Environmental Exposure to Endocrine Disruptors: What Are the Human Health Risks?

Order Code RL31267

CRS Report for Congress

Received through the CRS Web

Environmental Exposure to Endocrine Disruptors:

What Are the Human Health Risks?

February 4, 2002

Linda-Jo Schierow

Specialist in Environmental Policy

and

Eugene H. Buck

Specialist in Natural Resources Policy

Resources, Science, and Industry Division

Congressional Research Service ˜ The Library of Congress

Environmental Exposure to Endocrine Disruptors:

What Are the Human Health Risks?

Summary

Exposure to certain environmental pollutants may disrupt the human endocrine

system causing adverse effects on development, growth, reproduction, metabolism,

or other hormone-dependent processes, according to some scientists. Although there

is no conclusive evidence to support this hypothesis, evidence is mounting, and

research interest is growing. Chemicals of potential concern include certain

pesticides (e.g., DDT or lindane), medicinal drugs (e.g., synthetic hormones),

naturally occurring plant hormones (e.g., in soy beans), and industrial compounds

(e.g., polychlorinated biphenyls (PCBs)), some dioxins, lead, mercury, arsenic, and

organotins. Potential sources of such chemicals include wastewater discharges,

industrial releases, and consumer products. Research is being conducted to identify

the range of potential health effects and vulnerable animal species (perhaps including

humans), sensitive periods of development, and chemicals with endocrine-disrupting

potential.

Proponents of the hypothesis that environmental exposure to endocrine

disruptors may be affecting human health point to apparent increases in U.S. rates of

certain cancers, reported declines in sperm counts in various nations, and some

scientific evidence of increasing rates of some birth defects, thyroid disorders,

attention deficit disorder, premature births, and premature puberty. There appears to

be a worldwide increase in cases of testicular cancer, for which there is no clear

cause. The reason for reported increases in rates of other cancers has not been

determined: such increases may reflect improvements in diagnostic tools or reporting

rather than increases in disease. Research on trends in male fertility has produced

inconsistent results. In some nations, research found a decline in sperm quality over

the last few decades and increasing rates of deformities of male reproductive organs

until 1985 after which rates apparently stabilized. Any of these effects could be

linked to hormone disruption, because they are hormone mediated, but such links

have not been established. Although high doses of some chemicals have been shown

to affect hormonal processes in people, sometimes beneficially and sometimes

adversely, many scientists believe that environmental levels of potential disruptors

are too low to influence human endocrine systems. The effect of long-term exposure

to low levels of multiple endocrine disruptors is a key question for scientific research.

Research interest is spurred by evidence that the endocrine systems of some

wildlife, especially fish, are being affected by environmental pollutants, the

ubiquitous presence of some potential hormone disruptors in the environment at low

levels, lack of scientific understanding of endocrine chemistry, and lack of exposure

data.

Congress has mandated chemical screening to assess the potential of pesticides

and drinking water contaminants to affect hormone systems. As evidence

accumulates, legislators may decide to increase or decrease funding for the endocrine

disruptor screening program, or to expand its requirements to include additional

chemicals or hormone functions. This report provides references to additional

sources of information. It will be updated as the issue warrants.

Contents

Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Endocrine Disruptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Congressional and Administrative Attention . . . . . . . . . . . . . . . . . . . . . 2

Current Research Initiatives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Scientific Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Human Health Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Human Evidence of Potential Chemical Toxicity to

Endocrine Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Animal Evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Environmental Exposure to Potential Endocrine Disruptors . . . . . . . . 10

Policy Issues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Pace of FQPA Implementation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Welfare of Test Animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Legislation in the 107th Congress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Additional Resources . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Environmental Exposure to Endocrine

Disruptors: What Are the Human Health

Risks?

Background

Endocrine Disruptors. Endocrine disruptors”1 are chemical compounds in

drugs, food, consumer products, or the ambient environment that can interfere with

internal biological processes of animals that normally are regulated by their

hormones. Development, growth, reproduction, and metabolism, for example, are

hormone-dependent processes that might be affected by exposure to endocrine

disruptors.

Some endocrine disruptors exist naturally, for example, the

phytoestrogens in some plants. Others are the products of human industry – e.g.,

some pesticides and pharmaceuticals.

Some endocrine disruptors are similar in form and action to natural hormones;

these are called “hormone mimics.” The terms “environmental estrogen” and

“xenoestrogen” are narrower, referring only to those chemicals that mimic the action

of the female sex hormone estrogen. Other endocrine disruptors do not mimic, but

otherwise modify the synthesis, secretion, transport, binding, action, or elimination

of natural hormones. Some scientists prefer the more neutral but just as inclusive

term “endocrine modulators” over the better known term “endocrine disruptors.”

Exposure to high levels of manufactured endocrine disruptors in the

environment has been shown to harm insects, some vertebrate wildlife, and aquatic

life by interfering with the action of reproductive and other hormones. Selected,

peer-reviewed studies are described and references are cited below.2 There also is

scientific evidence that relatively low environmental levels of endocrine disruptors

may be harmful, particularly when they bioaccumulate, exposing animals higher on

the food chain to greater chemical concentrations. Some scientists hypothesize that

1

The endocrine system includes the glands (e.g., thyroid, pituitary gland, pancreas, ovaries,

or testes) and their secretions (i.e., hormones), that are released directly into the body’s

circulatory system (rather than through ducts). The endocrine system controls blood sugar

levels, blood pressure, metabolic rates, growth, development, aging, and reproduction.

