STAR

REPORT

Vol. 2 Issue 1 Jan. 1998 A product of the National Center for Environmental Research and Quality Assurance

Because the endocrine system plays a critical role in growth, development and

reproduction, even small disturbances in endocrine function can have profound

and lasting effects.

THE ENDOCRINE DISRUPTOR PROBLEM

U.S. EPA Office of Research

and Development’s Science

To Achieve Results (STAR)

Research in Progress

In recent years there have been reports of

wildlife with reproductive disorders, deformities

and other developmental disorders caused by

environmental chemicals that affected the animals’ endocrine systems. The endocrine system

is a complex of organs, tissues and hormones in

humans and other living things. The system is

responsible for maintaining normal reproduction, development and other aspects of “homeostasis” (maintaining equilibrium of the

body’s chemistry and other condition factors).

Substances that interfere with these processes

are called "endocrine disruptors".

Endocrine disruption problems have been

identified primarily in wildlife and laboratory animals exposed to relatively high concentrations

of some chemicals, most of which are man-made

environmental contaminants, but some of which

occur naturally. These include organochlorine

pesticides and breakdown products, industrial

chemicals such as polychlorinated biphenyls

(PCBs) and organometals, waste chemicals such

as dioxins, a few plastics-related chemicals such

as bisphenol, nonaphenols and phthalates, synthetic hormones and natural plant-derived hormones. Whether effects are occuring in humans,

or whether wildlife frequently incur harm from

environmental concentrations of these substances

is not yet known, although conditions in some

locations indicate cause for concern. While

some studies find declines in

the quantity

and quality of

sperm production in humans

over the last four decades, other studies show

no decrease. Reported increased incidences of

human cancers in organs of the reproductive and

hormonal systems (breast, testes, prostate) have

led to speculation that this could be related to

environmental endocrine disruption. And correlational evidence from many areas indicates that

some populations of birds, fish, reptiles and mammals have been harmed by environmental contaminants affecting their endocrine systems.

Some endocrine disruptor research focuses on the ways these chemicals interfere

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General Information: The Environmental Protection Agency’s STAR Research Program

Grants described in this report are part of EPA’s Science to Achieve Results (STAR) program, a major research

initiative designed to improve the quality of scientific information available to support environmental decision

making. The STAR program is managed by EPA’s National Center for Environmental Research and Quality Assurance in the Office of Research and Development (ORD). The program funds approximately 200 new grants every

year, with the typical grant lasting three years. Funding levels vary from $50,000 to over $500,000 per year, with

FY 1997 funding level at about $80 million for grants to individual principal investigators or groups of investigators.

Additional STAR funds are provided for a number of Research Centers specializing in scientific areas of particular

concern to EPA, and for a fellowship program supporting graduate students conducting environmental research.

with reproduction, including the production of normal germ

cells (eggs and sperm). In addition, it is known that impacts of

endocrine disturbances in humans or animals can be particularly

damaging if exposure occurs during the highly sensitive prenatal and early postnatal periods. Small changes in endocrine

status during gestation can have delayed consequences that are

evident much later in adult life or in a subsequent generation.

Consequently, other studies are targeted towards understanding

effects of exposures during pregnancy.

THE NATIONAL ENDOCRINE

DISRUPTORS RESEARCH INITIATIVE

Because of the potential for serious consequences to

humans or wildlife, the United States has joined with other

nations to conduct laboratory and field research of many types

to investigate whether human health is being threatened by

endocrine disruptors in the environment, and whether environmental harm to wildlife is more widespread than had previously

been understood. A coordinated research effort is being led in

the U.S. by the National Science and Technology Council

(NSTC) Committee on Environment and Natural Resources.

The NSTC is a cabinet-level council chaired by the President

that serves as the principal means for coordinating science and

technology issues across the Federal government.

This report summarizes academic research into endocrine

disruptors supported by the U.S. Environmental Protection

Agency (EPA). This work is supported through EPA’s principal

external scientific research program, the Science to Achieve

Results (STAR) program. Other federal agencies also support

academic research on endocrine disruptors. In addition, EPA,

Many of the chemicals associated with endocrine disruption,

such as the pesticide DDT and

the industrial compounds PCBs,

have been banned for U.S.

manufacture and new use for

a number of years. However,

they remain in the U.S. environment because of residual contamination, or possibly because

of illegal use or disposal, or air,

water or human transport

across international boundaries. Another important question is the extent to which

chemicals currently in production and use may be acting as

endocrine disruptors of wildlife

or humans in the United States.

continued from page 1
3

the National Institute of Environmental Health Sciences (NIEHS),

the Department of the Interior and other agencies are conducting research addressing the national agenda in their own laboratories. Information on the overall body of research coordinated

through the NSTC Endocrine Disruptors Research Intiative

(EDRI) can be found at EDRI and EPA sites on the World Wide

Web, or by mail, at websites and addresses listed at the end of

this report.

