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

Environmental Exposure

to Endocrine Disruptors:

What Are the Human Health Risks?

-name redactedSpecialist in Environmental Policy

-name redactedSpecialist in Natural Resources Policy

April 29, 2009

Congressional Research Service

7-....

www.crs.gov

R40177

CRS Report for Congress

Prepared for Members and Committees of Congress

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

Summary

In 2008, Congress banned the use in children’s toys and child care articles of several chemicals

known to disrupt normal development and reproduction of mice and rats. The legislation was a

response to accumulating scientific evidence supporting the hypothesis that exposure to certain

chemicals in consumer products and the environment might be adversely affecting human

reproduction, growth, development, or metabolism by interfering with endocrine systems. This

report summarizes the science underlying the environmental endocrine-disruptor hypothesis, and

describes congressional actions and related programs and policy issues at the U.S. Environmental

Protection Agency (EPA).

This report focuses on the potential human health effects of environmental exposure to endocrine

disruptors. The potential effects on fish and wildlife also are of concern. Scientists have

discovered many egg-bearing male (intersex) bass in the Potomac River, as well as intersex fish

of other species in other U.S. waters. Chemicals of interest include certain pesticides (e.g., DDT),

synthetic hormones administered to cattle and poultry, both prescription and over-the-counter

drugs and ingredients of some personal-care products (e.g.,triclocarban in antibacterial soaps),

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

polychlorinated biphenyls (PCBs)), some dioxins, lead, mercury, cadmium, uranium, arsenic, and

organic compounds of tin. Potential sources of such chemicals include runoff from animal

feedlots and agricultural fields, wastewater discharges, industrial releases, and consumer

products. In the 111th Congress, H.R. 1145 would require each water resources research and

technology institute to conduct technical research on prevention and removal of contaminants of

emerging concern, including endocrine-disrupting compounds.

Support might be found for the hypothesis that chemicals in the environment are disrupting

human endocrine systems in the apparent increases in rates of certain cancers, reported declines

in sperm counts, and reported 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. Any of these

effects could be linked to hormone disruption because they are hormone dependent and have been

chemically induced in experimental animals. However, scientifically demonstrating a cause-effect

relationship between environmental exposure to a particular chemical and human health effects is

difficult. Many scientists hypothesize that environmental levels of potential endocrine disruptors

are too low to influence human endocrine systems. Others argue that significant adverse effects

might result from long-term exposure to low levels of multiple endocrine disruptors.

Congress began investigating the presence and possible effects of endocrine disruptors in the

environment at a hearing in 1993. In 1996, Congress directed EPA to establish and implement an

endocrine-disruptor screening program for pesticides and drinking water contaminants. As of

April 2009, chemical screening under that program has not begun, and funding for the program

has declined, and legislators have expressed concern about the pace of program development.

However, EPA this month promulgated final rules establishing the list of 67 pesticide ingredients

and procedures that will be followed when the first set of testing orders is issued to

manufacturers. EPA has stated that orders will be issued during the summer of 2009. Once the

program is implemented, Congress might consider whether statutes and regulations provide

adequate authority and direction with respect to the influence of any findings of endocrine

disruption on the regulation of specific chemicals, chemical groups, uses, or products.

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

Contents

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

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

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

The Endocrine Disruptor Screening Program...................................................................3

Research Initiatives .........................................................................................................6

Scientific Evidence .....................................................................................................................7

Human Health Trends ...........................................................................................................7

Human Studies of Chemical Effects on Endocrine Systems ...................................................8

Animal Studies.................................................................................................................... 12

Fish............................................................................................................................... 13

Other Wild Vertebrates .................................................................................................. 15

Invertebrates ................................................................................................................. 16

Laboratory Rodents....................................................................................................... 17

Environmental Exposure to Potential Endocrine Disruptors................................................. 18

Policy Issues ............................................................................................................................. 20

Pace of FQPA Implementation ............................................................................................ 20

Welfare of Test Animals ...................................................................................................... 21

Regulation of Endocrine Disruptors..................................................................................... 21

Conclusion................................................................................................................................ 23

Contacts

Author Contact Information ...................................................................................................... 24

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

Background

Scientific reports of reproductive failure among migratory birds exposed to DDT during the

1950s provided some of the earliest evidence that chemical pollutants in the environment might

affect hormone-mediated processes in wildlife. 1 In 1996, several scientists brought the endocrine

2

disruptor hypothesis to public attention with the release of a book, Our Stolen Future. In the

same year, Congress directed the U.S. Environmental Protection Agency (EPA) to develop and

implement a program to screen all pesticides and suspect drinking water contaminants for

endocrine-disrupting potential. Ten years later, the screening program was not yet launched, when

scientists reported finding a large number of feminized male fish in the Potomac River and other

U.S. waters. In response, Congress held hearings and urged federal agencies to expedite related

research. In 2008, the National Toxicology Program issued a report indicating scientific concern

about fetal and child exposure to several chemicals with endocrine-disrupting potential. In the

same year, Congress enacted legislation banning those chemicals in children’s toys and child care

3

articles. H.R. 1523/S. 593 and S. 753 in the 111th Congress would regulate certain uses of

bisphenol A, another potential endocrine disruptor.

This report summarizes the science underlying the endocrine disruptor hypothesis, describes

congressional actions, outlines EPA’s efforts to implement legislation, and discusses some policy

issues that have been raised. The report is intended to support Congress as it considers legislation

to control potential endocrine disruptors and as it oversees EPA’s programs. With a few

exceptions, the report does not discuss in detail all of the various specific chemicals that might be

endocrine disruptors and particular source categories for such chemicals that might be in the

environment. Several CRS reports on specific chemicals and sources are referenced where

relevant.

Endocrine Disruptors

Endocrine disruptors4 are chemical compounds in drugs, food, consumer products, or the ambient

environment that can interfere with biological processes normally regulated by hormones within

animals. Physical 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 (or plant estrogens, which

are responsible for female sexual characteristics) in some plants. Others are the products of

human industry—for example, some pesticides and pharmaceuticals.

1

Hoffman, David J., Barnett A. Rattner, G Allen Burton, Jr., and John Cairns, Jr. (Eds.) 2003. Handbook of

Ecotoxicology. 2nd ed. Lewis Publishers: New York. p. 76.

2

Colburn, Theo, Dianne Dumanoski, and John Peterson Myers. 1996. Our Stolen Future: Are We Threatening Our

Fertility, Intelligence, and Survival? A Scientific Detective Story. New York: Penguin. 316 p.

3

The chemicals banned were di-(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), or benzyl butyl phthalate

(BBP). The ban was enacted through Section 108 of P.L. 110-314, the Consumer Product Safety Improvement Act of

2008.

4

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 metabolic rates, blood pressure, growth, development, aging, blood sugar levels, and

reproduction.

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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 hormones. (Similarly,

environmental androgens are chemicals that mimic the action of the male sex hormones.) Other

endocrine disruptors do not mimic, but block the action of hormones (for example, the antiestrogens or anti-androgens) or 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 certain manufactured chemicals in the environment has been shown to

harm insects, some vertebrate wildlife, 5 and aquatic life by influencing the normal activities or

effects of reproductive and other hormones. 6 There also is scientific evidence that relatively low

environmental levels of some chemicals may be harmful to the endocrine systems of fish and

wildlife, particularly when low chemical concentrations are continuous or bioaccumulate,

exposing animals higher on the food chain to greater chemical concentrations. Selected, peerreviewed studies are described and references are cited under the next major section of this report,

“Scientific Evidence.” Some scientists hypothesize that existing environmental levels of potential

endocrine disruptors also may be harming human health, but other scientists believe that current

levels of such chemicals in the environment are too low to exert significant adverse effects on

people.

Congressional and Administrative Attention

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

7

in 1993. Among those testifying at that hearing were several researchers who later published

8

their findings in the book, Our Stolen Future. It summarized a number of studies by wildlife

biologists, epidemiologists, and other scientists, and hypothesized that endocrine disruption by

environmental pollutants might be responsible for increases in deformities and population

declines of amphibians, declining human fertility in various geographical regions, and reported

increases in human rates of breast, testicular, and prostate cancers, as well as endometriosis. In

9

the next few years, research produced evidence both for and against that hypothesis.

5

Generally, scientists have studied effects in vertebrates (animals with spines), especially amphibians, freshwater fish,

and mammals.

6

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 insects 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. This is not meant to

imply that any adverse effects on beneficial insects (such as the honeybee) might not be important. It is simply beyond

the scope of this paper.

7

U.S. Congress. 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.

8

Colburn et al., 1996.

9

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

environmental chemicals,” S.F. Arnold, D.M. Klotz, and B.M. Collins, et al., 1996, Science, v. 272, pp. 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, pp. 459-463). The original report indicated that effects of

(continued...)

