Chapter 2: Introduction/Background

2.1 General Background 2.2 Generic Issues

Since the publication of Rachel Carson’s Silent Spring (Carson, There are a number of complex issues that must be considered when
1962), there has been increasing awareness that chemicals in the evaluating the effects of endocrine disruptors (Ashby et al., 1997b;
environment can exert profound and deleterious effects on wildlife Ashby, 2000). These are summarized in this chapter and are
populations and that human health is inextricably linked to the discussed in detail in subsequent chapters (detailed references are also
health of the environment. The last two decades, in particular, have provided in subsequent chapters). Studies that clearly address
witnessed a growing scientific concern, public debate, and media exposure–outcome relationships are the most valuable in assessing
attention over the possible deleterious effects in humans and wildlife the impact of EDCs on wildlife and human health. Unfortunately,
that may result from exposure to chemicals that have the potential to many of the epidemiological or wildlife studies do not have good
interfere with the endocrine system. The intensity of the concerns measures of exposure, which limits our ability to draw firm
and lack of consensus among scientists can best be ameliorated by an conclusions from them. This problem is especially prevalent for
objective evaluation of the available scientific data on the potential those EDCs that are rapidly degraded in the environment or in the
adverse effects of these chemicals from a global perspective. human body. This means that the exposure that might have caused
Countries lacking the necessary infrastructure to monitor and an adverse outcome (e.g., a reproductive deficit) is not detectable at
evaluate these chemicals expressed a particular need for an objective the time that clinical manifestations become evident. For this reason,
international assessment. The document builds on existing most of the EDCs that are relied on to draw cause-and-effect
assessment documents and reviews (see Table 2.1) and is not relationships are those that are biologically and ecologically persistent
intended as a thorough, comprehensive literature review. Only peer- (e.g., PCBs, DDT, and dioxins). A number of these POPs are
reviewed literature or publicly available reports were evaluated. It is known to endanger human health and ecosystems and have been the
not a risk assessment or consensus document. Neither is it an subject of global conventions. Twelve POPs were singled out for
assessment of available test methodologies for detecting EDCs. Both elimination and/or reduction in a legally binding global treaty,
the OECD and a number of national organizations are addressing which was signed by 115 countries in Stockholm in May 2001.
these issues (ECETOC, 1996; OECD, 1998a, 1998b, 1999a; US These initial 12 high-priority POPs were selected based on data that
EPA, 1998a; Kanno et al., 2000). demonstrate adverse exposure–outcome relationships in humans and
EDCs encompass a variety of chemical classes, including natural wildlife, and processes are being implemented to add additional
and synthetic hormones, plant constituents, pesticides, compounds chemicals to the list.
used in the plastics industry and in consumer products, and other This document emphasizes those chemical exposures and
industrial by-products and pollutants. They are often pervasive and adverse human and ecological outcomes where an indication of cause
widely dispersed in the environment. Some are persistent, can be and effect via multiple mechanisms of endocrine disruption has been
transported long distances across national boundaries, and have been demonstrated or hypothesized. These case studies also illustrate the
found in virtually all regions of the world. Others are rapidly degraded types of interferences that are of importance and the variety of
in the environment or human body or may be present for only short adverse health outcomes that can be exhibited.
periods of time but at critical periods of development. One of the major issues that needs to be addressed when
evaluating the impact of EDCs on human health and the
environment is whether effects reported in the literature represent
List of Abbreviations isolated cases or more global responses. For example, diminished
wildlife populations adjacent to a significant point source may not be
AhR Aryl hydrocarbon receptor
indicative of global responses. In contrast, relatively small effects on
DDE Dichlorodiphenyl dichloroethylene
DDT Dichlorodiphenyl trichloroethane
wildlife or human health points might have great impact if those
EDCs Endocrine-disrupting chemicals responses are global in nature. Another problem in assessing the
ECETOC European Centre for Ecotoxicology and Toxicology of Chemicals health impacts of EDCs is that some of these chemicals have been
ER Estrogen receptor (α and β isoforms) shown to contribute to the incidence of common diseases of
IUPAC International Union of Pure and Applied Chemistry multifactorial etiology (e.g., infertility, cancer, neurobehavioral
JEA Japan Environment Agency deficits). Therefore, it will be difficult to attribute effects in
LH Luteinizing hormone traditional epidemiology studies to EDCs unless those effects are
MRC Medical Research Council seen in large numbers of people.
NRC National Research Council
NTP National Toxicology Program 2.3 Mechanisms of Endocrine Disruption in
OECD Organisation for Economic Co-operation and Development Humans and Wildlife
PCBs Polychlorinated biphenyls
PCDDs Polychlorinated dibenzodioxins There are a number of mechanisms whereby EDCs can modulate
PCDFs Polychlorinated dibenzofurans endocrine systems and potentially cause adverse effects (see also
POPs Persistent organic pollutants Chapter 3). The generally accepted paradigm for receptor-
SETAC Society for Environmental Toxicology and Chemistry mediated responses includes binding of hormone to its receptor at
TCDD 2,3,7,8-Tetrachlorodibenzyl-p-dioxin the cell surface, cytoplasm, or nucleus, followed by a complex series
UBA Umweltbundesamt (German Environmental Agency) of events that lead to changes in gene expression characteristic for a
UNEP United Nations Environment Programme specific hormone (Birnbaum, 1994). It is thought that changes in
US EPA United States Environmental Protection Agency gene expression represent an early but critical step in the regulation

