnant women. Evaluation of these issues resulted in the banning of DES
as a way to manage the unacceptable risks resulting from exposure to DES. There are a variety of other
ways to effectively manage potential risks from hazardous chemicals that limit exposure and/or utilize
less potent substances.
Dr. Gardiner stressed a need to identify causal links between specific chemicals and adverse human
health or wildlife effects, such as lower sperm count, breast and male reproductive cancers, and
developmental problems in offspring. To date, adverse endocrine effects have been linked primarily to a
handful of chemicals that have already been banned from commerce or to catastrophic environmental
releases.
In conducting its generic ED research program, CMA considers (1) applicability of research
methodology to a broad range of chemicals, (2) support of industry product stewardship, and (3)
usefulness of data for policy-makers. CMA will make its final research results available to members of
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA. |
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the public. Under this research program, CMA is evaluating endocrine screening tests and examining
methods for prioritizing chemicals for testing (including quantitative structure activity relationship
models). CMA is also examining current risk assessment methods and considering how to modify them
to consider low-dose extrapolation, background levels of naturally-occurring EMs, and differences
between species. CMA is incorporating exposure mechanisms and toxicokinetics in the risk assessment
process. Research issues include data needed for risk assessment, the adequacy of current toxicology
tests, and the relationship between subtle and adverse ED effects. CMA is expanding its endocrine
research to include wildlife, male issues, transgenerational issues, and immunotoxicity. Its research data
are being published in peer-reviewed journals.
CMA member company representatives are also participating in the Endocrine Disrupter Screening and
Testing Advisory Committee (EDSTAC) process together with other stakeholders. EDSTAC's goal is to
advise EPA on appropriate screens and tests for EDs. EDSTAC's efforts focus on estrogen, androgen,
and thyroid exposure endpoints for humans and wildlife, and on evaluating and validating screening test
methods.
Dr. Gardiner concluded by explaining CMA's commitment to public health and safety and to improving
the environmental performance of the chemical industry through the Responsible Care* initiative.
Dr. Tom Gardiner is Product Stewardship and Regulatory Affairs Coordinator of Resins Chemicals for
Shell Chemical Company. In addition, he has been active for many years in leadership positions with
trade association groups, including CMA.
All opinions expressed in (his report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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ECOLOGICAL RESEARCH
Dr. Mary Walker
University of Wisconsin - Madison
Dr. Mary Walker provided an overview of the rationale for assessing potential developmental impacts in
wildlife resulting from endocrine disrupter (ED) exposures, described her research to develop dose-
response curves for dioxin exposures in wildlife and to assess ED teratogenicity mechanisms, and
recommended several options for future research regarding the effects of dioxins and other EDs on
wildlife.
EDs include a broad range of organic and inorganic chemicals, such as polychlorinated biphenyls (PCB),
dioxins, and mercury. Toxics Release Inventory (TRI) data indicate that the Great Lakes basin is a
potential "hot spot" for observing endocrine disruptive effects in wildlife because of the large volumes of
reported ED releases frcm Great Lakes states. As a result, observed impacts in key Great Lakes wildlife
populations or communities may be linked to ED exposures. For example, Great Lakes lake trout
populations declined rapidly in the 1940s and 1950s to the point of virtual extinction in the early 1960s.
At that time, sea lamprey predation was thought to have caused the lake trout population decline. As a
result, chemical sea lamprey control was coupled with restocking programs to repopulate the trout.
Despite these efforts, self-sustaining lake trout populations have not returned to the Great Lakes.
Therefore, other factors are likely affecting the survival of lake trout offspring.
Dr. Walker's research focuses on replicating the potential effects resulting from wildlife exposures to
polycyclic aromatic hydrocarbons (PAH) and halogenated aromatic hydrocarbons (HAH) to assess the
hypothesis that EDs affect wildlife fetal survival and development. Dr. Walker is using
2,3,7,8- trichlorodibenzo-p-dioxin (TCDD) in her studies as a representative of the class of HAHs
suspected of causing endocrine disruptive effects. Her research focuses on quantifying the effects of
exposure. The mechanisms that cause these effects are still not well understood.
Prior to 1990, toxicology research focused on the carcinogenic effects caused by exposure to TCDD and
other HAHs. However, the U.S. Environmental Protection Agency (EPA) conducted a dioxin
reassessment that indicated that other toxic effects caused by HAH exposure were also of concern,
including effects on estrogenic activity, antiestrogenic activity, and development. These effects are
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA
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probably occurring at exposure levels lower than those suspected to cause cancer. As a result, ecological
risk assessments need to start examining ED effects as an endpoint for quantification.
Dr. Walker described her approach for developing dose-response curves for specific toxic effects and for
single- and multiple-chemical exposures. She used two experimental models to assess the effects
resulting from HAH exposure: the first model assessed overt mortality to lake trout sac fry as a result of
TCDD exposure, and the second model assessed sublethal developmental effects in chick embryos as a
result of ED toxicity mechanisms.
Under the first model, lake trout sac fry were exposed to TCDD shortly after fertilization to determine
lethal effect concentrations. TCDD exposure results in fluid accumulation beneath the fry yolk sac
epithelial membrane, disruption of vitelline vasculature, and cranial facial malformations. The sac fry
exhibited 100 percent mortality (LDIOO) at an egg TCDD concentration of 110 parts per trillion (ppt) and
50 percent mortality (LDX) at 65 ppt. The no observed adverse effect level (NOAEL) was found to be
34 ppt. TCDD concentrations resulting in lethal effects to 25 and 75 percent of the sac fry population
were also derived to develop a complete dose-response curve.
Dose-response curves were then derived for other HAHs and HAH mixtures. The tested HAHs were
found to result in the same toxic effects on lake trout sac fry as TCDD but at higher dose levels. In fact,
for two PCB congeners, no toxic effects were observed even at very high dose levels. Mixtures of HAHs
representative of HAH mixtures present in the Great Lakes were also tested and found to exhibit additive
toxic effects. The sum of these effects are expressed as "dioxin equivalents" to allow comparison of the
relative toxicities of different HAH mixtures.
Dated sediment cores from Lake Ontario indicate that the dioxin equivalent exposure concentrations
from HAH mixtures for lake trout sac fry exceeded LD100 levels in the 1950s, 1960s, and 1970s. Dioxin
equivalent levels peaked in the 1970s and declined through the 1980s. The 1990s sediment layers
indicate that the level of dioxin equivalents in Lake Ontario has declined to approximately 40 ppt, or the
lowest observed adverse effect level (LOAEL) for lake trout sac fry. This reduction in dioxin
equivalents is reflected by recent improvements in lake trout recruitment. However, dioxin equivalent
reductions appear to be leveling off, and it is not likely that dioxin equivalent concentrations will reach
All opinions expressed in this report are those of the GLEOS speakers and do not necessarily reflect the opinions of EPA.