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Congress continued to study the issue, and in 1996 concluded that there was a need to screen

pesticide chemicals and drinking water contaminants for their potential to disrupt endocrine

systems. A screening program was established by the Food Quality Protection Act (P.L. 104-170)

and the 1996 Amendments to the Safe Drinking Water Act (P.L. 104-182).

The Endocrine Disruptor Screening Program

The Food Quality Protection Act (FQPA) Section 408(p)10 directs EPA, not later than three 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, as well as other substances identified by the Administrator which might

have a cumulative effect together with pesticides and to which a substantial population may be

11

exposed.

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

12

disruption potential of contaminants found in sources of drinking water. Under both statutes,

actual screening of chemicals for toxic effects is to be conducted by manufacturers of suspect

chemicals (or laboratories hired by manufacturers) following protocols approved by EPA. The

laws authorize EPA to take appropriate action to protect public health under existing statutory

authority if substances are found to have endocrine effects in humans.13

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 Science

Advisory Board. EPA generally accepted the EDSTAC recommendations and officially

“established” the Endocrine Disruptor Screening Program (EDSP) in 1998. Under this program,

pesticides and other chemicals would be screened using a battery of tests known as Tier 1 assays,

which are relatively inexpensive short-term tests. Chemicals that tested positive for possible

endocrine disruption in one or more Tier 1 assays would be subjected to one or more Tier 2

toxicity tests, to confirm or refute Tier 1 results, and if confirmed, to determine the dose of the

chemical that caused the effects. Tests would screen for effects on estrogen, androgen (hormones

(...continued)

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).

10

See §405 of P.L. 104-170, amending §408 of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 346a).

11

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

Disruptor Screening Program at http://www.epa.gov/scipoly/oscpendo/.

12

See §136 of P.L. 104-182, adding a new §1457 to the Safe Drinking Water Act (42 U.S.C. 300j-17).

13

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

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responsible for male sexual characteristics), and/or thyroid systems. The thyroid hormones

regulate growth and development and the rate of metabolism.

Chemical screening for potential effects on endocrine systems has not yet begun, however,

because EPA has not finished selecting and validating toxicity assays. An Endocrine Disruptor

Method Validation Subcommittee (EDMVS) was formed in 2001 to advise EPA on how it should

select and evaluate the screens and tests to be developed. This process proved to be controversial,

particularly with respect to the role of animal experimentation and the validation of tests

involving live animals. Three years later, the Endocrine Disruptor Methods Validation Advisory

Committee (EDMVAC) was formed to replace EDMVS. This group assisted EPA as it identified,

developed, and validated the various methods for detecting potential endocrine disruptors.

In 2004 and 2005, the EDSP was reviewed and evaluated at EPA’s request by the independent

Board of Scientific Counselors (BOSC) for EPA’s Office of Research and Development. A

subcommittee of the BOSC prepared a final report, which is summarized in a peer-reviewed

publication14 and posted on the BOSC website. 15 The BOSC subcommittee concluded that the

goals and science questions of the endocrine disruptor screening program were appropriate, and

EPA’s progress on implementing the program was good, although challenges remained. The

subcommittee advised EPA to

•

strengthen its expertise in wildlife toxicology;

•

expedite validation of the tests;

•

take a leadership role in applying “omics” technologies (such as proteomics or

metabolomics);

•

maintain funding; and

•

“continue to sponsor multidisciplinary intramural research and interagency

collaborations.”16

The BOSC again reviewed the program in 2008.17 BOSC reported that the program

... exceeds expectations in progress to address concerns of the previous 2004 program

review. ... The [Endocrine Disrupting Chemicals Research Program] has taken under

consideration all recommendations of the previous BOSC review and those

recommendations not implemented were held in abeyance because of budgetary

constraints.18

14

Harding, Anna K., George P. Daston, and Glen R. Boyd, et al. 2006. Endocrine disrupting chemicals research

program of the U.S. Environmental Protection Agency: Summary of a peer-review report. Environmental Health

Perspectives, v. 114, n. 8, pp. 1276-1282.

15

Board of Scientific Counselors, Office of Research and Development, U.S. EPA. Endocrine Disrupting Chemicals

(EDC) Research Program Review, Final Report of the Subcommittee on Endocrine Disrupting Chemicals. March 4,

2005. Revised April 21, 2005, http://www.epa.gov/OSP/bosc/pdf/edc0504rpt.pdf.

16

Harding, ibid.

17

Board of Scientific Counselors, Office of Research and Development, U.S. EPA. Mid-cycle Review of the Office of

Research and Development’s Endocrine Disrupting Chemicals (EDCs) Research Program at the U.S. Environmental

Protection Agency, Apr. 16, 2008, http://www.epa.gov/OSP/bosc/pdf/edcmc0804rpt.pdf.

18

Ibid., Cover letter.

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The BOSC noted that

... the budget to support this program has been cut substantially. The budget has been cut 20

percent since 2003, with a 4 percent cut proposed for this year. Funds for extramural STAR

grants for EDC research were completely eliminated in 2005.19

Largely as a result of the constrained budget, BOSC found that wildlife toxicology and

epidemiology remain areas of weakness in EPA’s EDSP.20

EPA also worked closely with the Interagency Coordinating Committee on the Validation of

Alternative Methods (to identify and validate test methods that reduce animal use or suffering)

and the Organization for Economic Cooperation and Development (to ensure international

21

acceptance of the methods.) EPA’s independent Science Advisory Panel (established under the

Federal Insecticide, Fungicide, and Rodenticide Act) has completed peer review of validated Tier

1 assays and approved EPA’s initial test battery, but some chemical manufacturers continue to

object to several of the Tier 1 assays. In July 2008, the Center for Regulatory Effectiveness (a

public policy advocacy group) filed a “Request for Correction” on one of the assay validations

under the Agency’s Information Quality Guidelines (IQG), and Crop Life America, a trade group

for pesticide manufacturers, filed a petition to delay the EDSP orders to initiate testing. As a

result, EPA delayed the issuance of orders until 2009. In April 2009, it was announced that EPA

denied the Crop Life petition22 and announced that orders would be issued during the summer of

2009.

At the same time that it was developing toxicity assays, EPA established a process for prioritizing

and selecting chemicals to be screened. 23 In June 2007, EPA proposed a draft list of 73 chemicals

for initial screening.24 The comment period for the draft list ended February 11, 2008. In April

2009, after considering comments on this list of chemicals, EPA published in the Federal Register

the final list of 67 chemicals.25 The list included pesticide active ingredients, “selected based on

their relatively high potential for human exposure”26 and other chemicals produced in amounts

greater than one million pounds per year that also are used in pesticide products but which are

categorized as inert (that is, not active) pesticide ingredients. EPA’s website “EDSP Phases”

provides additional details about the process EPA used to select chemicals for screening.27

19

Ibid., p. 5.

Ibid., p. 6, 8.

21

U.S. Congress. House of Representatives. Committee on Government Reform. Ova-Pollution in the Potomac: EggBearing Male Bass and Implications for Human and Ecological Health. 109th Cong., 2nd Sess., Oct. 4, 2006.

Washington, DC: Govt. Printing Off. (2006) p. 25 (Testimony of Benjamin H. Grumbles).

22

Bill Pritchard, “EPA Rejects CropLife Request for More Study of Endocrine Disruptor Screening Program,” Daily

Environment Report, Apr. 16, 2009, p. A-2.

23

70 Federal Register 56449-56465, Sept. 27, 2005.

24

72 Federal Register 33486-33503, June 18, 2007.

25

74 Federal Register 17579-17585, Apr. 15, 2009.

26

70 Federal Register 56449-56465, Sept. 27, 2005.

27

EPA. EDSP Phases, http://www.epa.gov/endo/pubs/edspoverview/components.htm#4.

20

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Late in 2007, EPA also solicited public comments about its proposed procedure for issuing orders

28

to manufacturers to conduct initial screening and for overseeing compliance with such orders.

The final version of these procedures was published in the Federal Register April 15, 2009.29

The House Committee on Government Reform held a hearing October 4, 2006, to learn about the

status of the EDSP and to examine the human and ecological health implications of the discovery

of egg-bearing male bass in the Potomac River. One year later, some Members of that committee

sent a letter to EPA Administrator Stephen L. Johnson asking him how EPA might speed up the

process of screening chemicals for endocrine effects, to provide a timetable for EDSP

implementation, and for explanations in response to specific questions about the process and

30

substance of the program as designed. EPA’s responses are posted on the Committee’s

31

website. The agency indicated that the list of chemicals, procedures, and peer review of Tier 1

tests should have been completed and Tier 1 test orders should have been issued to manufacturers

of the first 73 chemicals before mid-2008. An EPA website provides more information about

EDSP program development. 32

Research Initiatives

The hypothesis that existing environmental levels of chemical pollutants may be harming human

health by disrupting endocrine functions has been, and continues to be, hotly debated. At present,

there is no conclusive evidence to support this hypothesis.