2

The pesticide industry has studied and exploited chemicals that can disrupt the endocrine

systems of insects. For example, synthetic juvenile hormone analogs control insect pests

by interfering with the natural juvenile hormone, which suppresses metamorphic change

during molting and induces production of egg yolk protein during ovarian development. The

pesticides can act to enhance or obstruct these endocrine effects. Examples include

phenoxyphenoxy carbamate and methoprene. However, research on insecticides is not

described below, because it appears to be less relevant than research on vertebrates to the

question of human health effects from environmental exposures.

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existing environmental levels of endocrine disruptors also may be harming human

health.

Congressional and Administrative Attention. The U.S. Congress began

investigating the effects of endocrine disruptors in the environment at a hearing in

1993.3 Among those testifying at that hearing were several researchers who later

published their findings in the book, Our Stolen Future.4 It summarized studies by

wildlife biologists, epidemiologists, and other scientists, and hypothesized that

endocrine disruption by environmental pollutants might have caused observed

increases in deformities and population declines of amphibians, evidence of declining

human fertility, and alleged increases in human rates of breast, testicular, and prostate

cancers, as well as endometriosis.

In the next few years, research produced evidence both for and against the

hypothesis that environmental levels of endocrine disruptors are harming human and

ecological health.5 Congress continued to study the issue, and in 1996 concluded

that there was a need to screen pesticides and drinking water contaminants for

potential to disrupt endocrine systems. A screening program was established in the

Food Quality Protection Act (Public Law 104-170) and the 1996 Amendments to the

Safe Drinking Water Act (Public Law 104-182).

The Food Quality Protection Act (FQPA) Section 408(p)6 directs EPA, not later

than 3 years after August 3, 1996, to require validated tests to determine the potential

of pesticides to produce effects in humans similar to those produced by naturally

occurring estrogens or, at the discretion of the Administrator, other endocrine effects

in humans. The mandate covers all registered pesticide ingredients (both active and

inert), as well as other substances identified by the Administrator which might have

3

U.S. House of Representatives, Committee on Energy and Commerce, Subcommittee on

Health and the Environment. Health Effects of Estrogenic Pesticides. 103rd Cong., 1st Sess.,

Oct. 21, 1993. Washington, DC: U.S. Govt. Print. Off. (1994) 185 p.

4

Colburn, Theo, Dianne Dumanoski, and John Peterson Myers. Our Stolen Future: Are We

Threatening Our Fertility, Intelligence, and Survival? A Scientific Detective Story. New

York: Penguin. (1996) 316 p.

5

Initially, one of the most influential studies (“Synergistic activation of estrogen receptor

with combinations of environmental chemicals.” Arnold, S.F., D.M. Klotz, B.M. Collins,

et al. (1996) Science, v. 272, p. 1489-1492.) was later retracted, when the authors were

unable to replicate their results (McLachlan, J.A. (1997) “Synergistic effect of

environmental estrogens: report withdrawn.” Science, v. 277, p. 459-463.) The original

report indicated that effects of combined exposure to two different pesticides could be

greater than effects from an equivalent exposure to either of the individual pesticides alone.

However, synergy (as well as antagonism, in which effects are less than expected from

exposure to a combination of chemicals) has been demonstrated for other health effects of

exposure to PCBs and several pesticide formulations (Hook, G.E., and G.W. Lucier. (1997)

“Editorial: Synergy, antagonism, and scientific processes.” Environmental Health

Perspectives, v. 105, p. 784.)

6

See §405 of P.L. 104-170, amending §408 of the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 346a).

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a cumulative effect together with pesticides and to which a substantial population

may be exposed.7

The 1996 Safe Drinking Water Act Amendments (P.L. 104-182) authorize

screening for endocrine disruption potential of contaminants found in sources of

drinking water.8 Actual screening of chemicals for toxic effects will be conducted

by manufacturers of suspect chemicals. For substances found to have endocrine

effects in humans, the laws authorize EPA to take appropriate action to protect public

health under existing statutory authority.9

To help implement the new provisions, EPA organized the Endocrine Disruptors

Screening and Testing Advisory Committee (EDSTAC). This committee of

scientists (some independent and others representing various chemical manufacturers

and distributors, chemical users, public health advocates, environmentalists, and

other stakeholder groups), assisted EPA in designing the chemical screening and

testing program. The committee’s recommendations, released October 5, 1998, were

reviewed by a special peer review panel consisting of members of the Federal

Insecticide, Fungicide, and Rodenticide Act (FIFRA) Science Advisory Panel and the

independent Science Advisory Board. EPA relied heavily on EDSTAC

recommendations in developing the Endocrine Disruptor Screening Program.10

Although the program was designed and “established” in 1998, it is not yet operating.

EPA is still developing the methods that will be used to prioritize chemicals for

screening and is attempting to validate the methods that will be used to test highpriority chemicals. In addition, a new Endocrine Disruptor Method Validation

Subcommittee has been established to advise EPA on how it should evaluate the

screens and tests developed. The Subcommittee met for the first time in December

2001. The program is not yet operational.

Current Research Initiatives. The hypothesis that existing environmental

levels of endocrine disruptors may be harming human health is hotly debated. At

present, there is no conclusive evidence to support this hypothesis, but research

interest is growing. Scientists are working to better define the range of potential

health effects and to identify vulnerable animal species and chemicals with

endocrine-disrupting potential. Attention has focused on certain chemicals that are

ubiquitous at low levels in the air, surface water, and food, and at higher levels in

many consumer products, including medical devices and baby toys. Chemicals of

potential concern include a number of pesticides (e.g., DDT, lindane, and

vinclozolin), medicinal drugs (especially synthetic hormones), and certain industrial

7

The EPA Office of Science Coordination and Policy website describes the statutory

authority for the Endocrine Disruptor Screening Program.