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the NOAEL for lake trout sac fry in the near future. Because the Great Lakes encompass a highly
manipulated ecosystem, population- and community-level impacts resulting from past and ongoing HAH
and other ED releases are difficult to predict Furthermore, the sublethal effects caused by current and
future levels of exposure are still not well understood.
Other researchers have documented developmental effects from HAH exposures in a variety of other
species (for example, crossed bills in birds). Other teratogenic effects, such as cardiovascular deficits
and craniofacial defects, are also believed to be related to exposure to TCDD and other HAHs. However,
because of the low levels of exposure in the environment and the relatively low incidence rates observed
for certain sublethal effects, cause-and-effect relationships are often difficult to discern or predict.
Furthermore, different species exhibit a range of responses to similar dioxin doses in target organs.
To begin addressing the need to better predict sublethal effects resulting from HAH exposure,
Dr. Walker's research focused on developing dose-response relationships for target organs. Specifically,
her research addresses the incidence of cardiovascular deficits, such as septal defects, blood vessel
anomalies, decreased heart contractility, and vascular deficits, in TCDD-exposed chick embryos.
Fertilized chick eggs were exposed to TCDD, and the embryos were harvested 10 days later. Heart wet
and dry weights were found to increase with TCDD exposure, indicating cardiac hypertrophy. In
particular, a 150 ppt TCDD dose, which corresponds to a LD50 for chick embryos, resulted in a
statistically significant incidence of cardiac hypertrophy. As a result, many of the chicks exposed to
TCDD that survived to the hatching stage still exhibited cardiac deficits.
Research is now focusing on developing more sensitive markers for predicting developmental effects,
thus allowing for a better understanding of toxicity mechanisms. For example, cardiac hypertrophy
observed in chick embryos may indicate edema related to congestive heart failure later in life.
Understanding these mechanisms will, in turn, allow for better prediction of lethal and sublethal effects'
in other species. By understanding sublethal effects, population-level effects will also be better
understood.
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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Dr. Mary Walker is an Assistant Professor of Pharmacology/Toxicology at the College of Pharmacy,
University of New Mexico. Dr. Walker was formerly with the School of Pharmacy at the University of
Wisconsin-Madison, where she conducted research on TCDD-induced impacts in wildlife.
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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EPIDEMIOLOGY
Dr. Joseph Jacobson
Wayne State University
Dr. Joseph Jacobson presented his research findings regarding central nervous system (CNS) deficits and
developmental impacts in children resulting from prenatal and postnatal polychlorinated biphenyl (PCS)
exposure. The focus of this research stemmed from concerns over PCB levels in Lake Michigan fish
eaten by mothers, especially during the 1970s. The first epidemiological evidence of adverse human
health effects resulting from PCB exposure arose from the "Yusho Incident" in Japan, during which
mothers ate rice oil heavily contaminated with PCBs and polychlorinated dibenzofurans (PCDF). The
children of those mothers exhibited effects such as dark pigmentation of the skin and nails, early eruption
of teeth, swollen eyelids and gums, and distinctive grayish patches on the skin. These effects
demonstrated that PCBs could cross the placenta and cause fetal exposures, even many years after
maternal exposure. Upon reaching school age, the "Yusho children" were described as lethargic and
having low intelligence quotients (IQ). A similar contamination in Taiwan, the "Yucheng Incident,"
resulted in similar developmental impacts in children born to mothers exposed to PCBs and PCDFs.
To assess whether similar impacts have occurred in U.S. children whose mothers have been exposed to
lower levels of PCBs, Dr. Jacobson and his colleagues undertook a prospective, longitudinal study of
children born to mothers with elevated body-burden PCB levels. The study included 242 children of
mothers who had consumed relatively large quantities of Lake Michigan fish and 71 children of mothers
who were not Lake Michigan fish consumers. The rationale for the study recruitment strategy stemmed
from earlier findings that Lake Michigan sport fishermen had elevated PCB blood levels. The focus of
the study was on PCB concentrations in mothers resulting from exposure to all PCB sources, not just the
consumption of Lake Michigan fish. Because the mothers' intake of Lake Michigan fish was limited, the
study sample's exposure level was at the upper end of the average PCB body burden for the U.S.
population as a whole.
Prenatal PCB exposure was estimated by examining PCB levels in umbilical cord serum, maternal
serum, and breast milk. However, analytical methods used were sufficiently sensitive to detect PCBs in
only one-third of the umbilical cord serum samples. The actual amount of PCBs transmitted across the
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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placenta is quite low. In some cases, maternal serum and milk collected shortly after delivery were used
to estimate prenatal exposure because the PCB accumulation in these fluids is higher and therefore easier
to detect. Also, the mother is the sole source of PCB exposure to the fetus.
Postnatal exposures were assessed by examining breast milk PCB levels and the number of weeks the
exposed children were breast fed. Postnatal PCB exposure levels for breast-fed babies are likely to be
much higher than prenatal exposure levels. In fact, babies that breast fed for 1 year or longer exhibited
PCB concentrations in their blood serum proportionately equivalent to those of their mothers.
The study also measured a broad range of confounding influences, such as standard demographic factors,
alcohol consumption during pregnancy, postnatal lead exposure, and socio-environmental influences, to
ensure that other variables did not cause the observed effects.
The impact of PCB exposure on infant development was examined using the Pagan Visual Recognition
Memory (Pagan) Test, which assesses an infant's ability to recognize and differentiate images. Infants
who received the highest level of prenatal PCB exposure were less likely to differentiate between old and
new visual stimuli, indicating a deficit in information processing. These findings, which suggest long-
term cognitive problems for the children, were replicated when the Pagan test was given to infants of
mothers exposed to PCBs during the "Yucheng Incident" in Taiwan.
A follow-up test was conducted on the Michigan children at age 4 using the McCarthy Scales of
Childrens' Abilities. In general, high serum PCB levels were found to correlate with poorer short-term
memory and attention in the children.
A subsequent follow-up study using standardized IQ and school achievement tests was administered to
assess verbal comprehension, perceptual organization, and attention in the Michigan children at age 11.'
After controlling confounding variables, the study found that prenatal PCB exposure had an adverse
impact on full-scale IQ, verbal IQ, attention, and reading comprehension. However, only children
exposed to the highest prenatal PCB levels exhibited significant deficits. A 1.25 parts per million (ppm)
PCB concentration in mother's milk was associated with a 6.2 point reduction in child IQ.