Research interest is growing, and some epidemiological studies have found statistical associations

between human exposure and health effects that are consistent with the results of experiments

with animals, particularly with respect to potential effects on prenatal and infant development.

Research attention has focused on chemicals such as certain phthalates 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.33 Some other chemicals of potential concern include a

number of pesticides (e.g., DDT, lindane, and vinclozolin), medicinal drugs (especially synthetic

hormones), other synthetic compounds (e.g., nonylphenol, polychlorinated biphenyls (PCBs),

perchlorate), and some metals (e.g., lead, mercury, arsenic, and organotins). In recent years,

hundreds of studies have been conducted to determine possible health effects due to exposure to

34

components of plastics such as bisphenol A (BPA) and phthalates. EPA has posted an inventory

35

of endocrine research that it sponsors.

28

29

72 Federal Register 70842-70862, Dec. 13, 2007, http://www.epa.gov/endo/pubs/draft_policies_frn.pdf.

74 Federal Register 17560-17579.

30

Letter from Henry A. Waxman et al. to Administrator Johnson, Sept. 20, 2007, http://oversight.house.gov/

documents/20070920162537.pdf.

31

EPA. Responses to Questions from the House of Representatives, Committee on Oversight and Government Reform,

Chairman Henry Waxman, September 20, 2007, http://oversight.house.gov/documents/20071204153145.pdf.

32

EPA, Revised Policies and Procedures, http://www.epa.gov/scipoly/oscpendo/pubs/regaspects/.

33

For more information about phthalates, see CRS Report RL34572, Phthalates in Plastics and Possible Human

Health Effects, by (name redacted) and (name redacted).

34

For more information about BPA, see CRS Report RS22869, Bisphenol A (BPA) in Plastics and Possible Human

Health Effects, by (name redacted) and (name redacted).

35

EPA. Office of Research and Development. National Center for Environmental Research. Endocrine Disruptors

Research. Research Projects, http://es.epa.gov/ncer/science/endocrine/researchproj.html.

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

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.36 In the United States, work among federal public health and environmental agencies was

initially coordinated by the Endocrine Disruptor Working Group, which was established by the

National Science and Technology Council’s Committee on the Environment and Natural

37

Resources. However, this working group appears to have disbanded after 1999. Internationally,

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

international test guidelines to detect endocrine disruptors.

In the 111th Congress, H.R. 1145 would require each water resources research and technology

institute, established under the Water Resources Research Act of 1984, to conduct technical

research on prevention and removal of contaminants of emerging concern, including endocrinedisrupting compounds, pharmaceuticals, and personal care products. This bill also would

establish a national interagency coordinating committee to plan and report to Congress on waterrelated research.

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. and global rates of certain

cancers,38 reported declines in sperm counts in various nations,39 and scientific evidence of

increasing rates of type II diabetes,40 obesity (especially among children),41 some birth defects,42

36

EPA. Office of Research and Development. National Center for Environmental Research. Science Topics. Endocrine

Disruptors Research. Related Links, http://es.epa.gov/ncer/science/endocrine/relatedlinks.html.

37

For more information about this group, see the EPA website for the Endocrine Disruptor Research Initiative.

However, the workgroup does not appear to be active, http://www.epa.gov/endocrine/edrifact.html.

38

Hodgson, N.C., J. Button, and C.C. Solorzano, et al. 2004. Thyroid cancer: is the incidence still increasing? Annals

of Surgical Oncology, v. 11, n. 12, pp. 1093-1097.

Jemal, A., R. Siegel, and E. Ward, et al. 2008. Cancer statistics, 2008. CA: A Cancer Journal for Clinicians, v. 58, n. 2,

pp. 71-96.

Sedjo, Rebecca L., Tim Byers, and Ermilo Arrera, Jr., et al. 2007. A midpoint assessment of the American Cancer

Society challenge goal to decrease cancer incidence by 25% between 1992 and 2015. CA: A Cancer Journal for

Clinicians, v. 57, n. 6, pp. 326-340.

39

Rozati, R., P.P. Reddy, and P. Reddanna, et al. 2000. Xenoesterogens and male infertility: myth or reality? Asian

Journal of Andrology, v. 2, n. 4, pp. 263-269.

Aitken, R.J., N.E. Skakkebaek, and S.D. Roman. 2006. Male reproductive health and the environment. Medical Journal

of Australia, v. 185, pp. 414-415.

Travison, T.G., A.B. Araujo, and A.B. O’Donnell, et al. 2007. A population-level decline in serum testosterone levels

in American men. Journal of Clinical Endocrinology and Metabolism, v. 92, n. 1, pp. 196-202.

40

Lang, Iain A., Tamara S. Galloway, and Alan Scarlett, et al. 2008. Association of urinary bisphenol A concentration

with medical disorders and laboratory abnormalities in adults. Journal of the American Medical Association, v. 300, n.

11, pp. 1303-1355.

41

Hugo, Eric R., Terry D. Brandebourg, and Jessica G. Woo, et al., in press, “Bisphenol A at Environmentally

Relevant Doses Inhibits Adiponectin Release from Human Adipose Tissue Explants and Adipocytes,” Environmental

Health Perspectives, online Aug. 14, 2008, at http://www.ehponline.org/members/2008/11537/11537.pdf.

42

Centers for Disease Control and Prevention, Department of Health and Human Services. Hypospadias trends in two

(continued...)

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43

and other disorders. In some cases, these reported increases in rates of hormone-mediated

diseases or conditions may reflect improvements in diagnostic tools or reporting rates rather than

increased rates of disease. In other cases, disease rates may have increased in fact, but may be due

to medication use, smoking, or some other reason. However, in at least a few cases, increasing

exposure to chemicals in the environment seems to some a plausible hypothesis to explain an

increase in disease rates. Many developmental, reproductive, and carcinogenic conditions for

which increased incidences have been reported in humans are similar to effects that have been

44

observed in wildlife and fish exposed to endocrine disruptors.

Congress has indicated its interest in several recent health trends, including: reported declines in

45

certain nations in semen quality over the last few decades; increasing rates of deformities of

46

male reproductive organs before 1985, after which rates stabilized; and a worldwide increase in

the incidence of testicular cancer, for which there is no clear cause.47 Some researchers have

noted the similarity of these health concerns with effects seen in rats and mice prenatally exposed

to certain phthalates that act as anti-androgens. 48 One hypothesis is that human exposure to

combinations of phthalates and perhaps other ubiquitous endocrine disruptors might be

interfering with the development of baby boys, resulting in what is referred to as “testicular

dysgenesis syndrome.”49

Human Studies of Chemical Effects on Endocrine Systems

Except for strong poisons with clear, short-term effects on health, the effects of chemical

exposures on humans are difficult to demonstrate scientifically. Ethically, scientists cannot

manipulate levels of human exposure to a chemical if there is a chance that harm might result.

The alternative, so-called “natural experiments” (which compare the health of people with

accidental exposures to the health of people with no exposure), is rare because accidental

exposures of sufficient magnitude are few, and potentially contributing conditions (such as

exposure to other chemicals) are inadequately controlled. In particular, study of effects of lowlevel exposures to environmental chemicals is problematic, because the expected effects are

(...continued)

US surveillance systems. Press Release, Nov. 3, 1997, http://www.cdc.gov/media/pressrel/hypospad.htm.

43

Carpenter, D.O., Y. Shen, and T. Nguyen, et al. 2001. Incidence of endocrine disease among residents of New York

areas of concern. Environmental Health Perspectives, v. 109, Supp. 6, pp. 845-851.

Davis, Devra Lee, Pamela Webster, and Hillary Stainthorpe, et al. 2007. Declines in sex ratio at birth and fetal deaths in

Japan, and in U.S. whites but not african americans. Environmental Health Perspectives, v. 115, n. 6, pp. 941-946.

44

U.S. Environmental Protection Agency. 1997. Special Report on Environmental Endocrine Disruption: An Effects

Assessment and Analysis, EPA/630/R-96/012. p. 5.

45

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

46

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

Perspectives, v. 108, n. 6, pp. 487-493.

47

Safe, ibid.

48

Fisher, Jane S., S. Macpherson, and N. Marchetti, et al. 2003. Human “testicular dysgenesis syndrome”: a possible

model using in utero exposure of the rat to dibutyl phthalate. Human Reproduction, v. 18, n. 7, pp. 1383-1394.

Toppari, Jorma , John Chr. Larsen, and Peter Christiansen, et al. 1996. Male Reproductive Health and Environmental

Xenoestrogens. Environmental Health Perspectives, v. 104, n. S4, online at http://www.ehponline.org/members/1996/

Suppl-4/toppari.html.

49

For more information about phthalates, see CRS Report RL34572, Phthalates in Plastics and Possible Human

Health Effects, by (name redacted) and (name redacted)

.

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subtle and potentially affected by numerous conditions. Often, virtually everyone has been

exposed to the chemical being studied, and there are too few unexposed people to serve as a

control group for comparison.