Research Areas Particularly Supported by EPA

EPA supports endocrine disruptor research primarily in the following areas:

◊ Methods to monitor and characterize exposure of humans or wildlife to

endocrine disruptors;

◊ Models to estimate exposure to endocrine disruptors from different

sources and multiple pathways;

◊ Development of biomarkers of endocrine disruptor exposure and effects;

◊ Development and validation of test systems to screen for chemicals with

specific mechanisms of action that affect different endocrine pathways;

particularly methods that are applicable to many types of living organisms;

◊ Development of toxicological models describing how particular chemicals act to interfere with endocrine systems, based on species-specific

characteristics, with particular emphasis on models that can extrapolate

effects from one animal species to another, or to humans; and

◊ Methods and models that relate effects at subcellular levels to effects in

individual humans or animals, or in human or animal populations.

ENDOCRINE DISRUPTOR RESEARCH

SUPPORTED BY EPA’S “STAR” PROGRAM

Research Concerning Impacts on Humans

One of the few well-documented cases of widespread

human exposure to chemicals that may mimic the female

hormone estrogen, and thus may cause endocrine disruption,

was a 1973 incident in Michigan, in which cattle feed was

contaminated by polybrominated biphenyls (PBBs). After it was

determined that many people had been exposed to meat and

dairy products from contaminated cattle, the Michigan Department of Community Health began to gather public health data

on the exposed human population. This included data on

people’s blood levels of PBBs

three years after the exposure.

PBBs are of concern because

chemically similar compounds,

such as PCBs, are known to

impair female reproductive

development. A grant from

the EPA STAR program has

been awarded to Emory

University to assess whether

there have been any health

effects in Michigan in exposed

women or their daughters.

Data reviewed will include

reproductive defects or diseases, thyroid dysfunctions,

infertility or other endocrinerelated effects. The findings

concerning any effects in

humans, together with data

on known exposure to a

contaminant, will be invaluable in assessing potential

health risks from exposures in

other circumstances.

In an important federal/

academic research partnership, EPA is providing additional support to investigators

at the University of Missouri

who participate in the Food

and Drug Administration’s

program to develop an Estrogen Knowledge Base (EKB).

The EKB program incorporates

a wealth of data on observed

health impacts in humans and

animals with information on

theoretical impacts. Theoretical information is developed

through a statistical modeling
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EPA STAR RESEARCH: Building a Foundation for Sound Environmental Science

technique called the “Quantitative Structure Activity Relationships” approach. The

new EPA grant will allow

investigators to expand the

database to better establish

quantitative relationships

among effects in various

animals and in humans. This

will expand the number of

chemicals for which we can

obtain sound estimates of the

likelihood of adverse health

effects. This will help EPA and

the Food and Drug Administration more effectively target

their own screening and

testing programs, and those

they require chemical manufacturers to conduct.

Research into

Effects on Wildlife

The alligators of Florida’s

Lake Apopka have serious

reproductive failures that have

been attributed to endocrine

disruptors. Many of the

alligators are sterile, and

abnormalities such as

underedeveloped penises,

abnormal testes and abnormally high levels of estrogen

are common. Known endocrine disruptors found in the

lake at levels of concern

include the banned pesticides

dieldrin, toxaphene and DDT,

and DDT’s breakdown product DDE. The University of

Florida has received a STAR

grant to study the condition

of Lake Apopka alligators and

their eggs. Researchers will

investigate mechanisms by

which the chemicals may take

effect, including direct disruption of sex hormones, developmental effects before and

after hatching, and the additional possibility that harm to

immune systems increases

susceptibility to disease. In a

related study, Texas Tech

University will compare Lake

Apopka data to the conditions

of crocodiles in lagoons in

Belize, Central America,

some of which are contaminated with DDE. A full

analysis will be done of

chemicals present in each

lagoon, and of whether

endocrine disruption is

occuring in the crocodiles.

This study is important in

supporting risk assessment for

the Belize ecosystem, as well

as helping to establish the

relative severity of Lake

Apopka impacts.

Florida’s Mote Marine

Laboratory is leading a team

of investigators from Florida

and Oregon in a study of the

causes of infertility in

Bonnethead sharks in the

Tampa Bay area. Female

sharks are frequently retaining

unfertilized rather than fertilized eggs following mating,

either due to abnormal sperm

production in males, or damage to sperm stored in females. There may be other

impairments as well. Hypotheses include the possibility that

organochlorine pesticides are

the cause. A full range of

mechanisms will be assessed

by evaluating tissues, cells,

immune systems and hormone

levels.