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IPCS GLOBAL ASSESSMENT OF EDCS

Table 2.1 - Selected Workshop/Committee/Assessment Reports on Endocrine Disruption

Year Organization Purpose/Scope Reference
1992 World Wildlife Fund Examination of the commonalities of adverse effects in wildlife, experimental animals, Colborn and Clement, 1992
and humans. Produced the “Wingspread Consensus Statement”
1994 National Institute of Review of cellular biology, developmental effects, sources, and global health implications Maclachlan and Korach, 1995
Environmental Health Sciences of environmental estrogens
1995 German Federal Environmental Discussion about the occurrence and impact of endocrine disruptors and the potential German Federal Environment
Agency risks that may arise to humans and the environment Agency, 1996
1995 Ministry of Environment Evaluation of the effects of estrogens on male reproductive development and function Toppari et al., 1996
and Energy, Denmark
1995 US EPA Workshop on research needs for the Risk Assessment of health and environmental Kavlock et al., 1996
effects of endocrine disruptors (April 1995)
1995 Chemical Manufacturer’s Association; Workshop on screening methods for chemicals that alter thyroid hormone homeostasis, Ankley et al., 1998a
World Wildlife Fund; US EPA action, and function
1995 UK Medical Research Council Assessment on Environmental Estrogens: Consequences to Human Health and Wildlife MRC Institute for Environment
Institute for Environment & Health and Health, 1995
1996 European Commission European workshop on the impact of endocrine disruptors on human health and wildlife, European Commission, 1996
Wyebridge U.K.
1996 ECETOC Compendium of test methods for environmental estrogens ECETOC, 1996
1996 SETAC Workshop on principles and processes for evaluating endocrine disruption in wildlife Kendall et al., 1998
1996 US Committee on the Environment Development of a national planning framework for endocrine disruptor research and Reiter et al., 1998
and Natural Resources analysis of the existing federally funded research projects to help identify information gaps
1996 US EPA Workshop on the development of a risk strategy for assessing the ecological risk of Ankley et al., 1997
endocrine disruption
1997 UNEP, US EPA, White House Office International workshop on endocrine disruptors UNEP, 1997
of Science and Technology;
Alton Jones Foundation
1997 Federal Environment Agency, Germany Workshop on effects of endocrine disruptors on neuronal development and behavior UBA, 1997
1997 SETAC, OECD, European Commission Expert Workshop on Endocrine Modulators and Wildlife: Assessment and Testing SETAC, 1997
1997 US EPA Special report on environmental endocrine disruption: an effects assessment and analysis US EPA, 1997
1997 OECD Critical assessment of the ability of existing OECD test methods to detect sex hormones OECD, 1997
disrupting potential
1997 Health Council of the Netherlands Evaluation of the effects of endocrine disruptors on human reproduction and development Health Council, Netherlands,
1997
1997 International Life Sciences Institute; Scientific evaluation of the potential for substances in the diet to influence the ILSI, 1998
US EPA human endocrine system
1997 Japan Chemical Industry Association Evaluation of status and research needs of endocrine disrupting compounds in Japan Japan Chemical Industry
Association, 1997
1998 Swedish Environmental Protection Endocrine disrupting substances-impairment of reproduction and development Olsson et al., 1998
Agency
1998 International Union of Pharmacology Natural and anthropogenic environmental estrogens—the scientific basis for IUPAC, 1998
risk assessment
1998 Society of Environmental Toxicology Workshop on endocrine disruption in invertebrates DeFur et al., 1999
and Chemistry
1999 National Research Council Hormonally active agents in the environment NRC, 1999
1999 European Commission Scientific committee on toxicity, ecotoxicity, and the environment opinion on human Vos et al., 2000
and wildlife health effects of endocrine disruptors
2000 Health and Environment Canada Workshop on endocrine disrupting substances in the Canadian environment Servos and Van Der Kraak, 2001
2000 US National Toxicology Program Report of the endocrine disruptors low-dose peer review NTP, 2001a
2000 Finnish Environment Institute Research for Management of Environmental Risks from Endocrine Disruptors Assmuth and Louekari, 2000
2001 Federal Environment Agency, Germany Second status seminar on endocrine disruptors UBA, 2001a