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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The threshold for a detectable reduction in child reading comprehension was observed at a mother's milk
PCB concentration of 1.0 ppm. Furthermore, children who experienced the highest levels of prenatal
PCB exposure were three times more likely to score in the bottom 15th percentile on IQ tests compared
to the other children in the sample. In contrast, the study found that postnatal PCB exposure through
breast milk consumption was not related to developmental outcome. Therefore, even though children are
exposed to much higher levels of PCBs during breast-feeding, prenatal PCB exposure appears to have the
greatest impact on reduced cognitive ability.
Dr. Jacobson emphasized that this area of research is still in its early stages, but other research is
beginning to replicate these findings. Furthermore, little is known about the mechanisms that cause the
CNS deficits. Prenatal PCB exposure appears to result in a decrease in circulating thyroid hormones,
which can cause impaired fetal brain development. Thyroid hormones are important to neuronal
proliferation and differentiation, which is critical for cognitive development. Although this is a leading
hypothesis for the mechanism leading to CNS deficits resulting from prenatal PCB exposure, it is only
one of many hypotheses.
Based on these results, Dr. Jacobson recommends cost-benefit analysis to guide the selection of
appropriate management alternatives to reduce maternal PCB exposures, especially with regard to fish
advisories and other efforts to educate the public regarding the risks associated with consuming Lake
Michigan fish.
Dr. Joseph Jacobson is a Professor of Psychology at Wayne State University. He and his wife, Sandra
Jacobson, have been studying the effects of prenatal exposure to PCBs and related contaminants on
infant and child development since 1980.
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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IMPLEMENTING LEGISLATION THROUGH CONSENSUS: THE EDSTAC PROCESS
Mr. James V. Aidala
U.S. Environmental Protection Agency
This session gave a U.S. Environmental Protection Agency (EPA) perspective on the endocrine disrupter
(ED) issue. The presentation provided a brief overview of EDs; reviewed the legislative history of
testing authority over EDs; and described the implementation strategy of the Endocrine Disrupter
Screening and Testing Advisory Committee (EDSTAC).
The basis for public concern about EDs lies in a scientifically plausible hypothesis that EDs exist. This
hypothesis is supported by wildlife, epidemiological, and experimental toxicology studies; however, the
issue is confounded by several major uncertainties. Public awareness about EDs has increased over
recent years, as indicated by growing media attention, congressional interest, and ED-related
controversy.
Historical testing authority over EDs began with the Federal Insecticide, Fungicide, and Rodenticide Act
(FIFRA), which requires registration of pesticides. A FIFRA review revealed that 600 active
ingredients; 1,500 inert ingredients; and 20,000 formulated products are registered pesticides. The Toxic
Substances Control Act (TSCA) imposes a high-level burden on EPA to justify chemical testing
requirements. Testing requirements for existing chemicals are imposed by rule-making or consent
agreement requirements. Premanufacture notices are now a requirement for new chemicals. Structure-
activity relationships (SAR) serve as a basis for the estimation of hazards related to ED exposure, and
exposure is estimated by production volume and use of the ED.
The Food Quality Protection Act (FQPA) and amendments to the Safe Drinking Water Act (SDWA)
were enacted in August 1996. The new legislation requires the establishment of a screening program for
estrogenic effects. FQPA provides EPA authority to conduct ED screening and establishes a test
program to assess endocrine disruptive effects for all pesticides. To comply with FQPA, the EPA
Administrator is required by Section 405 to "(a) provide for the testing of all pesticide chemicals; and (b)
provide for the testing of any other substance that may have an effect that is cumulative to an effect of a
pesticide chemical if the Administrator determines that a substantial population may be exposed to such
a substance." The SDWA gives EPA the authority to regulate drinking water contamination. Section
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136 of the SDWA amendments calls upon the EPA Administrator to provide for testing of substances in
possible sources of drinking water if the Administrator determines that a substantial population may be
exposed to such substances.
Chemical manufacturers, referred to by the EPA as "owners" of the chemicals they produce, are required
to test their chemicals under FIFRA, TSCA, FQPA, and SDWA. For chemicals that do not have
"owners," such as disinfection byproducts, environmental degradation products, and out-of-production
chemicals, the federal government and research institutions generally bear the screening and testing
responsibility. To address this responsibility, EPA sponsored a meeting of major stakeholders on May
15,1996. The stakeholders recommended that EPA establish an advisory committee under the Federal
Advisory Committee Act (FACA). Advantages of a FACA committee include the fact that it is a public
process, brings in outside expertise, represents all views in controversial issues, promotes a consensus
approach, and reduces the potential for litigation.
EDSTAC was chartered on October 16,1996, under FACA and brings together government, regulated
industry, health and environmental, university expertise, and labor interests to address public concerns
and legal issues and to develop testing workshops related to EDs. EDSTAC has been tasked to provide
recommendations to EPA on (1) a strategy for selecting and prioritizing chemicals for screening and
testing; (2) a process for identifying new and existing screening tests and mechanisms for test results
validation; (3) available screening procedures for early application; and (4) test parameters in addition to
screening parameters.
To accomplish these tasks, EDSTAC is examining human health and ecological effects; estrogenic,
androgenic, and thyroid effects; single compounds; and compound mixtures. Committee work groups
discuss principles of endocrine disruption, prioritize issues, conduct screening and testing, and plan
communication and outreach programs. The group began meeting in December 1996 and will continue
to meet approximately every 2 months until February 1998. Work groups identify technical issues
between meetings. EDSTAC recommendations will be based on work group reports and comments from
the National Academy of Sciences.
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EDSTAC must meet several deadlines. A draft report of its findings is due in January 1998 for public
comment in February 1998. The EPA Science Advisory Board and the FIFRA Scientific Advisory Panel
are slated to review the report in April 1998. The last EDSTAC meeting to respond to comments and
finalize the report is scheduled for June 1998. EPA will use the EDSTAC report to help meet statutory
deadlines. EPA must propose a screening and testing program for EDs by August 1998. The ED
screening and testing program must be implemented by August 1999, and EPA must submit a report on
the program to Congress by August 2000.
EPA's Office of Research and Development issued "A Special Report on Environmental Endocrine
Disruption: An Effects Assessment and Analysis" in February 1997. The report is available at the
website address http://www.epa.gov/endocrine. The report, which grew out of an agency-wide
colloquium on EDs that convened in 1994, provides an overview of the state-of-the-science of EDs and
the EPA Science Policy Council's interim position on the issue, which is the only existing EPA policy
statement at present. EPA recognizes the potential for adverse reactions to the report because it focuses
more on assessing the exposure endpoints rather than the mechanisms of EDs.