[http://www.epa.gov/scipoly/oscpendo/]

8

See §136 of P.L. 104-182, adding a new §1457 to the Safe Drinking Water Act (42 U.S.C.

300j-17).

9

Federal Food, Drug, and Cosmetic Act, as amended; 21 U.S.C. 346a(p)(6).

10

U.S. Environmental Protection Agency. “Environmental Protection Agency Endocrine

Disruptor Screening Program, Report to Congress.” August 2000. p. 5.

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compounds (e.g., phthalates, bisphenol A, polychlorinated biphenyls (PCBs), some

dibenzodioxins, lead, methyl mercury, arsenic, and organotins).

Many U.S. and other governmental and intergovernmental organizations are

sponsoring and coordinating research efforts to clarify the scope and severity of

potential endocrine disruptor effects. In the United States, work within federal public

health and environmental agencies is being coordinated by the Endocrine Disruptor

Working Group, which was established by the National Science and Technology

Council’s Committee on the Environment and Natural Resources.11 Internationally,

the Organization for Economic Cooperation and Development (OECD) is developing

harmonized international test guidelines to detect endocrine disruptors.

Scientific Evidence

Human Health Trends. Proponents of the hypothesis that environmental

exposure to endocrine disruptors may be affecting human health have pointed to

apparent increases in U.S. rates of certain cancers, reported declines in sperm counts

in various nations, and some scientific evidence of increasing rates of some birth

defects, thyroid disorders, attention deficit disorder, premature births, and premature

puberty. In fact, there appears to be a worldwide increase in the incidence of

testicular cancer, for which there is no clear cause.12 Reported rates of other human

cancers also have increased, but these increases may reflect improvements in

diagnostic tools or reporting rates rather than increased rates of disease.

Research in some nations has found a decline in semen quality13 over the last

few decades and increasing rates of deformities of male reproductive organs (i.e.,

undescended testes and misplaced urethra opening) before 1985, after which rates

stabilized.14 Some researchers also have reported increased rates of thyroid

dysfunction, attention deficit disorder, and premature births, as well as a trend toward

onset of puberty at an earlier age. Any of these effects could be linked to hormone

disruption because they are hormone mediated, but such links have not been

established.

Human Evidence of Potential Chemical Toxicity to Endocrine

Systems. The hypothesized link between human health problems and the

disruption of hormone activity as a result of exposure to chemicals in the

environment is biologically plausible; some chemicals have been shown to affect

11

For more information about this group, see EPA’s website on the Endocrine Disruptors

Research Initiative.

[http://www.epa.gov/endocrine/]

12

Safe, S.H. (2000) Endocrine disruptors and human health: Is there a problem? An update.

Environmental Health Perspectives, v. 108, n. 6, p. 487-493.

13

Semen quality is based on ejaculate volume, sperm concentration, sperm motility, and

sperm morphology.

14

Safe, ibid.

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hormonal processes in people and wildlife,15 especially if the chemical is directly

administered or otherwise received in a concentrated dose during fetal or infant

development. For example, it is well known that daughters born to women who took

the drug diethylstilbestrol (DES), a synthetic estrogen, early in their pregnancies

between the mid 1940s and 1971, now have a greatly increased risk of vaginal

cancer.16 In addition, studies have documented a higher than normal incidence of

genital tract abnormalities in newborns following in utero exposure to DES.17 The

role of male and female sex hormones in the growth of prostate and breast cancer is

well established scientifically.18

Although the production and use of PCBs has been strictly regulated since 1976,

PCBs are ubiquitous in the air, water, soil, and many animal tissues due to their

environmental persistence and previously widespread use in electrical transformers,

plastics, and other industrial applications. Some PCBs are known to be estrogenic;

others may affect thyroid function.19 There is evidence that fetal exposure to PCBs

may affect cognitive development, although it is not known whether this toxicity is

related to hormone disruption.20 In addition, some studies have found an association

15

Generally, scientists have studied effects in vertebrates, especially amphibians, freshwater

fish, and mammals.

16

Herbst, A., H. Ulfelder, and D. Poskanzer. “Adenocarcinoma of the vagina: Association

of maternal stilbestrol therapy with tumor appearance in young women,” New England

Journal of Medicine, v. 284, (1971) p. 878-881.

17

Mittendorf, R. Teratogen update: Carcinogenesis and teratogenesis associated with

exposure to diethylstilbestrol (DES) in utero. Teratology, v. 51, n. 6, (1995) p. 435-445.

18

See the National Cancer Institute website at [http://www.nci.nih.gov]

19

Longnecker, M.P., W.J. Rogan, and G. Lucier. The human health effects of DDT

(dichlorodiphenyltrichloroethane) and PCBs (polychlorinated biphenyls) and an overview

of organochlorines in public health. Annual Review of Public Health, v. 18, p. 211-244.

(1997)

Brouwer, A., U.G. Ahlborg, F.X. van Leeuwen, and M.M. Feeley. Report of the WHO

working group on the assessment of health risks for human infants from exposure to PCDDs,

PCDFs and PCBs. Chemosphere, v. 37, n. 9-12, p. 1627-1643. (1998)

20

Stewart, P., J. Reihman, E. Lonky, T. Darvill, and J. Pagano. (2000) Prenatal PCB

exposure and neonatal behavioral assessment scale (NBAS) performance. Neurotoxicology

and Teratology, v.22, n. 1, p. 21-29.