Scientific studies have demonstrated the potential of hormones and some other chemicals acting

through hormone systems to harm human health, especially if the chemical exposure is highly

concentrated and occurs during fetal or infant development. For example, the role of naturally

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

established scientifically.50 Moreover, research has demonstrated that administration of the drug

diethylstilbestrol (DES), a strong, synthetic estrogen, to women early in their pregnancies greatly

increases risk that their daughters will develop vaginal cancer and reproductive abnormalities. 51

In addition, studies have documented a higher than normal incidence of genital tract

abnormalities in male babies following in utero exposure to DES.52

Some chemicals with effects on endocrine systems have therapeutic value. For example, sex

hormones are used to treat some forms of cancer. 53 There also is evidence that some plant-derived

endocrine disruptors54 (e.g., phytoestrogens prevalent in soy beans) may protect against disease.55

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.

Numerous epidemiologic studies56 have found associations between environmental levels of

potential endocrine disruptors and effects on human development or health. 57 For example, a

50

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

51

Herbst, A., H. Ulfelder, and D. Poskanzer. 1971. Adenocarcinoma of the vagina: Association of maternal stilbestrol

therapy with tumor appearance in young women. New England Journal of Medicine, v. 284, pp. 878-881.

52

Mittendorf, R. 1995. Teratogen update: Carcinogenesis and teratogenesis associated with exposure to

diethylstilbestrol (DES) in utero. Teratology, v. 51, n. 6, pp. 435-445.

53

Huggins, Charles B. 1967. Endocrine-induced regression of cancers. Science, v. 156, n. 778, pp. 1050-1054.

Machtens, S., D. Schultheiss, and M. Kuczyk, et al. 2000. The history of endocrine therapy of benign and malignant

diseases of the prostate. World Journal of Urology, v. 18, n. 3, pp. 222-226.

54

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

55

Warri, A., N.M. Saarinen, and S. Makela, et al. 2008. The role of early life genistein exposures in modifying breast

cancer risk. British Journal of Cancer. v. 98, n. 9, pp. 1485-1493.

Vincent, A. and L.A. Fitzpatrick. 2000. Soy isoflavones: are they useful in menopause? Mayo Clinic Proceedings, v.

75, n. 11, pp. 1174-1184.

Lakshman, M., L. Xu, and V. Ananthanarayanan, et al. 2008. Dietary genistein inhibits metastasis of human prostate

cancer in mice. Cancer Research, v. 68, n. 6, pp. 2024-2032.

56

“Epidemiologic” studies examine groups of people to determine rates of occurrence of particular outcomes (health

effects) relative to varying levels of chemical exposure. Such studies rely on statistical methods to evaluate the

likelihood of hypotheses about relationships between exposures and outcomes (that is, dose-response relationships).

“Associations” are regular patterns between frequencies of particular health outcomes and changes in exposure levels.

Associations do not necessarily indicate a causal relationship, but there can be no causal relationship without an

association.

57

Ibarluzea, J.M., M.F. Fernandez, and L. Santa-Marina, et al. 2004. Breast cancer risk and the combined effect of

environmental estrogens. Cancer Causes and Control, v. 15, n. 6, pp. 591-600.

Mocarelli, Paolo, Pier Mario Gerthoux, and Donald G. Patterson Jr., et al. 2008. Dioxin exposure, from infancy through

puberty, produces endocrine disruption and affects human semen quality. Environmental Health Perspectives, v. 116, n.

1, pp. 70-77.

Sharpe, Richard M., and D. Stewart Irvine. 2004. How strong is the evidence of a link between environmental

(continued...)

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study of newborns in Spain reported data that suggested that the combined effects of

bioaccumulated estrogenic substances in the placenta played a role in the risk of male urogenital

malformations. 58 However, causality has not been (and possibly cannot be) clearly demonstrated

for any adverse health effect as a result of exposure to an endocrine disruptor at levels typically

present in the environment.

Most studies focus on a single chemical or closely related group of chemicals. For example, many

scientists believe that the same phthalates that are toxic to rats and mice would be able to cause

similar malformations in humans, because the male hormones affected by phthalates are

important to the normal development of the male reproductive tract in all species of mammals. A

few human studies have been conducted. 59 Some scientists have found that relatively low levels

of exposure to phthalates may be associated with health effects. A study published in 2005

provided the first evidence of subtle developmental effects in baby boys exposed prenatally to

breakdown products of certain phthalates, and these effects were similar to those seen in

experiments with rats and mice exposed to phthalates.60 A high exposure to one breakdown

product of a phthalate was found to alter the development (in a laboratory culture) of human fetal

testes and to reduce the number of germ cells.61 Nevertheless, human health effects of

environmental phthalate exposure have not been conclusively demonstrated. Additional research

is seen as needed to confirm or refute these findings of effects at environmental levels of human

exposure.

Recently, scientists have been advising that risk assessments should consider the combined effects

of chemical exposures. For example, studies with rodents suggest there may be additive effects of

multiple phthalate exposures.62 A recent report issued by the National Research Council

(...continued)

chemicals and adverse effects on human reproductive health? British Medical Journal, v. 328, , n. 7437, pp. 447-451.

58

Fernandez, Mariana F., Begona Olmos, and Alicia Granada, et al. 2007. Human exposure to endocrine-disrupting

chemicals and prenatal risk factors for cryptorchidism and hypospadias: A nested case-control study. Environmental

Health Perspectives, v. 115, Supplement 1 (December), pp. 8-14.

59

Main, Katharina M., Gerda K. Mortensen, and Marko M. Kaleva, et al. 2006. Human breast milk contamination with

phthalates and alterations of endogenous reproductive hormones in infants three months of age. Environmental Health

Perspectives, v. 114, pp. 270-276.

Swan, Shanna H., Katharina M. Main, and Fan Liu, et al. 2005. Decrease in anogenital distance among male infants

with prenatal phthalate exposure. Environmental Health Perspectives, v. 113, n. 8, pp. 1056-1061.

60

Swan et al. 2005.

61

Lambrot, Romain, Vincent Muczynski, and Charlotte Lecureuil, et al. 2009. Phthalates impair germ cell development

in the human fetal testis in vitro without change in testosterone production. Environmental Health Perspectives, v. 117,

n. 1 (January), pp. 32-37.

62

Hotchkiss, A.K., L.G. Parks-Saldutti, and J.S. Ostby, et al. 2004. A mixture of the “antiandrogens” linuron and butyl

benzyl phthalate alters sexual differentiation of the male rat in a cumulative fashion. Biology of Reproduction, v. 71,

pp. 1852-1861.

Howdeshell, Kembra L., Vickie S. Wilson, and Johnathan Furr, et al. April 14, 2008. A mixture of five phthalate esters

inhibits fetal testicular testosterone production in the Sprague Dawley rat in a cumulative, dose additive manner.

Toxicological Sciences Advance Access. Reprint received from the author.

Rider, Cynthia V., Johnathan Furr, and Vickie S. Wilson, et al. 2008, A mixture of seven antiandrogens induces

reproductive malformations in rats. International Journal of Andrology, v. 31, pp. 249-262.

Crofton, Kevin M., Elena S. Craft, and Joan M. Hedge, et al. 2005. Thyroid-hormone-disrupting chemicals: evidence

for dose-dependent additivity or synergism. Environmental Health Perspectives, v. 113, n. 11, (November) pp. 15491554.

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concluded that there is a need to explore the additive effects of exposure to phthalates.63 Dr.

Andreas Kortenkamp has reviewed research on the effects of mixtures of endocrine-disrupting

chemicals and has called for additional, more systematic investigations of combinations of

endocrine disruptors.64

Human hormones other than sex hormones also might be affected by environmental chemicals. A

recently released study found that low-level human exposure to bisphenol A (BPA) inhibits the

release of adiponectin from adipose (fat) tissue. This result indicates a possible link of BPA to

diabetes, because adiponectin increases insulin sensitivity and helps regulate glucose

metabolism. 65 Because this study was well designed and controlled, its results are seen as

particularly interesting, but until it has been replicated by an independent team of scientists, any

conclusions are considered tentative.

Another chemical group that has been studied extensively is PCBs. Although the production and

use of PCBs has been strictly regulated since 1976, these chemicals are ubiquitous in the air,

water, soil, and many animal tissues due to their environmental persistence, tendency to

bioaccumulate in animal fat, and previous widespread use. Some PCBs are known to be

estrogenic. 66 In addition, PCBs may affect thyroid function,67 and there is evidence that fetal

exposure to PCBs affects cognitive development, but it is not known whether this toxicity is

related to thyroid or any other type of hormone disruption.68 In addition, some studies have found

63

Committee on the Health Risks of Phthalates, National Research Council. 2008. Phthalates and Cumulative Risk

Assessment: The Tasks Ahead. The National Academies Press, Washington DC, p. 6.