The ED issue is evolving and controversial, and ED-related science and regulatory policies are volatile.
Regulation will begin with the implementation of EDSTAC's recommendations, which will occur
through established EPA procedures under FIFRA, TSCA, FQPA, and SDWA. The EDSTAC process is
discussed in more detail at website address http://www.epa.gov/opptintr/opptendo.
Mr. James V. Aidala is Associate Assistant Administrator for the Office of Prevention, Pesticides, and
Toxic Substances at EPA. This office is responsible for implementing the nation's pesticide, toxic
substance, and pollution prevention laws.
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STATE ENVIRONMENTAL AGENCY PERSPECTIVE
Mr. Peter Wise
Illinois Environmental Protection Agency
This session presented a state environmental agency perspective on the endocrine disrupter (ED) issue
and discussed the Illinois Environmental Protection Agency's (Illinois EPA) "Endocrine Disrupter
Strategy" unveiled earlier this year. The strategy has since attracted national and international interest.
The strategy was initiated for four primary reasons: (1) the growing body of scientific evidence to
support the ED hypothesis, (2) Illinois EPA's responsibility to protect public health and the environment,
(3) the need to start a dialogue about the ED issue; and (4) Theo Colborn's book on EDs entitled Our
Stolen Future. Illinois EPA's ED strategy is to review existing research to identify suspected EDs;
conduct a preliminary analysis of the quantities and sources of these chemicals; provide suggestions for
new testing and reporting requirements; and identify gaps in existing data and regulatory programs.
Illinois EPA's strategy does not consist of original scientific research, a detailed action plan, nor an
attempt to set new standards or regulations.
One product of the Illinois EPA strategy is a list of 74 known, probable, or suspected endocrine
disrupting chemicals (EDC), compiled from an extensive literature review. EDCs can be classified into
three categories: (1) "known" EDCs identified from strong evidence of endocrine disruption in intact
animals; (2) "probable" EDCs identified from evidence of endocrine disruption in intact animals and
bioassays; and (3) "suspected" EDCs that lack strong evidence of endocrine disruption. Mr. Wise
showed a preliminary list of chemicals associated with endocrine system effects in animals and humans
in vitro. The list has generated a lot of interest as well as controversy. Illinois EPA has received
hundreds of national and international requests for its strategy. Although the chemical industry has
expressed concern with "The List," environmental groups generally have a favorable attitude toward it.
The State of Illinois is currently involved in several partnership opportunities involving EDs. For
example, Illinois EPA has established a Performance Partnership Agreement with the U.S.
Environmental Protection Agency (EPA) Region 5 regarding federal standards. The Illinois Department
of Public Health is also conducting ED studies, and the Illinois Department of Agriculture is responsible
for pesticide management plans.
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Mr. Wise recommended that ED policy should be dynamic and flexible. Regulators should work with
the chemical industry to organize ED workshops. ED management should be integrated into regulatory
programs for air, water, and soil. Beyond compliance issues, industries should engage in voluntary
control through strategies such as pollution prevention and ISO 14000.
Mr. Peter Wise is the Associate Director of Illinois EPA. He oversees the Agency's Offices of Pollution
Prevention, Small Business Assistance, Community Relations, Public Information, and Quality
Management.
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IMPLICATIONS FOR PUBLIC HEALTH DEPARTMENTS
Dr. Henry A. Anderson
Wisconsin Bureau of Public Health
This presentation provided a historical public health perspective on the endocrine disrupter (ED) issue,
discussed the impact of current regulatory activities on public health, and described public health
opportunities related to EDs.
Endocrinology is a relatively new science. Diabetes is the most commonly recognized endocrine
disease. In 1921, pancreatic extracts were used to develop the first form of insulin. In the 1930s, the
hormone structure of thyroxine, a steroid, was examined. Between 1948 and 1956, scientists synthesized
cortisone/cortisol. Studies of environmental goitrogens identified thiocyanates in central African root
plants and plant thioreas in cow milk in Finland and Tasmania.
Cost-benefit information is scarce, but data have been generated on the cost of diabetes in the United
States. The total annual cost in 1992 was $92 billion. In 1992, medical costs directly attributable to
diabetes totaled $45 billion a year, and indirect costs arising from disability, work loss, and premature
mortality totaled $47 billion per year.
The era of international interest in environmental EDs began in 1992 at the Wingspread Conference. In
1996, the U.S. Environmental Protection Agency formed the Endocrine Disrupter Screening and Testing
Advisory Committee. The Committee began by focusing on estrogenic activity, androgenic activity, and
thyroid function.
Public health departments are now striving to catch up in the identification of the impact of EDs. Core
public health functions related to EDs now include (1) assessment through the gathering and evaluation
of information, (2) policy development to provide for corrective and preventative measures, and (3)
assurance by implementing intervention and prevention measures.
In terms of assessment, public health agencies are evaluating scientific information on EDs; collecting
data on health conditions; conducting epidemiological investigations; performing risk assessments;
sampling food, water, air, and human tissues for contamination; and investigating citizen concerns.
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Policy development involves the development of educational strategies; drafting guidelines, standards,
and regulations; developing intervention strategies; and developing prevention strategies. Examples of
policy implications include sport fish consumption guidelines, private drinking water advisories, indoor
air contamination advisories, and contaminated site assessments. Finally, to achieve assurance, public
health agencies must monitor exposures, conduct sentinel disease surveillance, educate communities and
citizens so that they understand ED-related hazards and risk, and ensure regulation enforcement.
Health agencies can establish epidemiological surveillance for EDs; characterize the water, food, air, and
soil exposure pathways; and document completed exposure pathways. Dr. Anderson summarized the
impact of public health on EDs with the following statement: "Good epidemiological surveillance does
not necessarily ensure the making of the right decisions, but it reduces the chance of wrong ones."
Dr. Henry A. Anderson is Chief Medical Officer at the Bureau of Public Health in Madison, Wisconsin.
He is principal investigator on a cooperative agreement consisting of a consortium of five state health
departments studying the reproductive and endocrine functions of frequent Great Lakes sport fish
consumers.
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POLICY IMPLICATIONS: A TRIBAL PERSPECTIVE
Ms. Kristine Carre
Grand Portage Band of Chippewa
This presentation provided a tribal perspective on endocrine disrupters (ED). Ms. Carr6 gave some
background about the Grand Portage Reservation, its culture, and the subsistence way of life; described a
major study conducted in Wisconsin to evaluate environmental risks faced by Wisconsin tribes; and
discussed environmental justice and policy implications associated with the ED issue.