Jacobson, J.L., S.W. Jacobson, and H.E. Humphrey. (1990) Effects of exposure to PCBs

and related compounds on growth and activity in children. Neurotoxicology and Teratology,

v. 12, n. 4, p. 319-26.

Patandin, S., C.I. Lanting, P.G. Mulder, E.R. Boersma, P.J. Sauer, and N. WeisglasKuperus. (1999) Effects of environmental exposure to polychlorinated biphenyls and

dioxins on cognitive abilities in Dutch children at 42 months of age [see comments]. Journal

of Pediatrics, v. 134, n. 1, p.33-41.

Jacobson, J.L., and S.W. Jacobson. (1996) Intellectual impairment in children exposed

to polychlorinated biphenyls in utero [see comments]. New England Journal of Medicine,

v. 335, n. 11, p. 783-789.

Jacobson, J.L., and S.W. Jacobson. (1996) Dose-response in perinatal exposure to

polychlorinated biphenyls (PCBs): the Michigan and North Carolina cohort studies.

(continued...)

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between human PCB exposure and low sperm counts, undescended testes, altered

semen quality, lower age of onset of puberty, and shorter height at maturity.

Such developmental, reproductive, and carcinogenic effects for which increased

incidences have been reported in humans are similar to effects on reproductive

structure and function that have been observed in wildlife and fish exposed to

endocrine disruptors.21

On the other hand, some chemicals with effects on endocrine systems have

therapeutic value. For example, sex hormones are used to treat some forms of

cancer. There also is evidence that some plant-derived endocrine disruptors22 (e.g.,

phytoestrogens prevalent in soy beans) may protect against disease.23 Some scientists

argue that such evidence undermines the hypothesis that endocrine disruptors in the

environment are a threat to human health. Other scientists believe the evidence for

therapeutic effects only underscores the potency of hormonally active chemicals.

Animal Evidence. The most compelling evidence for endocrine disruption

due to environmental exposure to contaminants has been obtained in aquatic systems,

with most of the published literature based on studies of fish.24 In particular,

feminization of males due to endocrine disrupting chemicals is an increasing concern.

Feminization has also been reported in other vertebrate species including birds

(especially fish-eating species, such as gulls, terns, ospreys, eagles, and pelicans) and

Florida panthers.25 In addition, there is evidence of harmful effects of endocrine

disrupting chemicals on alligators26 and mink27 as well as circumstantial evidence

20

(...continued)

Toxicology and Industrial Health, v. 12, n. 3-4, p. 435-445.

21

U.S. Environmental Protection Agency (1997). Special Report on Environmental

Endocrine Disruption: An Effects Assessment and Analysis, EPA/630/R-96/012. p. 5.

22

Perhaps in this case, the term endocrine modulator is more appropriate.

23

Vincent, A. and L.A. Fitzpatrick. (2000) Soy isoflavones: are they useful in menopause?

Mayo Clinic Proceedings, v. 75, n. 11, p. 1174-1184.

Stephens, F.O. (1997) Breast cancer: aetiological factors and associations (a possible

protective role of phytoestrogens). The Australian and New Zealand Journal of Surgery, v.

67, n. 11, p. 755-760.

24

Jobling, Susan, et al. (1998) “Widespread sexual disruption in wild fish,” Environmental

Science and Technology, v. 32, p. 2498-2506.

25

Facemire, Charles F., Timothy S. Gross, and Louis J. Guillette, Jr., (1995) “Reproductive

impairment in the Florida panther: nature or nurture?” Environmental Health Perspectives,

v. 103, Supp. 4, p. 79-86.

26

Guillette, Louis J., et al. (1995) “Gonadal steroidogenesis in vitro from juvenile alligators

obtained from contaminated or control lakes,” Environmental Health Perspectives, v. 103,

no. 4, p. 31-36.

27

Golub, Mari S., James M. Donald, and Joe A. Reyes. (1991) “Reproductive toxicity of

commercial PCB mixtures: LOAELs and NOAELs from animal studies,” Environmental

Health Perspectives, v. 94, p. 245-253.

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for marine mammals.28 For example, the accumulation of persistent chlorinated

organic chemicals, such as PCBs, in seals and dolphins has been well documented.29

In addition, laboratory studies of a beluga whale protein that is key in many

endocrine disrupting effects (the aryl hydrocarbon receptor) reveal that it binds

strongly to dioxins and PCBs. This may increase the likelihood that toxic responses

can be turned on at physiologically relevant concentrations of contaminants.30

However, as is the case with humans, direct toxicity testing in marine mammals is

precluded by logistical, legal, and ethical constraints, which make cause-and-effect

relationships difficult (or impossible) to show experimentally.

Feminization of male fish collected from British rivers alerted the scientific

community to the potential hazard of chemicals (in those cases, xenoestrogens) in the

environment.31 Feminization of males was confirmed by the presence of eggs in the

testes and the female-specific yolk protein vitellogenin (a component of yolk for

eggs, usually made only by females) in the blood of male fish. While manufacture

of vitellogenin by males is clearly abnormal, it is not clear whether these males are

impaired in their normal male reproductive function. More recently, marine fish

populations in the English Channel and in Tokyo Bay have also shown evidence of

feminization. Less information is available for the United States. However, there is

a report of complete sex reversal of male salmon in Washington.32 Androgenic

substances (i.e., substances with an effect similar to that of male sex hormones) have

also been detected in environmental samples, especially in pulp mill effluents.

Bony fish33 appear to be useful as sentinels for the presence and possible hazard

of endocrine disrupting chemicals in the aquatic environment, since these fish are

currently the only vertebrates for which the connection between environmental

28

Cooper, Ralph L., and Robert J. Kavlock. (1997) “Commentary: endocrine disruptors and

reproductive development: a weight-of-evidence overview,” Journal of. Endocrinology, v.