64

Kortenkamp, Andreas. 2007. Ten years of mixing cocktails: A review of combination effects of endocrine-disrupting

chemicals. Environmental Health Perspectives, v. 115, Supplement 1 (December), pp. 98-105.

65

Hugo, Eric R., Terry D. Brandebourg, and Jessica G. Woo, et al., in press, “Bisphenol A at Environmentally

Relevant Doses Inhibits Adiponectin Release from Human Adipose Tissue Explants and Adipocytes,” Environmental

Health Perspectives, online Aug. 14, 2008, at http://www.ehponline.org/members/2008/11537/11537.pdf.

66

Longnecker, M.P., W.J. Rogan, and G. Lucier. 1997. 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, pp. 211-244.

Brouwer, A., U.G. Ahlborg, and F.X. van Leeuwen, et al. 1998. 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, pp. 16271643.

67

Ibid.

Turyk, M.E., H.A. Anderson, and S. Freels, et al. 2006. Associations of organochlorines with endogenous hormones in

male Great Lakes fish consumers and nonconsumers. Environmental Research, v. 102, n. 3, pp. 299-307.

68

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

Sagiv, Sharon K., J. Kevin Nugent, T. Berry Brazelton, et al. 2008. Prenatal Organochlorine Exposure and Measures of

Behavior in Infancy Using the Neonatal Behavioral Assessment Scale (NBAS). Environmental Health Perspectives, v.

116, n. 5, pp. 666-673.

Schantz, Susan L., John J. Widholm, and Deborah C. Rice. 2003. Effects of PCB exposure on neuropsychological

function in children. Environmental Health Perspectives, v. 111, n. 3, pp. 357-376.

Stewart, Paul, Jacqueline Reihman, and Edward Lonky, et al. 2000. Prenatal PCB exposure and neonatal behavioral

assessment scale (NBAS) performance. Neurotoxicology and Teratology, v.22, n. 1, pp. 21-29.

Stewart, Paul, Susan Fitzgerald, and Jacqueline Reihman, et al. 2003. Prenatal PCB Exposure, the Corpus Callosum,

and Response Inhibition. Environmental Health Perspectives, v. 111, n. 13, pp. 1670-1677.

Stewart, Paul W., Edward Lonky, and Jacqueline Reihman, et al. 2008. The Relationship between Prenatal PCB

Exposure and Intelligence (IQ) in 9-Year-Old Children. Environmental Health Perspectives, v. 116, n. 10, pp. 1416(continued...)

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

semen quality, lower age of onset of puberty, and shorter height at maturity.69

In recent years, Congress has expressed concern about the possible effects on thyroid function of

perchlorate, a common pollutant in drinking water and soil. Perchlorate is formed naturally but

also is manufactured for various products including explosives, fireworks, road flares, and solid

rocket fuel and often is associated in the environment with sites operated by the Department of

Defense. Perchlorate is known to disrupt the uptake of iodine by the thyroid, and health effects

associated with perchlorate exposure are expected to parallel those caused by iodine deficiency.

Iodine deficiency decreases the production of thyroid hormones, which help regulate the body’s

metabolism and growth. A key concern is that impairment of thyroid function in pregnant women

can affect brain development in fetuses and nursing infants and can lead to attention deficit

disorder, generally delayed development, and decreased learning capacity.70 Several studies have

found that at significantly higher levels of perchlorate exposure than the amounts typically

observed in the environment, thyroid changes occur in humans.71 However, a 2006 study by the

Centers for Disease Control and Prevention (CDC) of a representative sample of the general U.S.

population found that environmental exposures to perchlorate have an effect on thyroid hormone

levels in women who are deficient in iodine (and on levels of the pituitary gland’s thyroid

stimulating hormone in all women). (No effect was found in men.) Fully 36% of the 1,111 women

in this study were found to be iodine deficient.72

Animal Studies

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. 73

(...continued)

1422.

69

Dhooge, Willem, Nicolas van Larebeke, and Gudrun Koppen, et al. 2006. Serum Dioxin-like Activity Is Associated

with Reproductive Parameters in Young Men from the General Flemish Population. Environmental Health

Perspectives, v. 114, n. 11, pp. 1670-1676.

Hauser, Russ, Paige Williams, and Larisa Altshul, et al. 2005. Evidence of Interaction between Polychlorinated

Biphenyls and Phthalates in Relation to Human Sperm Motility. Environmental Health Perspectives, v. 113, n. 4, pp.

425-430.

70

Zoeller, R. Thomas, Amy L.S. Dowling, and Carolyn T.A. Herzig, et al. 2002. Thyroid hormone, brain development,

and the environment. Environmental Health Perspectives, v. 110, Supp. 3, pp. 355-361.

71

Kelsh, Michael A., Patricia A. Buffler, and Jorge J. Daaboul, et al. 2003. Primary congenital hypothyroidism,

newborn thyroid function, and environmental perchlorate exposure among residents of a southern California

community. Journal of Occupational Environmental Medicine, v. 45, n. 10, pp. 1116-1127.

72

Blount, Benjamin C., James L. Pirkle, and John D. Osterloh, et al. 2006. Urinary Perchlorate and Thyroid Hormone

Levels in Adolescent and Adult Men and Women Living in the United States, Centers for Disease Control and

Prevention, in Environmental Health Perspectives, v. 114, n. 12, pp. 1865-1871. For more information about

perchlorate, see CRS Report RS21961, Perchlorate Contamination of Drinking Water: Regulatory Issues and

Legislative Actions, by (name redacted).

73

Jobling, Susan, Monique Nolan, and Charles R. Tyler, et al. 1998. “Widespread sexual disruption in wild fish,”

Environmental Science and Technology, v. 32, n. 17, pp. 2498-2506.

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Fish

Feminization of male fish due to exposure to endocrine-disrupting chemicals in the environment

is an increasing concern.74 Fish appear to be useful as sentinels for the presence and possible

hazard of endocrine-disrupting chemicals in the aquatic environment, since they are currently the

only vertebrates for which the connection between environmental contamination and adverse

effects on health has been established in both field75 and laboratory76 studies. In addition, fish are

exposed to any contaminants in their aquatic habitats through skin absorption, food ingestion, and

dissolved gas absorption across the gills. Aquatic food chains often are long, relative to terrestrial

food chains, so bioaccumulation potential may be greater. 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.

Feminization of male fish collected from British rivers near the effluent from wastewater

treatment plants alerted the scientific community to the potential hazard of endocrine-disrupting

chemicals (specifically, synthetic female hormones) in the environment.77 Feminization of males

was confirmed by the presence of eggs in the testes and vitellogenin (a protein in the yolk of

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

ability to reproduce.) More recently, marine fish populations in the English Channel and in Tokyo

Bay have shown evidence of feminization.78

In the United States, studies have found feminized male fish in diverse locations. For example,

there is a report of complete sex reversal of male salmon in the state of Washington.79 Others have

74

However, feminization and any resulting effects on fish populations are not the only concerns. Another potential

effect might be immune system changes and perhaps greater susceptibility to infections and other diseases. It was fish

kills and skin lesions on a number of fish species in the South Branch of the Potomac River that prompted the Blazer et

al. (2007) study of smallmouth bass which is described below.

75

Folmar, Leroy C., George R. Gardner, and Martin P. Schreibman, et al. 2001. Vitellogenin-induced pathology in

male summer flounder (Paralichthys dentatus). Aquatic Toxicology, v. 51, pp. 431-441.

Folmar, Leroy C., Nancy D. Denslow, and Vijayasri Rao, 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, pp. 1096-1100.

Harries, J.E., D.A. Sheahan, and S. Jobling, et al. 1997. Estrogenic activity in five United Kingdom rivers detected by

measurement of vitellogenesis in caged male trout. Environmental Toxicology and Chemistry, v. 16, pp. 534-542.

Jobling, Susan, Monique Nolan, and Charles R. Tyler, et al. 1998. Widespread sexual disruption in wild fish.

Environmental Science and Technology, v. 32, pp. 2498-2506.

76

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, pp. 243-253.

77

Jobling, Susan, Monique Nolan, and Charles R. Tyler, et al. 1998. Widespread sexual disruption in wild fish.

Environmental Science and Technology, v. 32, n. 17, pp. 2498-2506.

78

Gross-Sorokin M.Y., S.D. Roast, and G.C. Brighty. 2006. Assessment of feminization of male fish in English rivers

by the Environment Agency of England and Wales. Environmental Health Perspectives, v. 114 (Supplement 1), pp.

147-151.

79

James J. Nagler, Jerry Bouma, and Gary H. Thorgaard, 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, pp.

67-69.