The Grand Portage Reservation is located in the northeastern tip of Minnesota along the northern shore
of Lake Superior and next to the Canadian border. The reservation has a total land area of about 87
square miles (56,000 acres) and a population of 550. The indigenous people at Grand Portage live a
subsistence way of life (that is, they hunt, fish, and gather).
In 1992, the U.S. Environmental Protection Agency (EPA) conducted a comparative risk study to
evaluate environmental risks faced by the 11 tribes in the State of Wisconsin. This study was the first
conducted by EPA that focused on Native Americans. The report concluded that tribes of Wisconsin
have a lifestyle, a culture, values, and an environment that differ from most Americans. Their
reservations are relatively isolated and undeveloped. The tribes rely more extensively on harvesting
local fish, game, and plants for subsistence. However, stresses from growing development outside the
reservations and pressures for economic growth on the reservations have combined to generate
significant environmental problems.
The study revealed that food contamination, probably resulting from bioaccumulation of environmental
contaminants in the large quantities of local fish and game that comprise the Native American diet, was a
significant problem in the tribes. The study recommended that EPA and other federal agencies use
existing risk factors to help guide risk management activities on tribal lands. EPA has begun to address
tribal environmental risks through its environmental justice program.
Ms. Carre presented the following examples of federal land management decisions that have adversely
impacted tribal lands in the past:
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• Coal and uranium mining on the Navajo reservation has destroyed large areas of land,
polluted air and water, and caused untold long-term health problems.
• Cyanide heap-leach mining in Montana is polluting water on the Fort Belknap
Reservation.
• Radioactive pollution and hazardous waste from the Kanford nuclear weapons plant
threatens all tribes who depend on Columbia River salmon as a food source.
• Industrial waste dumps surround the St. Regis Indian Reservation, polluting the St.
Lawrence River.
Today, Americans are taking a closer look at environmental justice, a movement that emerged in the
early 1980s. Environmental justice promotes the fair treatment of people of all races, income, and
culture with respect to the development and implementation of environmental laws, regulations, and
policies. It has become a priority both in the White House and EPA, as evidenced by the Clinton
Administration's issuance of Executive Order 12898, "Federal Actions to Address Environmental Justice
in Minority Populations and Low-Income Populations," on February 11,1994. The order requires that
federal agencies, including EPA, provide for the identification and protection of subsistence consumption
offish and wildlife.
The Penobscot Indian Nation, the Environmental Defense Fund, and the National Association for the
Advancement of Colored People Legal Department have developed recommendations to the EPA
Administrator to implement the President's executive order on environmental justice. They point out
that fish consumption for subsistence and for recreational fishing among subpopulations may vary and
that fishery uses of specific waterways also vary. Fish consumption in tribes is often higher than levels
modeled by EPA. For example, many Grand Portage residents eat more than 100 grams offish each day.
The group has recommended the use of higher fish consumption rates (for example, 90 to 150 grams per
person per day) to account for tribal population fish consumption.
Although the long-term effects of chemicals used today are still unknown, growing evidence suggests
that these chemicals are contributing to cancers and reproductive disorders throughout the animal
kingdom. One way in which tribes are beginning to take control over their environments and lower risks
is to develop and assume regulatory authority to implement their own environmental protection
programs. There is a serious need to prevent damage to reservation environments, first, to protect
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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cultural and religious values, and second, to maintain subsistence resources for future generations.
Tribes need the capability, knowledge, and resources to manage and protect reservation environments
and to influence policy decisions made off the reservations that will impact their health and environment.
Tribes have actually come a long way in the past 10 years. Many federal environmental statutes have
provisions for tribes to assume management authority and to develop tribal environmental programs.
Tribes are currently developing administrative and infrastructure capabilities to manage environmental
problems on the reservation. However, tribal staffs are still minimal, few tribal laboratories exist, and
tribes are just beginning to develop environmental monitoring capabilities.
Ms. Kristine Carre is Environmental Director for the Grand Portage Band of Chippewa in northeastern
Minnesota. She is responsible for developing tribal environmental programs, codes, and policies related
to air, water, wetlands, solid and hazardous wastes, emergency planning, and land use.
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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PANEL DISCUSSION SUMMARY
The Great Lakes Endocrine Disrupters Symposium concluded with an open panel discussion of issues
raised during the meeting. The following panelists participated in the discussion:
• Mr. James V. Aidala, U.S. Environmental Agency (EPA) Office of Prevention,
Pesticides, and Toxic Substances (OPPTS)
Dr. Henry A. Anderson, Wisconsin Bureau of Public Health (WBPH)
• Ms. Kristine Carre, Grand Portage Band of Chippewa
• Dr. Thomas Gardiner, Chemical Manufacturers Association (CMA) and Shell
Chemical Company
• Dr. Joseph Jacobson, Wayne State University
• Dr. Anthony Maciorowski, EPA OPPTS
• Dr. Lara Pullen, EPA Region 5
• Dr. Ted Schettler, Physicians for Social Responsibility
• Mr. Gary Timm, EPA Office of Pollution Prevention and Toxics
• Dr. Mary Walker, University of Wisconsin-Madison
• Mr. Peter Wise, Illinois Environmental Protection Agency (Illinois EPA)
Questions and responses from the panel discussion are summarized and grouped as they relate to the
following four general questions, which were developed by EPA Region 5:
Is there evidence that chemicals are resulting in endocrine disrupting effects on
humans and wildlife at current levels of exposure?
Do current environmental regulations protect humans and wildlife from endocrine
disruptive effects?
What steps need to be taken to ensure that endocrine disruptive endpoints are
incorporated into environmental assessments?
What specific roles and appropriate actions should scientists, governmental agencies,
industries, environmental groups, and the public take to address endocrine disrupter
issues?
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Additional questions and responses raised about issues related to endocrine disrupters are also
summarized. Although it was not expected that panel members could provide definitive answers to
many of the overarching questions related to endocrine disrupters, it was intended that the audience
would gain further insight about issues discussed earlier in the day.
Is there evidence that chemicals are resulting in endocrine disrupting effects on humans and
wildlife at current levels of exposure?
In response to this general question, Dr. Joseph Jacobson of Wayne State University stated that evidence
of endocrine disrupting effects on wildlife is better documented than for humans. It is still unknown
whether disruption of hormone-mediated processes at current levels of exposure is significant for
humans. Dr. Jacobson commented that from a scientific point of view, it is sometimes frustrating to
watch regulators try to address endocrine disrupting effects without sufficient scientific evidence.