152, n. 2, p. 159-166.

Ross, Peter S. (2000) “Marine mammals as sentinels in ecological risk assessment,”

Human and Ecological Risk Assessment, v. 6, p. 29-46.

29

Watanabe, M., K. Kannan, A. Takahashi, et al. (2000) “Polychlorinated biphenyls,

organochlorine pesticides, tris(4-chlorophenyl)methane, and tris(4-chlorophenyl)methanol

in livers of small cetaceans stranded along Florida coastal waters, USA,” Environmental

Toxicology and Chemistry, v. 19, n. 6, p. 1566-1574.

Reddy, M.L., J.S. Reif, A. Bachand, et al. (2001) “Opportunities for using Navy marine

mammals to explore associations between organochlorine contaminants and unfavorable

effects on reproduction,” Science of the Total Environment, v. 274, n. 1-3, p. 171-182.

30

Jensen, Brenda A., and Mark E. Hahn. (2001) “cDNA cloning and characterization of a

high affinity aryl hydrocarbon receptor in a cetacean, the beluga, Delphinapterus leucas,”

Toxicological Sciences, v. 64, p. 41-56.

31

Jobling, Susan, et al. (1998) “Widespread sexual disruption in wild fish,” Environmental

Science and Technology, v. 32, p. 2498-2506.

32

James J. Nagler, James J., et al. (2001) “High incidence of a male-specific genetic marker

in phenotypic female Chinook salmon from the Columbia River,” Environmental Health

Perspectives, v. 109, n. 1, p. 67-69.

33

As opposed to cartilaginous fish, such as sharks and rays.

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contamination and adverse effects on organism health has been established in both

field34 and laboratory35 studies. The aquatic environment is especially well suited for

these studies as it is the ultimate sink for many natural and anthropogenic compounds

released into the environment. Fish, in turn, are well suited for such research as our

understanding of their endocrinology is far superior to that of aquatic invertebrates.

Both androgenic36 and estrogenic37 effects have been observed and published, with

34

Folmar, Leroy C., et al. (2001) “Vitellogenin-induced pathology in male summer flounder

(Paralichthys dentatus),” Aquatic Toxicology, v. 51, p. 431-441.

Folmar, Leroy C., et al. (1996) “Vitellogenin introduction and reduced serum testosterone

concentrations in feral male carp (Cyprinus carpio) captured near a major metropolitan

sewage treatment plant,” Environmental Health Perspectives, v. 104, p. 1096-1100.

Harries, J.E., et al. (1997) “Estrogenic activity in five United Kingdom rivers detected by

measurement of vitellogensis in caged male trout,” Environmental Toxicology and

Chemistry, v. 16, p. 534-542.

Jobling, Susan, et al. (1998) “Widespread sexual disruption in wild fish,” Environmental

Science and Technology, v. 32, p. 2498-2506.

35

Panter, Grace H., R. S. Thompson, and John P. Sumpter. (1998) “Adverse reproductive

effects in male fathead minnows (Pimephales promelas) exposed to environmentally

relevant concentrations of the natural oestrogens, oestradiol and oestrone,” Aquatic

Toxicology, v. 42, n. 4, p. 243-253.

36

Galloway, Brendan, et al. (2000) “Examination of the cumulative responses of slimy

sculpin (Cottus cognatus) and white sucker (Catostomus commersoni) collected on the Saint

John River downstream of a pulp mill, paper mill, and sewage discharges,” Society of

Environmental Toxicology and Chemistry (SETAC), p. 255, SETAC: Nashville, TN.

Joakim Larsson, D.G., et al. (1999) “More male embryos near a pulp mill,” In 6th

International Symposium on the Reproductive Physiology of Fish, (ed. B. Norberg, et al.).

Bergen, Norway.

Munkittrick, Kelly R. et al. (1999) “Secondary sex characteristics and gonadal size in

white sucker (Catostomus commersoni) during modernization at a pulp mill,” In 6th

International Symposium on the Reproductive Physiology of Fish, (ed. B. Norberg, et al.),

Bergen, Norway.

37

Bayley, Mark, Jacob R. Nielsen, and Erik Baatrup. (1999) “Guppy sexual behavior as an

effect biomarker of estrogen mimics,” Ecotoxicology and Environmental Safety, v. 43, p.

68-73.

Bjerselius, Rickard, et al. (1999) “Estrogen in food or water severely effect the male

goldfish (Carassius auratus) sexual behavior,” In 6th International Symposium on the

Reproductive Physiology of Fish, (ed. B. Norberg, et al.), Bergen, Norway.

Haek, R.A., et al. (1997) “During development, 17a-estradiol is a potent estrogen and

carcinogen,” Environmental Health Perspectives, v. 105, p. 577-581.

Jobling, Susan, et al. (1996) “Inhibition of testicular growth in rainbow trout

(Oncorhynchus mykiss) exposed to estrogenic alkylphenolic chemicals,” Environmental

Toxicology and Chemistry, v. 15, p. 194-202.

Kime, David E., and Jon P. Nash,(2000) “Estrogenic endocrine disruptors act on many

components of reproduction, over multiple generations to cause reproductive failure in

zebrafish (Dania rerio),” In 4th International Symposium on Fish Endocrinology, p. Poster,

Seattle, WA.

Kramer, V.J., et al. (1998) “Reproductive impairment and induction of alkaline-labile

phosphate, a biomarker of estrogen exposure, in fathead minnows (Pimephales promelas)

exposed to waterborne 17b-estradiol,” Aquatic Toxicology, v. 40, p. 335-360.