A particularly severe case

of ecosystem contamination

was the manufacturer’s release
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of DDT in the 1960s and ‘70s

to the Southern California

sewer system, which discharges to the sea. The near

extinction of brown pelicans in

the area was widely reported,

and fish and other animals also

experienced reproductive

disorders. Since the release

ended and DDT was banned,

the pelican population has

recovered, but contamination

remains in marine sediments

and fish. The University of

Texas is conducting a laboratory study to try to elucidate

possible endocrine disruption

mechanisms in fish exposed to

endocrine disruptors that

mimic combinations of DDTs

and DDEs found in California

fish tissues.The study will

determine mechanisms of

impairment to gonads, other

organs and embryos. Fish

used will be a well-established

laboratory test species, a

croaker, not native to California. However, investigators feel

any findings will be sufficiently

generalizable that they would

be relevant to risk assessments

for the California fishes, as well

as to species in other locations.

Many birds, including all

songbirds, are “altricial”

species whose chicks are

incompletely developed at

hatching, requiring weeks for

full development of brains,

reproductive systems and

other organs. We know that

endocrine disruptors such as

DDT and DDE cause reproductive damage in some species

such as bald eagles, osprey

and pelicans. These chemicals are “xenoestrogens”,

estrogen-like chemicals

found in the environment.

They are also anti androgenic, interfering with

hormones involved in male

development and reproduction. The University of

California at Davis has received a STAR grant to study

effects of xenoestrogen exposure on hormonal processes

and development of altricial

chicks.

Research Using

Laboratory Animals

as Models of

Potential Risk to

Humans or Wildlife

The University of Missouri is studying effects of the

pesticide methoxychlor, an

environmental estrogen, on

mice whose characteristics

make them a good model to

assess how endocrine

disruptors act in other animals

and humans. Such mechanis-
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tic animal studies can help in

developing treatments or

interventions to protect

human health. The university

received a grant from NIEHS

for research with a mouse

strain lacking a functional

estrogen receptor gene.

Comparing effects of exposure

in these and normal mice will

reveal whether certain nonestrogen receptor proteins are

involved in responses to

methoxychlor. The University

has also received an EPA STAR

grant to clone the gene

believed to serve as the methoxychlor receptor. This cloned

gene is needed to fully investigate whether the methoxychlor receptor mechanism

operates in the way hypothesized by these investigators.

A STAR grant to study

PCB effects in rats has been

awarded to Mississippi State

University. Questions to be

asked include: 1) whether

organ dysfunctions are caused

by mechanisms involving

reduced blood or liver levels of

sex steroids; and 2) whether

such effects occur at exposures

that might occur in the environment. The dioxin TCDD, a

potent endocrine disruptor,

and other dioxins and

dibenzofurans, are waste

products of a number of

industrial processes, including

chlorine-using processes and

waste combustion. The

University of Kansas is studying ovarian disorders and

other effects caused by exposing rats to TCDD, other

dioxins, furans and PCBs.

Preliminary data indicate that

direct ovarian damage, rather

than indirect effects from

influences on organs such as

the pituitary, is one reason

endocrine disruptors impair

female reproduction. In a

study of another aspect of

female reproduction, the

enzymes responsible for

maintaining healthy endometrial condition, Vanderbilt

University is using cell cultures, corroborated by mouse

experiments, to evaluate the

hypothesis that TCDD may

interfere with normal regulation of these hormones.

To study impacts in a

mammal whose life span and

gestation are longer than in

rodents, and thus more like

humans, Colorado State

University is investigating

effects of DDT and the pesticide vinclozolin in male rabbits. Sub-cellular changes and

abnormalities in levels of

pituitary and sex hormones

will be among the mechanisms investigated. Another

study of male reproductive

system impacts uses dogfish

sharks. This species is of

ecological importance in its

own right, and is a model of

possible effects in other

animals or humans. Investigators at Boston University will

expose male sharks to a

number of xenoestrogens.

Objectives are to understand

It is known that impacts of endocrine disturbances

in humans or animals can be particularly damaging if

exposure occurs during the highly sensitive prenatal

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Find Out More About the STAR Research Program

For further information about the National Endocrine Disruptors

Research Initiative is available at the following Internet websites:

The Endocrine Disruptor Research Initiative website of the NSTC Committee

on the Environment and Natural Resources: www.epa.gov/endocrine/

edrifact.html

EPA's Endocrine Disruptor Screening and Testing Advisory Committee website:

www.epa.gov/opptintr/opptendo/index.htm

General information on EPA’s STAR research program is available from

the following sources:

ORD’s National Center for Environmental Research and Quality Assurance

(NCERQA): Internet website: http://www.epa.gov/ncerqa

Mailing Address:

Office of Research and Development

National Center for Environmental Research and Quality Assurance

Office of the Director (8701 R)

401 M Street, SW

Washington, DC 20460

well documented reproductive

cycle and physiology. Results

will be relevant to a range of

bird species.