* * *
Audience member Ms. Mary Beth Doyle of the Ecology Center of Ann Arbor asked Dr. Jacobson how
his research results compare to those obtained by the Helen Daley Research Team, specifically regarding
the six-point intelligence quotient drop that Dr. Jacobson observed among children exposed in utero to
high levels of endocrine disrupting chemicals. Dr. Jacobson responded that it was difficult to compare
the two studies; as far as he knew, the Daley study has only reported newborn effects to date. In
addition, Dr. Jacobson stated that the exposure levels studied by the Daley team were probably lower
than those reported in his studies.
* * *
Audience member Mr. Michael Collins of the Biochemistry Department of Loyola Medical University
asked the panelists if any relationship has been drawn between endocrine disrupters and diseases of the
brain during aging, particularly Alzheimer's and Parkinson's diseases. Mr. Collins was aware of some
indication that environmental agents could trigger or promote Parkinson's disease and cited a study
where post-mortem dieldrin levels of patients afflicted with Parkinson's disease were higher than in
control subjects. Mr. Collins also predicted that we might see increased incidences of diseases with age
resulting from exposure to endocrine disrupters within the next 80 years.
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Dr. Jacobson responded that he knew of a study by Ms. Susan Schantz at the University of Illinois that
involved older individuals who ate Lake Michigan fish. He noted that the studies cited by Mr. Collins
are controversial because of limited research in this area. However, a lot of interest exists in researching
this topic.
An unidentified audience member added that an important epidemiological study conducted in 1992 is
reported in the Journal of Neurology. The study examined herbicide exposure to 130 Canadians and had
230 control subjects. The study found a five times higher risk of Parkinson's disease with frequent
occupational exposure to herbicides. However, these herbicides were not identified. The audience
member cited another study of a fanner who accidentally spilled diquat on his skin; within 1 week he
was totally catatonic with Parkinson's disease.
* * *
Dr. Lara Pullen asked Dr. Joseph Jacobson to describe the type of study that he thinks would directly
address the question of whether current human exposure to chemicals is resulting in endocrine disruptive
effects. According to Dr. Jacobson, one needs to measure endocrine disruption more directly. For
example, a study that he is currently conducting examines exposure to endocrine disrupters at
background levels. Adverse effects have been observed, but their mediating mechanism is unknown.
Dr. Jacobson believes that the public is primarily interested in endocrine disruptive effects on sexual
maturation and differentiation, sperm count, breast cancer, and sexual behavior instead of focusing on
cognitive development as an endpoint.
Dr. Ted Schettler of the Physicians for Social Responsibility disagreed that the public is not interested in
the effects of endocrine disrupters on cognitive development. Although the sperm count debate emerged
first, the issue of cognitive development and assessment of other endpoints has sparked public interest as
other research has also emerged.
Dr. Schettler cited studies of humans occupationally exposed to endocrine disrupters, as opposed to
accidentally exposed. For example, workers who were occupationally exposed to dioxin had depressed
testosterone levels and women occupationally exposed to styrene had elevated prolactin levels.
Although Dr. Schettler was uncertain what these findings mean, he stressed the importance of examining
the interaction of endocrine disrupters and a variety of hormones such as estrogen, progesterone, and
prolactin in breast development.
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Mr. Chris Bradley of Wayne State University asked Dr. Mary Walker of the University of Wisconsin-
Madison if she believed endocrine disruption to be directly responsible for heart malformations in chick
embryos based on her findings that dioxin exposure resulted in adverse effects on fish and chick embryo
development. Dr. Walker responded that the mechanism of toxicity is still unclear and she therefore
could not assert whether endocrine disruption was responsible for the malformations. However, she
stated that many of the abnormal developmental changes in the embryos resulted from exposure to
endocrine disrupters coupled with endocrine hormones. For example, it has been observed that thyroid
hormones affected by dioxin and polychlorinated biphenyls had adverse effects on embryonic heart
development. She concluded that it was possible that endocrine disruption could have been responsible
for adverse development effects but stated that clear evidence of these effects as a result of exposure to
endocrine disrupters is lacking.
* * *
An unidentified audience member stated that apparently most of the compounds in the list developed by
IEPA are probably good intercalators in terms of fitting in between the chains of a deoxyribonucleic acid
molecule and disrupting the transcription process. He wondered if a tie could exist between a possible
screening method and this physical-chemical phenomenon, which might also yield information about the
mechanism of the endocrine disruption process. He suggested that the audience also consider the issue
of androgen disrupters.
Do current environmental regulations protect humans and wildlife from endocrine disruptive
effects?
Dr. Anthony Maciorowski of EPA's OPPTS commented that a complex set of issues is related to this
general question. Because endocrine disruption appears to be a sublethal type of problem, one issue is
how far traditional toxicology will be redefined based on endocrine disruption. The chemicals for which
most evidence of endocrine disruption exist have been problematic for a long time, and their toxicity is
still unknown. In addition, many chemicals do not bioaccumulate. It is still unknown whether endocrine
disrupting chemicals act together to cause the toxic effects and at what levels. However, it is believed
that science will ultimately find the answers to these issues. Other issues involve decision-making,
policy, socioeconomic, and political aspects that contribute to the complexity and controversy of
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regulatory issues related to endocrine disrupters. It is difficult to act from a regulatory basis to solve
these problems.
Dr. Henry Anderson of WBPH noted that some evidence exists of poisoning in humans at very high
levels of exposure to endocrine disrupters. However, no evidence indicates that the typical median
exposure level caused significant impacts on human health. A lot of information is available on some
chemicals (such as pesticides). However, endocrine disruptive effects on humans of another 70,000
chemicals, many of which are produced in large quantities and are widely used, are still unknown. A
testing and screening program is therefore important for determining regulations that will protect people
with high-end exposures.
* + *
An unidentified audience member stressed that although there is no clear evidence of chemicals having
endocrine disruptive effects on humans, EPA has enough clear evidence of such effects on wildlife to
establish regulations. In response, Mr. James Aidala of EPA's OPPTS stated that it would be more
difficult to make a statutory decision based on wildlife impact than it would be based on human impact.
However, EPA does have the authority to make such a decision. In essence, from a regulatory
standpoint, endocrine disrupter-related regulations depend not only on scientific findings, but also on
available regulatory tools. Mr. Aidala stated that an unfortunate common mind set is that "making no
decision is making a decision."