(continued...)

CRS-9

estrogenic activity appearing to be more ubiquitous and hence better studied. It has

become almost routine in laboratories around the world to isolate xenoestrogens from

the aquatic environment, expose fish to the isolated compounds in the laboratory, and

achieve similar endocrine modulation (i.e., vitellogenin induction) as was observed

at the corresponding field site. Other endocrine modulating effects (e.g., hormone

levels, behavior, reproductive success, intersex) are much less successfully

reproduced in the laboratory. Currently laboratories in the United States, Europe, and

Japan are working to develop a biomarker38 to assess adverse health effects due to

exposure to endocrine disrupting chemicals or xenoestrogens, in particular.

The endocrinology of most invertebrates is less well understood. Reproductive

impairment has been noted in some species of snails exposed to very low amounts

of tributyltin (TBT), a constituent in anti-fouling paints used on boats. This chemical

causes female snails to grow male reproductive organs in addition to normal female

ones, a condition called “imposex.” When this condition becomes severe, affected

females cannot function as females or as males; the resulting reproductive failure

caused severe population declines in some species. While the use of TBT in antifouling paints has been severely restricted in the United States (P.L. 100-333,

Organotin Antifouling Paint Control Act of 1988) and European countries, it remains

in use in other parts of the world. In addition, ambiguous genitalia have been found

by the EPA in Maine bivalves, allegedly due to herbicides.39

In laboratory experiments with rodents, there is clear evidence that exposure to

some endocrine disruptors affects the development of reproductive organs and causes

tumor development. For example, one study found that exposure of newborn mice

to genistein (a naturally occurring plant estrogen) at a level “within the range to

which humans may be exposed in soy-based infant formulas” caused growths on

oviducts that would impair fertility, and lack of certain cell masses indicating

impaired ability to ovulate in every exposed mouse and in no mouse that was

37

(...continued)

Matthiessen, P. (1998) “Effects on fish of estrogenic substances in English rivers,” In

Principles and Processes for Evaluating Endocrine Disruption in Wildlife, (ed. R. Kendall,

et al.), p. 239-247, Pensacola, FL: SETAC Press.

Panter, Grace, R. S. Thompson, and John P. Sumpter. (1998) “Adverse reproductive

effects in male fathead minnows (Pimephales promelas) exposed to environmentally

relevant concentrations of the natural oestrogens, oestradiol and oestrone,” Aquatic

Toxicology, v. 42, n. 4, p. 243-253.

38

A biomarker is a biochemical, morphological, or functional change that indicates exposure,

response, or potential susceptibility to an environmental substance or agent. Biomarkers are

generally used to increase sensitivity, specificity, or response capacity, the objective being

to establish a causal relationship between a chemical agent and its effect on an organism.

39

Van Beneden, R.J., et al. (1993) “Implication for the presence of transforming genes in

gonadal tumors in two bivalve mollusk species,” Cancer Research, v. 53, p. 2976-2979.

Van Beneden, R.J. (1996) “Comparative studies of molecular mechanisms of tumorigenesis

in herbicide-exposed bivalves,” In Interconnections between Human and Ecosystem Health

(eds. R. DiGiulio and E. Monosson), Chapman and Hall Ecotoxicology Series, London,

England, p. 29-43.

CRS-10

unexposed, and uterine cancer in about one-third of the exposed mice and none of the

unexposed mice.40

Environmental Exposure to Potential Endocrine Disruptors. Concern

about possible human hormone disruption has been fueled by the limited information

available about levels of potential hormone disruptors in the environment. It is

known that some potential endocrine disruptors are heavily used and, in some cases,

released to the environment. For example, wastewater effluent from sewage

treatment plants contains many potential endocrine disruptors, including synthetic

(pharmaceutical) hormones. Other potential endocrine disruptors are prevalent in

certain foods, such as soy-based milk substitutes, because soy beans contain

phytoestrogens (i.e., isoflavonoids) at relatively high levels.41 Some argue that the

high phytoestrogen concentrations in food far exceed concentrations of endocrine

disruptors in the environment, implying that environmental exposures are likely to

be relatively insignificant. However, this conclusion is not necessarily justified,

because it is based on a comparison of apples with oranges, or rather a mixture of

isoflavonoids and other phytohormones with a mixture of synthetic industrial

compounds, including pharmaceuticals and other chemicals, each of which may exert

a different biological effect and be more or less potent at various concentrations.

Of course, release of a chemical does not necessarily imply that environmental

levels of exposure are toxic, even to vulnerable populations of animals or people.

Available data are somewhat reassuring, because known potential disruptors of

endocrine function generally are present in the environment at very low levels.42 On

the other hand, little is known about possible health effects for children of exposure

to low levels of contamination, and there are no measurements at all of ambient

concentrations for most chemicals in the environment, some of which may be

affecting hormones. Many known hormone disruptors are ubiquitous at low levels,

raising the question of long-term effects and possible additive or synergistic effects

with continual exposure.43 Foods and surface water often contain trace amounts of

pesticides, and many consumer products contain low levels of endocrine modulators

such as phthalates or bisphenol A. For example, PCBs and some dioxins are very

persistent in the environment and are known to bioconcentrate in the food chain.

Children are exposed to PCBs through breast milk, and by eating fish and other fatty

40

Newbold, R.R., E.P. Banks, B. Bullock, et al. (2001) “Uterine adenocarcinoma in mice

treated neonatally with genistein,” Cancer Research, v. 61, n. 11, p. 4325-4328.