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reported intersex trout in Rocky Mountain National Park and Glacier Park,80 hornyhead turbot in

southern California,81 and white sucker in Boulder, CO.82

In spring of 2004, scientists found a high prevalence of feminized smallmouth bass in the South

Branch of the Potomac River, which drains a rural area of West Virginia.83 Water samples in the

area detected a number of known endocrine disruptors with estrogenic activity including several

pesticides, a degradation product of industrial phenols, and two polybrominated diphenyl ethers

(PBDEs), but the study authors concluded that a combination of contaminants probably was

responsible for the observed effects on fish. 84 Recent research has demonstrated that mixtures of

estrogenic chemicals can act in combination, exerting adverse effects on fish even when each

component is present at a level below the threshold level for producing such effects.85 Fish were

also taken from several other rural sites in West Virginia that were characterized by low human

population and low intensity agriculture. At these sites scientists found a lower prevalence of

feminized bass.86 In contrast, in a more heavily populated and more intensely agricultural part of

Virginia, 80 to 100% of male bass taken from the Shenandoah River were feminized.87 The

cellular responses to ethynylestradiol (the bioactive component of contraceptive pills) that lead to

feminization have been documented.88

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

have been detected in environmental samples, especially in pulp mill effluents, and studies have

linked such effluents to masculinized female fish.89 Although both androgenic and estrogenic

effects have been observed in fish, estrogenic activity appears to be more ubiquitous and hence

80

National Park Service. News release, Feb. 26, 2008. “Airborne contaminants study released: Measurable levels

detected in twenty western U.S. and Alaska National Parks.” p. 2.

81

Renner, Rebecca. 2009. Sex-changing fish: caused by contamination or nature? Environmental Science &

Technology, Article ASAP, Publication Date (Web): January 14, 2009, http://pubs.acs.org/doi/abs/10.1021/es8036912,

visited Jan. 21, 2009.

82

Vajda, Alan, Larry Barber, and James L. Gray, et al. 2008. Reproductive disruption in fish downstream from an

estrogenic wastewater effluent. Environmental Science & Technology, v. 42, n. 9, pp. 3407–3414.

83

Blazer, V.S., L.R. Iwanowicz, and D.D. Iwanowicz, et al. 2007. Intersex (testicular oocytes) in smallmouth bass from

the Potomac River and selected nearby drainages. Journal of Aquatic Animal Health, v. 19, pp. 242-253.

84

Ibid., p. 250.

85

Brian, Jayne V., Catherine A. Harris, and Martin Scholze, et al. 2007. Evidence of estrogenic mixture effects on the

reproductive performance of fish. Environmental Science & Technology, v. 41, n. 1, pp. 337-344.

86

Ibid.

87

Ibid.

88

Filby, A.L., K.L. Thorpe, G. Maack and C.R. Tyler. 2007. Gene expression profiles revealing the mechanisms of

anti-androgen- and estrogen-induced feminization in fish. Aquat. Toxicol. 81(2):219-231.

89

Larsson, D.G., M. Adolfsson-Erici, and P. Thomas. 2006. Characterization of putative ligands for a fish gonadal

androgen receptor in a pulp mill effluent. Environmental Toxicology and Chemistry, v. 25, n. 2 (Feb.), p.419-427.

Galloway, Brendan, K.R. Munkittrick, and S. Currie, 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.

Larsson, D.G.J., H. Hallman, and L. Forlin. 2000. More male embryos near a pulp mill. Environmental Toxicology and

Chemistry, v. 19, n. 12, pp. 2911-2918.

Munkittrick, Kelly R., M.E. McMaster, and M.R. Servos, et al. 2000. 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 (1999), (ed. Bergitta Norberg), Bergen, Norway.

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better studied. 90 Moreover, the presence of estrogenic substances in some U.S. rivers and streams,

especially near outfalls from wastewater treatment plants, has been well documented. 91

The significance of the numerous observations of feminized male fish for the sustainability of

wild populations was unknown until recently. The results of a study in the Experimental Lakes

Area of northwestern Ontario, Canada, demonstrated that sustainability might be adversely

affected by endocrine-disrupting chemicals. Chronic exposure of fathead minnow in one lake to

low concentrations92 of the potent synthetic estrogen 17α-ethynylestradiol (EE2) nearly

extinguished this population after only two years.93 EE2, which is the most common component

of birth control pills, is often found in wastewater plant effluent and has been found in U.S.

surface water at concentrations ranging from 0.1 to 5.1 ng/l. 94 Academic scientists working

together with pharmaceutical company scientists have derived a predicted no-effect concentration

for EE2 of 0.35 ng/l for aquatic life in general.95

Other Wild Vertebrates

Reproductive or developmental problems potentially resulting from hormone exposure have been

observed in other wild vertebrate species, especially fish-eating species, including birds (such as

gulls, terns, ospreys, eagles, and pelicans), polar bears,96 Florida panthers,97 alligators,98 river

90

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, pp. 68-73.

Bjerselius, Rickard, K. Lundstedt-Enkel, and K.H. Olsen, et al. 2000. Estrogen in food or water severely [a]ffect the

male goldfish (Carassius auratus) sexual behavior. In: 6th International Symposium on the Reproductive Physiology of

Fish (1999), (ed. Bergitta Norberg), Bergen, Norway.

Jobling, Susan, D. Sheahan, and J.A. Osborne, et al. 1996. Inhibition of testicular growth in rainbow trout

(Oncorhynchus mykiss) exposed to estrogenic alkylphenolic chemicals. Environmental Toxicology and Chemistry, v.

15, pp. 194-202.

Nash, J.P., D.E. Kime, and L.T. Van der Ven, et al. 2004. Long-term exposure to environmental concentrations of the

pharmaceutical ethynylestradiol causes reproductive failure in fish. Environmental Health Perspectives, v. 112, n. 17,

pp. 1725-1733.

Kramer, V.J., S. Miles-Richardson, and S.L. Pierens, et al. 1998. Reproductive impairment and induction of alkalinelabile phosphate, a biomarker of estrogen exposure, in fathead minnows (Pimephales promelas) exposed to waterborne

17b-estradiol. Aquatic Toxicology, v. 40, pp. 335-360.

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.) pp. 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, pp. 243-253.

91

Campbell, Chris G., Sharon E. Borglin, and F.Bailey Green, et al. 2006. Biologically directed environmental

monitoring, fate, and transport of estrogenic endocrine disrupting compounds in water: A review. Chemosphere, v. 65,

p.1265-1280.

92

The concentrations were 5-6 nanograms of EE2 per liter of water (ng/l), which also may be expressed as 5-6 parts per

trillion (ppt).

93

Kidd, Karen, A., Paul J. Blanchfield, and Kenneth H. Mills, et al. 2007. Collapse of a fish population after exposure

to a synthetic estrogen. Proceedings of the National Academy of Sciences, v. 104, n. 21, pp. 8897-8901.

94

Campbell et al. op cit.

95

Caldwell, Daniel J., Frank Mastrocco, and Thomas H. Hutchinson, et al. 2008. Derivation of an aquatic predicted noeffect concentration for the synthetic hormone, 17α-ethinyl estradiol. Environmental Science & Technology, v. 42, pp.

7046-7054.

96

Braathen, Marte, Andrew E. Derocher, and Oystein Wiig, et al. 2004. Relationships between PCBs and thyroid

(continued...)

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otters,99 and mink.100 In addition, there is growing evidence for effects of environmental exposure

to endocrine disruptors in marine mammals.101 The accumulation of persistent chlorinated organic

chemicals, such as PCBs, in seals and dolphins has been well documented, 102 and research

indicates that the thyroid hormone system in harbor seals is “highly sensitive to disruption by

environmental contaminants,” particularly by PCBs.103 Laboratory studies of a beluga whale

protein that is key in many endocrine-disrupting effects (the aryl hydrocarbon receptor) reveal

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

responses can be elicited by contaminants in the environment.104

However, as is the case with humans, cause-and-effect relationships are difficult (or impossible)

to show experimentally for marine mammals, because direct toxicity testing is precluded by

logistical, legal, and ethical constraints.

Invertebrates

There is evidence of endocrine effects in some marine invertebrates. Ambiguous genitalia have

been found by the EPA in Maine bivalves, allegedly due to herbicides. 105 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

(...continued)

hormones and retinol in female and male polar bears. Environmental Health Perspectives, v. 112, n. 8, pp. 826-833.

97

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, pp. 79-86.

98

Guillette, Louis J., Timothy S. Gross, and Denise A. Gross, et al. 1995. Gonadal steroidogenesis in vitro from

juvenile alligators obtained from contaminated or control lakes,” Environmental Health Perspectives, v. 103, n. 4, pp.

31-36.

99

Grove, R.A., and C.J. Henny. 2008, Environmental contaminants in male river otters from Oregon and Washington,

USA, 1994-1999. Environmental Monitoring and Assessment, v. 145, pp. 49-73.

100

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, pp. 245-253.

101

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, pp. 159-166.

Ross, Peter S. 2000. Marine mammals as sentinels in ecological risk assessment, Human and Ecological Risk

Assessment, v. 6, pp. 29-46.