The unidentified audience member further asserted that making policy should not be the end of the
scientific investigation process. Historically, scientific investigation often stopped pursuant to the
promulgation of policy. The result of a policy decision should spark a dynamic process that continues
the search for better answers. Policies should constantly be reexamined and redefined. We must
acknowledge that we have imperfect systems and methodologies and, based on this, refinements should
constantly be made.
* * *
Audience member Ms. Ellen Sullivan of the Institute of Food Technologists announced that the EPA has
proposed policy to regulate plant pesticides that are based on inherited pest-resistant plant traits. A
workshop regarding the matter is scheduled for July 17 and 18,1997, in Washington, DC. The Institute
of Food Technologists is one of 11 scientific societies that belong to a consortium that has raised
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concerns about EPA's proposal. The consortium feels that the proposed policy will result in regulatory
barriers to research using recombinant DNA techniques. Ms. Sullivan explained that the scientists
involved are developing new varieties of wheat and other crops that are naturally resistant to pests and
that would ultimately reduce the use of chemical pesticides. She asked if the Endocrine Disrupter
Screening and Testing Advisory Committee (EDSTAC) was planning on or thinking about encouraging
EPA to include policies that promote research and development into alternatives to chemical pesticides
use. Mr. Aidala stated that although he did not think the proposed plant biotechnology policy was
considered by the EDSTAC, he agreed that the issue of regulation without restraint of innovation is key.
* * *
Audience member Mr. Charlie Cray of Greenpeace raised the problem of exposure from direct use of
products such as hospital intravenous bags that may leach phthalates directly into the body. He felt that
the lack of regulation by the Food and Drug Administration (FDA) and the Consumer Safety
Commission resulted from their unfamiliarity with endocrine disrupter issues and that this lack
contributed to the occurrence of these exposures. He asked for comments on how to involve other
agencies in this issue. Mr. Gary Timm of EPA's Office of Pollution Prevention and Toxics commented
that he attended a conference in June, 1997, where FDA representatives began discussing how the
endocrine disrupter issue would impact the FDA and its regulations.
* * *
Audience member Mr. Chris Merritt of the Zoology Department at the University of Wisconsin-Madison
asked Ms. Kris Carre of the Grand Portage Band of Chippewa whether she knew if the Native American
tribes' policy of prohibiting the use of pesticides on reservation land would be taken as standard policy for
all tribes. He observed that the Lacouderey tribe did not allow the use of pesticides on their reservation
land, although in the previous year they allowed small amounts of pesticides to be used on their cranberry
crop. Ms. Carre responded that she did not believe that such policy would be standard and that each tribe
would probably set its own policy on the issue.
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What steps need to be taken to ensure that endocrine disruptive endpoints are incorporated into
environmental assessments?
While there were no direct responses to this general question, several specific questions were raised by
audience members that related to the issue of incorporating endocrine disruptive endpoints into
environmental assessments.
Audience member Mr. Chris Bradley asked Dr. Tom Gardiner of CMA and Shell Chemical Company
whether bioassay methods are currently available to conclusively identify a chemical as an endocrine
disrupter. Dr. Gardiner responded that there are tests that evaluate certain parameters that are related to
the endocrine system, but since the criteria for endocrine disruption have not been established, further
research is needed. The chemical industry continues to follow all these studies as they emerge and is
exploring better ways to assess environmental effects of endocrine disrupters by sponsoring research.
Toxicity tests used for many years to evaluate a chemical's potential to cause adverse endocrine effects
include multigeneration reproductive toxicity studies, tests of potential teratogenicity or developmental
toxicity, and long-term repeat dosing studies that evaluate reproductive organs and reproductive
behavior.
Mr. Bradley further asked whether the panel could reach a consensus about endpoints such as
reproductive system and immune system effects.
Mr. Timm responded that the current guidelines for assessing developmental, reproductive, and fertility
effects are gross endpoints neither specific to the exposure mechanism nor to the endocrine system. The
guidelines recommended by EPA are being updated to include more sensitive parameters that would
include consideration of some endocrine effects as part of the overall larger environmental assessment.
Dr. Jacobson admitted that he is relatively new to the issue of the environmental assessment guidelines
but pointed out that some endpoints are more directly linked to endocrine function than others. For
example, sperm count is likely to be endocrine-mediated, but central nervous system deficiencies may or
may not be endocrine-mediated.
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Mr. Timm added that EDSTAC will concentrate on proposing assays that will measure the mechanisms
of endocrine action, including receptor binding, transcription mediation, mediated events, and higher tier
phenomenon. These assays may be the traditional two-generation studies with some endocrine disrupter
endpoints added. EDSTAC is examining the development of new, shorter term tests for endocrine
effects, which has been the subject of various workshops such as the Kansas City Workshop on Wildlife
and the Duke Workshop on Mammalian Tests.
In terms of screening methods and assessment of criteria for determining risk, Mr. Aidala stressed the
importance of EDSTAC's advice regarding endocrine disrupter screening criteria. He is confident that
EDSTAC will accomplish much to meet statutory deadlines. Mr. Timm added that although he expects
that EDSTAC will make some specific recommendations about screening assays, EDSTAC is taking
great care to provide EPA with guidance on how to proceed after EDSTAC ends it* work.
What specific roles and appropriate actions should scientists, governmental agencies, industries,
environmental groups, and the public take to address endocrine disrupter issues?
Mr. Peter Wise of Illinois EPA responded to this general question by noting that there are some EPA
regulatory tools such as the Safe Drinking Water Act and the Pesticides Law that can by used by
EDSTAC and other involved parties as guidelines to address the endocrine disrupter issue. A regulatory
agency should begin by ensuring that it fully understands the sources and migratory mechanisms of
endocrine disruptive chemicals and the magnitudes of their effects. The agency needs to publicize
findings based on citizen's right-to-know provisions. According to Mr. Wise, endless opportunities exist
for pollution prevention with regard to endocrine disrupters and it is the agency's responsibility to be
proactive in this regard.
Ms. Carre said that she could not really speak for all the tribes but stated that she agreed with Mr. Wise's
response.
Dr. Anderson stressed the need for better communication and more coordination of effort among all
parties involved. He also stressed the importance of public involvement.
All opinions expressed in (his report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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Mr. Aidala urged Dr. Jacobson to reconsider questions about "the definitive study" and to secure funds to
conduct this study. Mr. Aidala alluded to the possibility that some additional regulatory tool would be
needed to carry out EDSTAC's suggestions.
Dr. Gardiner noted that industries were already involved in a number of endocrine disrupter-related
research activities, including participation in cooperative research programs, which involved investment
of a lot of resources, practicing the principles of product stewardship, and fulfilling commitments under
the CMA's Responsible Care program. Dr. Gardiner said that industries are striving to be the best
responsible corporate citizens possible and will continue to work cooperatively with academia and
regulatory agencies.