41

The isoflavonoids appear to exert both estrogenic and anti-estrogenic effects which are not

completely understood.

42

Toxicologists generally assume that toxicity increases with increasing levels of exposure.

But concentrations of some chemicals measured in the environment are similar to those

measured in the bodies of some healthy animals. Moreover, some scientists argue that low

levels of exposure to hormones may exert a disproportionately large effect compared to

higher doses.

43

National Academy of Sciences (1999). Hormonally Active Agents in the Environment,

National Academy Press, Washington, DC.

U.S. Environmental Protection Agency. (1997) Special Report on Environmental

Endocrine Disruption: An Effects Assessment and Analysis, EPA/630/R-96/012.

CRS-11

foods that contain relatively high concentrations of PCBs.44 Children can also be

exposed in the womb, as PCBs move across the placenta.

One reason for concern about potential human health effects from hormone

disruptors is the high level of biological availability and potency of some

pharmaceutical and agricultural chemicals that may be released to the environment.

Synthetic hormones are an obvious example. Birth control compounds, synthetic

estrogen for postmenopausal women, and synthetic thyroid hormone are three

common contaminants of wastewater.

Potential toxicity (i.e., ability to adversely affect hormone function) and

potential exposure are not necessarily sufficient to demonstrate significant public

health or ecological risks. Knowledge about the range of potential health effects in

immature, as well as mature wildlife and humans, and actual exposure measurements

are needed to accurately assess risks. Existing data sometimes support conflicting

views, leading to controversies about the extent to which people generally are

exposed to endocrine modulators, whether very low levels of exposure potentially

could affect human health, and whether exposure to very low levels of chemicals in

the environment currently is affecting reproduction, fetal development, or other

hormone-dependent functions in animal or human populations. Nevertheless, a panel

convened by the National Academy of Sciences concluded –

Environmental [hormonally active agents] probably have contributed to declines

in some wildlife populations, including fish and birds of the Great Lakes and

juvenile alligators of Lake Apopka, and possibly to diseases and deformities in

mink in the United States, river otters in Europe, and marine mammals in

European waters. Such contaminants, along with inbreeding, might have

contributed to the poor reproductive success of the endangered Florida panther

and the increased embryonic mortality of the snapping turtle in the Great Lakes.45

Those skeptical of the disruptor hypothesis argue that mammals have

homeostatic mechanisms to moderate small fluctuations in hormone levels, so they

are unlikely to be overwhelmed by low levels of environmental exposure. To the

argument that low concentrations of several chemicals may additively exert influence

on those exposed, skeptics counter that multiple disruptors are just as likely to

compete, resulting in combined effects that are less than additive.

Some on-going studies of developmental effects in rats have found effects on

the reproductive organs from very low levels of exposure to DES and bisphenol-A,

an ingredient in some plastic. Similarly, preliminary results indicate low-dose effects

on the brain and immune system from genistein and nonylphenol (a chemical in

detergents). An expert workshop to evaluate the data on low-dose effects of

endocrine disruptors recently concluded that biological effects have been shown to

occur following exposure to some estrogenic compounds at very low levels.46 The

44

Longnecker et al., ibid.

45

National Academy of Sciences, p. 7.

46

National Toxicology Program’s Report of the Endocrine Disruptors Low Dose Peer

(continued...)

CRS-12

question remains whether those effects would adversely affect human health,

however.47

Policy Issues

Pace of FQPA Implementation. Environmental, consumer, and public

health advocacy groups accuse EPA of “dragging its feet” in implementing many

provisions of the Food Quality Protection Act (FQPA), including the mandate to

establish an endocrine disruptor screening program. The Natural Resources Defense

Council (NRDC) and six California-based public interest groups alleged in a lawsuit

filed August 3, 1999, in the U.S. District Court for the Northern District of California

that delays had caused EPA to miss FQPA deadlines (Natural Resources Defense

Council v. U.S. Environmental Protection Agency, No. C993701CAL). On January

19, 2001, EPA and NRDC agreed to settle the lawsuit. The settlement agreement

states that endocrine disruptor screening will begin no later than spring 2004 (Natural

Resources Defense Council v. EPA, No. C993701CAL, Jan. 19, 2001).

Although grower groups and the pesticide industry have echoed complaints

about delays in overall FQPA implementation, they also have complained that EPA

is proceeding too fast, jeopardizing the scientific basis for decisions about the

screening program. Currently, few test protocols have been developed and validated

for screening chemicals for endocrine disruption. Since chemical producers will

conduct the actual screening of chemicals, they want to ensure that screening

requirements established by EPA will be cost-effective in identifying potentially

hazardous pesticides rather than wasteful of company resources. Thus, they generally

would prefer relatively quick and inexpensive screens to quickly rule out (or at least

delay) the need to pursue testing of chemicals that are less likely to pose health risks.

This approach would allow time for additional, and perhaps improved, test methods

to be validated. Public health advocates would prefer more thorough testing of a

larger number of chemicals, to ensure that all potentially hazardous substances are

identified and quickly regulated.

Some scientists are concerned about adopting and implementing a program at

this time to screen chemicals for endocrine effects, because the field of study is so

new and developing rapidly. Almost certainly, better tests will be developed as

scientists gain understanding of the endocrine systems, how they develop, how they

respond to variations in hormone levels, and how they might be disrupted. A key

question then is how flexible the adopted program should be: Will it be allowed to

evolve quickly in response to new knowledge? On the other hand, most scientists

appear optimistic about the value of screening chemicals with the methods that are

46

(...continued)

Review. (2001) National Toxicology Program, U.S. Department of Health and Human

Services.