102

Watanabe, M., K. Kannan, and 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, pp. 1566-1574.

Reddy, M.L., J.S. Reif, and 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, pp. 171-182.

103

Tabuchi, Maki, Nik Veldhoen, and Neil Dangerfield, et al. 2006. PCB-related alteration of thyroid hormones and

thyroid hormone receptor gene expression in free-ranging harbor seals (Phoca vitulina). Environmental Health

Perspectives, v. 114, n. 7, pp. 1024-1031.

104

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, n. 1, pp. 41-56.

105

Van Beneden, R.J., G.R. Gardner, and N.J. Blake, et al. 1993. Implication for the presence of transforming genes in

gonadal tumors in two bivalve mollusk species. Cancer Research, v. 53, pp. 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, pp. 29-43.

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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 anti-fouling 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.

Laboratory Rodents

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 effects that would impair fertility in every exposed mouse, but in no unexposed

mouse. 106 In addition, uterine cancer occurred in about one-third of the exposed mice, but not in

the unexposed mice.107 (An expert panel of the National Toxicology Program’s Center for the

Evaluation of Risks to Human Reproduction found in 2006 that the results of rodent studies were

sufficient to conclude that genistein produces reproductive and developmental toxicity in

offspring of rodents, 108 but another expert panel report concluded that evidence was insufficient to

demonstrate that soy formula would or would not produce such effects.109)

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

organs from very low levels of exposure to DES, bisphenol-A, an ingredient in some plastic, and

other substances.110 Other studies found no effects.111 The resulting controversy has prompted

some scientists to note that the design of laboratory studies often has contributed to the confusion,

because statistical measures were not employed to ensure adequate power to detect subtle

effects.112 In 2001, an expert workshop to evaluate the data on low-dose effects of endocrine

disruptors concluded that biological effects have been shown to occur following exposure to

106

Newbold, R.R., E.P. Banks, and B. Bullock, et al. 2001. Uterine adenocarcinoma in mice treated neonatally with

genistein. Cancer Research, v. 61, n. 11, pp. 4325-4328.

107

Ibid.

108

U.S. Department of Health and Human Services, National Toxicology Program, Center for the Evaluation of Risks

to Human Reproduction. 2006. NTP-CERHR Expert Panel Report on the Reproductive and Developmental Toxicity of

Genistein. NTP-CERHR-GENISTEIN-06.

109

National Toxicology Program, Center for the Evaluation of Risks to Human Reproduction. 2006. NTP-CERHR

Expert Panel Report on the Reproductive and Developmental Toxicity of Soy Formula. NTP-CERHR-SOY

FORMULA-06.

110

U.S. Department of Health and Human Services (HHS), National Toxicology Program, Center for the Evaluation of

Risks to Human Reproduction, “NTP-CERHR Monograph on the Potential Human Reproductive and Developmental

Effects of Bisphenol A,” NIH Publication No. 08-5994, September 2008, 321pp, at

http://cerhr.niehs.nih.gov/chemicals/bisphenol/bisphenol.pdf.

111

Ibid.

112

Scholze, Martin, and Andreas Kortenkamp. 2007. Statistical power considerations show the endocrine disruptor

low-dose issue in a new light. Environmental Health Perspectives, v. 115, Supp. 1, pp. 84-90.

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some estrogenic compounds at very low levels. 113 The question remains whether those effects

would adversely affect rodent health, however.114

Environmental Exposure to Potential Endocrine Disruptors

Concern about possible human or wildlife hormone disruption has been fueled by the limited

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

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

released to the environment. For example, pesticides such as DDT and dieldrin, now banned, still

are found in many rivers and streams.115 Wastewater effluent from sewage treatment plants

contains many potential endocrine disruptors, including synthetic (pharmaceutical) hormones.116

The U.S. Geological Survey has found synthetic hormones in U.S. streams.117 Concentrated

animal feeding lots are another potential source of environmental contamination. 118 Other

potential endocrine disruptors are prevalent in certain foods, such as soy-based milk substitutes,

because soy beans contain phytoestrogens (i.e., isoflavonoids such as genistein) at relatively high

levels.119 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.120 Others say 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.

Data collected during the National Health and Nutrition Examination Survey indicates that most

people in the United States are exposed to various potential endocrine disruptors that are in

widespread use. Bisphenol A was detected in more than 90% of the surveyed population.121 In

113

National Toxicology Program’s Report of the Endocrine Disruptors Low Dose Peer Review. (2001) National

Toxicology Program, U.S. Department of Health and Human Services, http://ntp.niehs.nih.gov/ntp/htdocs/liason/

LowDosePeerFinalRpt.pdf.

114

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.

115

National Park Service. News release, Feb. 26, 2008. “Airborne contaminants study released: Measurable levels

detected in twenty western U.S. and Alaska National Parks.” p. 2.

116

Liney, Katherine E., Josephine A. Hagger, and Charles R. Tyler, et al. 2006. Health effects in fish of long-term

exposure to effluents from wastewater treatment works. Environmental Health Perspectives, v. 114, Supp. 1, pp. 81-89.

EPA. Expanded investigations of pharmaceuticals in fish tissue, http://www.epa.gov/waterscience/ppcp/studies/fishexpand.html.

117

Kolpin, Dana W., Edward T. Furlong, and Michael T. Meyer, et al. 2002. Pharmaceuticals, hormones, and other

organic wastewater contaminants in U.S. streams, 1999-2000: A national reconnaissance. Environmental Science &

Technology, v. 36, n. 6, pp. 1202-1211.

118

Durhan, Elizabeth J., Christy S. Lambright, and Elizabeth A. Makynen, et al. 2006. Identification of metabolites of

trenbolone acetate in androgenic runoff from a beef feedlot. Environmental Health Perspectives, v. 114, Supp. 1, pp.

65-68.

119

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

120

Easterbrook, Gregg. 1999. Another phony health scare. Science fiction. New Republic, v. 221, Aug. 30, 1999, pp.

20-22.

121

For more information about bisphenol A, see CRS Report RS22869, Bisphenol A (BPA) in Plastics and Possible

Human Health Effects, by (name redacted) and (name redacted).

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addition, the survey found almost universal American exposure to low levels of the most common

phthalates, usually multiple phthalates.122 Women tend to have greater exposure than men, but

children appear to be the group most exposed to di-(2-ethylhexyl) phthalate (DEHP), dibutyl

phthalate (DBP), and benzyl butyl phthalate (BBP). Studies of amniotic fluid have also

documented exposure to multiple phthalates for human fetuses. 123 More generally, babies may be

the most heavily exposed group.124 Children may be exposed to such chemicals through their

mothers’ blood prenatally, through breast milk, or by eating certain foods.125

Release of a chemical to the environment and even proof of exposure to the chemical do not

necessarily lead to toxic effects, even for vulnerable populations of animals or people. Some

believe that available data are reassuring, because known potential disruptors of endocrine

function generally are present in the environment at very low levels. 126

On the other hand, there are no measurements at all of environmental concentrations for most

chemicals in the environment, some of which might be affecting hormones. Some known

hormone disruptors, such as phthalates or bisphenol A, are ubiquitous at low levels, raising the

question of long-term effects and possible additive or synergistic effects with continual

exposure. 127 Of particular concern are chemicals designed to be biologically active in humans or

in pests that are 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. Other chemicals, such as PCBs and

some dioxins, are persistent in the environment and are known to bioconcentrate in the food

chain.

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 in 1999:

122

Ibid.

Silva, M.J., J.A. Reidy, and A.R. Herbert, et al. 2004. Detection of phthalate metabolites in human amniotic fluid.

Bulletin of Environmental Contamination and Toxicology, v. 72, pp. 1226-1231.

124

Wormuth, Matthias, Martin Scheringer, and Meret Vollenweider, et al. 2006. What are the sources of exposure to

eight frequently used phthalic acid esters in Europeans? Risk Analysis, v. 26, n. 3, pp. 803-824.

125

For more information about phthalates, see CRS Report RL34572, Phthalates in Plastics and Possible Human

Health Effects, by (name redacted) and (name redacted).

126

Scientists disagree about whether it is likely that animals or people would experience adverse effects of exposure to

very low doses of chemicals with the potential to disrupt endocrine function. Detailed arguments for and against the

hypothesis of low-dose effects are provided in Richter, C.A., et al. 2007, In vivo effects of bisphenol A in laboratory

rodent studies, Reproductive Toxicology, v. 24, n. 2, pp. 199-224; and Willhite, C.C., et al., 2008, Derivation of a

bisphenol A oral reference dose (RfD) and drinking-water equivalent concentration, Journal of Toxicology and

Environmental Health, Part B, Critical Reviews, v. 11, n. 2, pp. 69-146.

127

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.

123

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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.128

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.129 On January 19, 2001, EPA and NRDC agreed to settle the

lawsuit. The settlement agreement states that endocrine disruptor screening would begin no later

than spring 2004.130 That did not occur.