Dr. Schettler suggested continually revisiting the issue of the burden of proof. Recurring issues related
to exposure to endocrine disrupters include (1) with whom the burden of proof should He, (2) what
justifications and regulations would clearly represent widespread exposure, and (3) what process would
be used to shift the burden of proof in cases of widespread exposure.
Dr. Maciorowski stated that he was fascinated by how this issue has broken the barrier between
disciplines. He noted the wide range of expertise present as opposed to 5 years ago, when disciplines
would not have been able to interact on any specific issue.
* * *
Audience member Mr. Tim Eder of the National Wildlife Federation asked Mr. Wise for comments on
Dr. Anderson's suggestion during his presentation about considering aggregate exposures of people from
a variety of sources. He also asked about EPA regulatory programs that provide for corrective and
preventive measures. Mr. Wise responded Illinois EPA was examining the suggestions made by Dr.
Anderson. Mr. Eder suggested that Illinois EPA examine a broad range of exposures instead of
exposures at an isolated facility. Mr. Aidala stated that EDSTAC is studying cumulative effects across
common exposure mechanisms. EDSTAC is required to complete its examination of endocrine disrupter
tolerances within a 10-year period; currently, 9,000 tolerances are being studied. Mr. Aidala anticipated
that the potentially most controversial examination will occur in the next 3 or 4 years.
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Audience member Mr. David Baltz of Commonwealth asked Mr. Aidala about the role of EDSTAC in
policy development, endocrine disruption, and in particular, the appropriateness of risk assessment.
Mr. Aidala said EDSTAC should not be strictly bureaucratic but should provide recommendations for the
screening and testing element of statutory requirements related to endocrine disrupters. The issue of risk
assessment is still being deliberated. Dr. Maciorowski added that the term "risk assessment" has been
interpreted differently by many. For example, scientists view risk assessment as a purely scientific exercise
that has no relation to decision-making. Another view of risk assessment is that it maintains a status quo
and draws economics into the decision-making process. He had never attended a risk assessment
conference where the definition of the term was not an issue. In Dr. Maciorowski's opinion, risk
assessment is a scientific exercise that should be considered during the decision-making process. He
suggested that when people begin to discuss risk assessment, it is best if everybody starts by defining risk
assessment as clearly as possible.
Other Endocrine Disrupter-Related Questions
Audience member Mr. Dave Thomas of the Illinois Waste Management Research Center asked for
comments on a possible strategy for using pollution prevention and other preventive techniques to reduce
the release of potential endocrine disruptive compounds. Mr. Wise agreed that this approach makes
sense and suggested that Mr. Thomas' agency and Illinois EPA talk with industries about pollution
prevention strategies. Pollution prevention would not only save industries money but might also reduce
their long-term liability.
Mr. Aidala added that EPA's pesticide program has involved agricultural groups in the issue of
pesticides use reduction, where "less use means less pollution." Regarding an earlier question about
biological pesticides, Mr. Aidala commented that half of the biological or nonconventional pesticides in
the market were approved by EPA within the last 3 years. This expediency indicates the increasing
importance of pollution prevention.
Dr. Schettler raised a concern regarding pollution prevention efforts involving medical waste
incinerators. He commented that while the draft EPA regulations for medical waste incinerators require
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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every medical center or every operator of an incinerator to develop a waste segregation plan,
implementation of the plan is not always enforced.
* * *
Audience member Mr. Paul Herche asked if anyone knew the current status of the endocrine disrupter
issue in the Baltic Republic, Eastern Europe, and former Soviet Union. Mr. Aidala commented that the
general issue of pesticides and endocrine disrupters was brought up recently in a meeting between EPA
and its Russian counterpart. The symposium took place about a month ago, and the debate is still in its
early stages. The Russian regulatory agencies are starting to address the issue. In particular, the Russians
are concerned about so-called "obsolete stocks" of pesticides; the owners of these large amounts of unused
pesticides are still unknown. EPA and its Russian counterpart are raising the issue to the pesticides
industry and requesting technical advice on the issue.
* * *
An unidentified audience member said that millions of years of evolution allowed mechanisms to deal with
naturally occurring phytoestrogens, and we have only had a relatively short period of time to begin to react
to organochlorines. He asked about the significance of a discussion of phytoestrogen to the endocrine
disruption issue. Dr. Gardiner acknowledged that differences between phytoestrogens and manmade
chemicals are not completely understood. Mr. Timm said that it would be useful to examine natural
evolutionary developments related to naturally occurring phytoestrogens. Dr. Anderson agreed that many
things can be learned from studying phytoestrogens; most of the medicines used today originate from
plants and natural conditions. Dr. Schettler recommended keeping in mind that phytoestrogens are
engaged in multiple mechanisms of action. He felt that it would be too simplistic to think that weighing
mechanisms based on toxic equivalence can result in the conclusion that phytoestrogenic effects outweigh
the synthetic effects of estrogens.
* * *
Audience member Mr. Mark Homer of the Chemical Industry Counsel of Illinois asked Mr. Wise why
Illinois EPA took only 2 to 3 weeks to compile its list of endocrine disruptive chemicals. He questioned
whether it was normal procedure for Illinois EPA to base policy on its director reading one book, Theo
Colborn's Our Stolen Future, which had mixed reviews at best. From a scientific perspective Mr. Homer
was dubious about Illinois EPA's development of a far-reaching policy document in 1 month without any
input from involved stakeholders. Mr. Wise acknowledged that the list was completed within a short
timeframe, but he stated that its compilation took longer than 1 month. During that time, Illinois EPA did
All opinions expressed in this report are those of the GLEDS speakers and do not necessarily reflect the opinions of EPA.
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engage in a dialogue with stakeholders, including the Chemical Industry Counsel. The list is flexible to the
extent that any information missed will be considered and discussed. Mr. Wise also stated that the
director's reading of the book was not the only input into her decision to direct Illinois EPA staff into
developing a strategy for endocrine disrupter policy. Mr. Wise stated that the director had years of
experience as the Deputy Assistant Administrator for U.S. EPA's Office of Solid Waste and Emergency
Response and that this issue had been a concern of hers for years. He added that Illinois EPA was pleased
to be able to invite Dr. Colbom to talk to Illinois EPA senior staff. Mr. Wise directed other questions
about the list of chemicals to Dr. Tom Hornshaw, Illinois EPA lexicologist, who played a key role in its
development.
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