Some endocrine

disruptors are natural substances. Duke University has

received a grant for work

using laboratory rats to assess

whether some phytoestrogens,

compounds that occur naturally in plants, could potentially have endocrine disrupting effects at concentrations

that could occur in human

diets. This study will look for

any impacts from soy

phytoestrogens on the rats’

brain or reproductive system

development, mating or

related behaviors such as

adolescent behavior patterns.

Developing Screening

Procedures for Endocrine Disruptors

In an effort to develop a

practical screening procedure

for endocrine disrupting

effects in aquatic vertebrates,

the University of Alabama is

leading a project to refine a

mosquitofish test system. A

range of chemicals will be

tested and readily observed

effects on developmental

abnormalities and blood

chemistry will be defined as

screening procedures. North

Carolina State University is

working under a STAR grant to

develop routine testing procedures for potential endocrine

disruptors, using water fleas as

a model for other aquatic

invertebrates.

genetic or cellular mechanisms

by which the chemicals act; to

seek molecular markers that

indicate that an animal has

been exposed; and to document health impacts such as

sterility or testicular cancer.

Duke University is using

zebrafish embryos for a related

study. Advanced gene scanning techniques will characterize the structure and location

of estrogen receptor RNA, to

increase understanding of how

genes act in response to

environmental estrogens.

The University of California at Davis is assessing

effects of two chemicals, one a

xenoestrogen, and one an

anti-androgen, on males and

females of a fish called

medaka. Potential impacts

include gonad and liver

damage, disturbed mating

behavior, abnormal sperm or

eggs, and low survival of the

young.

One animal study uses a

bird as the model species. The

University of Maryland will

work with Japanese quail to

assess when in their life cycle

susceptibility to endocrine

disruption is the greatest.

Impacts on gonads and other

glands, including the hypothalamus and pituitary, will be

assessed. This species is used

because it is a good laboratory

subject with an exceptionally
 STAR Research Projects Described in this Report

United States

Environmental Protection Agency

Mail Code 8701R

Washington, D.C. 20460

Offical Business

Penalty for Private Use

$300

EPA/600/F-98/003

1996 STAR Awards

Duke Medical Center, Examination of the Estrogen Response

Pathways in a New Vertebrate

Model

U. California-Davis, Critical

Stages in Avian Development:

Estrogenic Hazards to Altricial

and Precocial Birds

Mississippi State University,

Biochemical and Reproductive

Effects of Gestational/Lactational

Exposure to PCB's with Respect

to Endogenous Sex Steroids and

the Proestrogen, Methoxychlor

U. California-Davis, An in Vivo

Model for Detection of Reproductive Effects of Endocrine

Disruptors

Duke University, Developmental

Effects of Dietary Soy

Phytoestrogens

Emory University, The Michigan

PBB Cohort 20 Years Later:

Endocrine Disruption?

Boston University, Xenoestrogen

Effects During Premeiotic Stages

of Spermatogenesis: Development of an in Vitro Test System

and Molecular Markers of Action

U. Missouri-Columbia,

Methoxychlor and Environmental Estrogen Receptors in ERMinus Mice

1997 STAR Awards

Colorado State University,

Anti-androgenic Pesticides:

Impact on Male Reproduction

Duke University, Developmental Effects of Dietary Soy

Phytoestrogens

Mote Marine Laboratory, The

Mechanisms and Effects of

Endocrine Disruption on

Infertility in the Bonnethead

Shark on Florida's Gulf Coast

North Carolina State University,

Metabolic Androgenization of

Invertebrates by EndocrineDisrupting Chemicals

Texas Tech University,

Exposure and Response of

Morelet's Crocodile (Crocodylus

moreletii) Populations to

Endocrine Disrupting Compounds in Belize, Central

America

U. Alabama - Birmingham, A

Short-Term in Vivo Screening

System for Endocrine Disruptors

Utilizing Mosquito-Fishes

(Gambusia affinis or G.

holbrooki)

U. California - Davis, Environmental Endocrine Disruption in

Avian Wildlife

University of Florida, Endocrine

Disruptors and Host Resistance

in Lake Apopka Alligators

U. Kansas Medical Center,

Endocrine Disruptors: Effects on

the Thyroid

U. Kansas Medical Center,

Models Assessing Direct Effects

of Dioxins and Related Compounds on the Ovary

U.Maryland - College Park,

Critical Stages in Sublethal

Exposure to EDCs in a Quail

Model System

U. Missouri - St. Louis ,

Computational Tools for the

Prediction and Classification of

Estrogenic Compounds

U. Texas - Austin, Reproductive

and Endocrine Effects of o,p'-

DDT, an Environmental

Estrogen, and p,p'-DDE, an

Antiandrogen, in Male and

Female Atlantic Croaker during

Critical Periods of their Reproductive Life History Cycles

Vanderbilt University, Dioxin

and Steroid Regulation in an

Endometriosis Model