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. Several test protocols

approved for use in the screening program have been inadequately validated, according to these

stakeholders. Since chemical producers would conduct the actual screening of chemicals, they

want to ensure that screening requirements established by EPA would 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. On the other hand, most scientists appear optimistic about the value of

screening chemicals with the methods that are being developed, as long as they are validated prior

to being employed on hundreds, if not thousands, of chemicals.

A key question then is how flexible the adopted program should be: Would it be allowed to

evolve quickly in response to new knowledge?

128

National Academy of Sciences, op cit., p. 7.

Natural Resources Defense Council v. U.S. Environmental Protection Agency, No. C993701CAL, Jan. 19, 2001.

130

Ibid.

129

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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 inspection of internal

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.

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. Others contend that animal models provide

valuable information about the potential human health effects of chemical exposure, and animal

welfare is protected by laboratory guidelines for their care. Alternative test methods for many

kinds of effects have not been developed, it is argued.

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” (P.L. 103-43, 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 (P.L. 106-545). EPA is a member of this committee.

Regulation of Endocrine Disruptors

If EPA determines through the endocrine disruptor screening program or some other program that

a chemical poses a risk to public health due to its effects on endocrine systems, the agency is

authorized to act under its existing legal authorities. The authorities available to EPA that are

likely to be most relevant to the protection of public health from toxic chemicals derive primarily

from the Safe Drinking Water Act, the Federal Water Pollution Control Act, the Federal

Insecticide, Fungicide, and Rodenticide Act (FIFRA), and the Toxic Substances Control Act.131

131

For brief summaries of these laws, see CRS Report RL30030, Clean Water Act: A Summary of the Law, by (name re

dacted); CRS Report RL31921, Pesticide Law: A Summary of the Statutes, by (name redacted); CRS Report

(continued...)

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Alternatively, EPA may refer a substance to another agency for action. For example, EPA might

suggest that the Food and Drug Administration or the Occupational Safety and Health

Administration regulate the use of particular chemicals to reduce risks.

Because many chemicals that may be endocrine disruptors have a variety of uses and may be

released to the environment at several stages in their lifecycles, multiple agencies are likely to

have a stake in their regulation. In such cases, any overlapping or inconsistent risk assessments,

guidelines, or regulations are likely to spark controversies. For example, EPA and FDA at one

time published risk assessments for mercury and guidance for consumers of fish containing

mercury that appeared to be inconsistent. The resulting controversy was quelled only when the

two agencies issued a joint communication. Some in Congress might be expected to urge

coordination of agency efforts to avoid such controversies. Cooperation among agencies also

might lead to more cost-effective regulation, an objective of President Obama and many

Members of Congress.

Another concern due to multiple uses and releases of chemicals and divided authorities for

regulating them might be that risks could be under-estimated and thus under-regulated if they

were assessed for each source of exposure and each exposed population individually, rather than

aggregated from all sources, combined with risks from chemicals with similar effects, and

calculated cumulatively over time. This is a particular concern when the health effects of

exposure are not immediate or not obvious, as might be the case for certain reproductive or

developmental effects. This situation arguably occurred with respect to phthalates: it was the

cumulative risk assessment conducted by the interagency National Toxicology Program that

caused scientists to express concern about possible consequences of exposure to phthalates from

multiple sources for infants and fetuses. Scientists’ concern prompted Congress to require action

by regulatory agencies.

Congress might wish to evaluate whether agencies are adequately assessing cumulative and

aggregate risks. Various groups of scientists have called for increased use of cumulative risk

assessments.132 Congress has acted in the past to require cumulative and aggregate risk

assessments for pesticides, when it enacted the FQPA. The Kid-Safe Chemicals Act (H.R. 6100/S.

3040) in the 110th Congress would have extended that requirement to other chemicals.

The nature of endocrine disruption may challenge would-be regulators. Disruption may consist of

enhancement or inhibition of effects that vary widely within populations of humans and wildlife.

Under some circumstances, disruption of a hormonally regulated process even may be beneficial.

Moreover, endocrine disruption may not fit the traditional model of the relationship between

increasing chemical exposure and effects, and effects may vary depending on the timing of

(...continued)

RL31243, Safe Drinking Water Act (SDWA): A Summary of the Act and Its Major Requirements, by (name redacted);

and CRS Report RL31905, The Toxic Substances Control Act (TSCA): A Summary of the Act and Its Major

Requirements, by (name redacted). These and other environmental laws also are summarized in CRS Report

RL30798, Environmental Laws: Summaries of Major Statutes Administered by the Environmental Protection Agency

(EPA), by (name redacted) et al.

132

Committee on Improving Risk Analysis Approaches Used by the U.S. EPA, National Research Council of the

National Academies. 2008. Science and Decisions: Advancing Risk Assessment. Prepublication Copy. Washington

DC: The National Academies Press. p. 9.

Committee on the Health Risks of Phthalates, National Research Council of the National Academies. 2008. Phthalates

and Cumulative Risk Assessment: The Tasks Ahead. Washington, DC: The National Academies Press. 142 p.

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exposure and other factors. Early indicators of endocrine disruption may not be considered

adverse. At what point might regulators intervene, and under what authority? Some laws might

require substantial evidence of severe effects prior to agency action, while others might authorize

action when risks are less certain. Congress may consider whether statutes provide agencies with

appropriate authority and directives for regulating endocrine-disrupting chemicals.

Congress might also consider whether agency budgets are adequate to support appropriate levels

of research and regulatory activity. Within the context of the overall federal budget, funding for

research, chemical screening programs, and regulatory activity, in the view of some, should be

proportionate to congressional concern about the potential risks to human or animal health posed

by endocrine disruptors.

In the 111th Congress, H.R. 1145 would require each water resources research and technology

institute, established under the Water Resources Research Act of 1984, to conduct technical

research on prevention and removal of contaminants of emerging concern, including endocrinedisrupting compounds, pharmaceuticals, and personal care products. This bill also would

establish a national interagency coordinating committee to plan and report to Congress on waterrelated research. In addition, H.R. 1145 would direct an interagency committee to evaluate the

adequacy of funding levels and the distribution of funding across agencies. The bill would

authorize to be appropriated to the National Oceanic and Atmospheric Administration for

coordination and outreach activities $10 million through 2014.

Conclusion

Chemicals with the potential to disrupt endocrine systems are frequently present in the

environment, particularly in rivers and streams, and in some consumer products. Exposure to high

levels of some of these chemicals has been shown to harm insects, some vertebrate wildlife, and

aquatic life by affecting reproductive and other hormone-dependent processes. In controlled

laboratory experiments, some scientists have found that relatively low levels of certain chemicals

harm the endocrine systems of fish and wildlife, particularly when exposure is continuous,

chemicals bioaccumulate, or animals are exposed simultaneously to several chemicals with

similar effects. Fish studies provide the most compelling evidence that endocrine disruption

might be occurring due to environmental exposures to contaminants. Reproductive or

developmental problems potentially resulting from hormone exposure also have been observed in

birds, polar bears, Florida panthers, alligators, river otters, mink, and marine invertebrates.

Some scientists have hypothesized that existing environmental levels of chemical pollutants

might be harming human health by disrupting endocrine functions. They point to increased rates

of certain human health problems, demonstrated harm to human endocrine systems when people

have been exposed to high levels of certain chemicals, and epidemiologic studies that have found

statistical associations between exposure to environmental levels of potential endocrine disruptors

and diabetes, malformations, sexual function, cognitive development, thyroid function, and other

potentially hormone-mediated effects. The environmental endocrine disruptor hypothesis is

disparaged by other scientists, because known potential disruptors of endocrine function generally

are present in the environment at very low levels, especially compared to the levels of hormones

that are naturally present in the human body, as well as in some of the plants that humans eat.

Many scientists who are not convinced there is an environmental problem nonetheless are

concerned about the issue, because there are no measurements at all of environmental

concentrations for most chemicals, people are known to be exposed to low levels of multiple

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environmental contaminants with endocrine-disrupting potential for which potential cumulative

effects have not been assessed, and some studies suggest the public health consequences of

exposure might be significant.

Congress might be asked to consider various issues connected to the endocrine disruptor

hypothesis. In 1996, Congress mandated chemical screening for endocrine-disrupting potential.

The screening program has not yet been launched, and some argue that it should not be launched

until the complete test battery is validated. Others are concerned about the extent to which EPA

might rely on animal experimentation in its screening program. Once the program is

implemented, Congress might consider whether statutes and regulations provide adequate

authority and direction with respect to the influence of any findings of endocrine disruption on

the regulation of specific chemicals, chemical groups, uses, or products.

Author Contact Information

(name redacted)

Specialist in Environmental Policy

[redacted]@crs.loc.gov, 7-....

Congressional Research Service

(name redacted)

Specialist in Natural Resources Policy

[redacted]@crs.loc.gov, 7-....

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