[http://ntp-server.niehs.nih.gov/htdocs/liason/LowDoseWebPage.html]

47

That is, the effects observed are not known to be adverse. For example, at certain very low

doses fetal exposure to bisphenol-A produces enlarged prostates in male rats, but it is not

clear that an enlarged prostate is an adverse health impact.

CRS-13

being developed, as long as they are validated prior to being employed on hundreds,

if not thousands, of chemicals.

Welfare of Test Animals. Traditional methods of toxicity testing often

involve administration of measured doses of chemicals to groups of laboratory

animals (usually rodents), which are then observed for health effects. Test animals

may be affected in a positive way (if the chemical at the administered dose improves

health), unaffected, mildly adversely affected, severely adversely affected or even

killed by the administered dose. If they survive (which generally is the scientifically

preferable result), they may be sacrificed (i.e., killed) at some future date to permit

internal inspection of tissues, or they may be allowed to live a normal lifespan. In

some cases, test animals are allowed to reproduce, so that any adverse health effects

on the reproductive process or on offspring may be observed. Standard scientific

protocols generally require the use of groups of animals for such tests, so as to permit

statistical analysis of the results. For example, many tests require the use of 25 or 50

rats of each gender at each dose level.

As mentioned above, few test protocols have been developed and validated for

screening chemicals for endocrine disruption. At the end of August 2001, only one

(the uterotrophic assay for estrogenic effects) of the 13 tests proposed for the

endocrine disruptor screening program was validated, although work was proceeding

on most of the other tests as well. According to the NRDC-EPA settlement

agreement, all eight “tier 1" screening tests must be validated by December 2003, so

that testing can begin in spring 2004. The second tier of five tests must be validated

by December 2005.

Animal welfare advocates are concerned that a large number of animals might

be sacrificed for the Endocrine Disruptor Screening Program, and they have

questioned the value of such tests for assessing human health risks. They argue that

alternatives to animal tests exist, and that others should be developed, both to

improve the predictive value of the tests for human health and to protect the animals

that otherwise might suffer or die.

For several years, federal agencies have been evaluating alternative methods for

screening chemicals for toxicity, which would require the use of fewer laboratory

rodents or other animals than are required using traditional toxicity tests. Alternative

toxicity testing methods exist, but their results are more difficult to interpret, in terms

of what they might mean for human health, and few are used routinely by federal

agencies. The 103rd Congress established the Applied Toxicological Research and

Testing Program within the National Institute of Environmental Health Sciences

(NIEHS), in part, “to develop and validate assays and protocols, including alternative

methods that can reduce or eliminate the use of animals in acute or chronic safety

testing,” “to establish criteria for the validation and regulatory acceptance of

alternative testing[,] and to recommend a process through which scientifically

validated alternative methods can be accepted for regulatory use” (Public Law 10343, Section 1301(a)). To implement the program, NIEHS established an ad hoc

Interagency Coordinating Committee on the Validation of Alternative Methods

(ICCVAM). The 106th Congress made ICCVAM a permanent interagency

coordinating committee (Public Law 106-545). EPA is a member of this committee.

CRS-14

To date, ICCVAM has endorsed one alternative method, the so-called Up-and-Down

Procedure, which reduces the number of rodents needed to evaluate acute toxicity.

Agencies reportedly are spending approximately $13 to $15 million to support

research and development of endocrine disruptor methods in FY2002 and FY2003.48

Legislation in the 107th Congress

The 107th Congress may consider proposals to increase or decrease funding for

the endocrine disruption screening program, or to expand its requirements to include

additional chemicals or endocrine effects. For example, S. 1712 in the 106th

Congress would have required screening of substances discharged into the nation’s

water. Congress appropriated $20.6 million for EPA’s endocrine disruptor screening

program and research in FY2000; $22.9 million in FY2001; and $20.3 million, the

full amount requested in the President’s budget, in FY2002. The House Committee

on Appropriations urged EPA “to develop validation processes that incorporate the

advice of the EDMVS” (Endocrine Disruptor Methods Validation Subcommittee),

“and to provide a report to the Committee on the status of the EDMVS by March 15,

2002" (H. Rept. 107-159, p. 59).

Other legislative proposals in the 107th Congress (H.R. 1990, S. 855, and S. 940)

would expand the reporting or regulatory requirements of other environmental

statutes to cover chemicals with possible estrogenic or other hormonal effects. Such

proposals may garner greater support if scientific evidence accumulates indicating

significant adverse environmental or human health effects. On the other hand, ongoing studies may not substantiate claims of widespread adverse health or ecological

effects of exposure to endocrine disruptors at environmental levels, leading to less

support from appropriators and fewer proposals for additional research or regulation.

Additional Resources

Additional information about endocrine disruptor science, the human health

effect hypothesis, and the views of various stakeholders may be found on the World

Wide Web. The views of the authors of Our Stolen Future and other environmental

protection advocates may be explored at [http://www.pmac.net/theos.htm]. A

skeptical view of the hypothesis that pollutants are disrupting the endocrine systems

of

humans

and

wildlife

may

be

found

at

[http://www.acsh.org/press/releases/endmod062999.html]. EPA programs, policies

and activities are summarized at [http://www.epa.gov/scipoly/oscpendo/]. A site that

provides links to many other websites with information about endocrine disruptors

is the Endocrine/Estrogen Letter at [http://www.eeletter.com/links.htm].

48

“Research on Endocrine Disruptor Exposure Focus of Grants from EPA, Other Agencies,”

Daily Environment Report, Nov. 1, 2001, p. A-7-8.