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of normal biological function, including cell proliferation and antiandrogenic effects may also be facilitated by the effects of DDE
differentiation responses essential for normal development and on steroid-metabolizing enzyme expression.
the function of multiple organ systems. Although there is There are many factors that should be considered when
considerable information on the early molecular events involved utilizing mechanistic information on EDCs in health assessments.
in hormone response, there is very little knowledge concerning Of particular concern are species, interindividual, and tissue
the relationship between those molecular events and adverse specificity in endocrine signaling pathways. Differential
health effects such as cancer or reproductive toxicity. This responsiveness to EDCs has been observed between different
knowledge gap is perhaps the most limiting factor in our ability to species and extends to interindividual differences within a species
evaluate exposure–response relationships, particularly following and between different tissues as well. The biologic and molecular
low-level exposure to potential EDCs. The use of new approaches mechanisms underlying this specificity are quite diverse.
in molecular epidemiology and animal model systems has the Determinants of species specificity include differences that exist
potential to yield additional valuable information for elucidating between species in receptor binding, gene transcription patterns of
the role of these mechanistic determinants of specificity at low- gene expression, and cellular responses to endocrine-active
dose exposures to potential EDCs and for improved risk compounds. Interindividual differences in responsiveness may be
evaluations for the adverse health effects of EDCs. There are determined at the level of genetic polymorphisms in hormone-
numerous experimental systems available for evaluating the metabolizing enzymes, hormone receptors, and those genes that are
interactions of exogenous or synthetic chemicals with hormone activated by these receptors. Our rapidly growing knowledge base
systems, particularly those that interact with the estrogen, emerging from the human genome project will enable the design of
androgen, thyroid, and AhRs (Bolander, 1994). However, there is rational studies on the impact of EDC exposures on hormonally
a growing body of knowledge that interactions of chemicals with sensitive end points in groups that may be genetically predisposed.
other receptor systems also may be important in the EDC arena. Extrinsic factors such as diet can also impact individual
These include the retinoic acid receptor, cytokine systems, and a susceptibility to endocrine-active agents.
number of so-called orphan receptors (receptors without The organochlorine chemicals provide interesting insights
unknown ligands and/or functions) such as the peroxisome regarding the mechanisms of action for EDCs. In the case of the
proliferator receptor system. In general, these receptor systems are dioxins, the scientific consensus is that most, if not all, of their
remarkably well conserved phylogenetically, suggesting that data effects require an initial interaction with a cellular protein termed
from wildlife and experimental models should be useful, although AhR (Poland and Glover, 1977). As discussed in Chapter 3, the
not necessarily definitive, for estimating risks from EDC exposure ligand-bound AhR is capable of interacting with a number of
to humans. critical signal transduction pathways, leading, for example, to
The mechanism or mode of action of EDCs is not limited to involvement with xenobiotic metabolizing enzymes, steroid
those agents that interact directly with hormone receptors. Other receptor signaling, growth factor expression, circadian clocks,
mechanisms of interest include inhibition of hormone synthesis, responses to hypoxia, and angiogenesis. Through these varied
transport, or metabolism and activation of receptor through interactions, such chemicals are able to induce a wide spectrum of
processors such as receptor phosphorylation or the release of cellular biological effects at a number of different life stages in a variety of
complexes necessary for hormone action. In the case of hormone species, and some of these responses do not easily fit the traditional
synthesis, considerable research has been conducted on the definition of endocrine-mediated events. Although adverse
aromatase inhibitors that prevent the conversion of androgens to biological effects mediated via the activation of AhR are certainly of
estrogens through a cytochrome P450 system that is highly concern, a higher burden of proof is needed to identify such effects
conserved in many species. Several fungicides have been shown to as due to endocrine disruption than merely the correlation between
cause infertility by aromatase inhibition. In addition, there is a ability to bind to the receptor and the elicitation of some biological
growing awareness that multiple receptor systems act in concert to effect. In this regard, the considerations detailed in section 3.16
regulate biological functions. For example, “cross talk” between the were used in evaluating the extent to which information would be
ER and growth factor receptors appears necessary for estrogen included in this document. Although information on the
signaling of mammary cells to divide or differentiate. These events involvement of the AhR in wildlife is limited, in our final
are critical for explaining several risk factors for breast cancer such conclusions on the strength of the evidence for relationships
as age at menarche, age at menopause, or effects of numbers of between chemicals and endocrine-mediated effects, the same
pregnancies. There are numerous other kinds of cross talk between criteria were applied for both humans and wildlife.
various constituents of the endocrine system, and an understanding
of the mechanisms involved could improve our ability to produce 2.4 Dose–Response Relationships
credible health assessments of EDCs. One well-known example of The issue of dose–response relationships is perhaps the most
“cross talk” involves antiandrogen-mediated elevation of controversial issue regarding EDCs. One of the reasons is that
endogenous estrogen levels due to increased LH production. EDCs often act by mimicking or antagonizing the actions of
Other examples of EDCs capable of acting at multiple cellular naturally occurring hormones. These hormones are already at
sites via multiple endocrine mechanisms are discussed in detail in physiologically functional concentrations, so the dose–response
Chapter 3. For example, the pesticide methoxychlor displays considerations for EDCs are often different than for other
estrogen agonist (ER-β) activity because some of its metabolites chemicals that are not acting directly on the endocrine system.
bind to the ER. It also possesses antiandrogenic actions through a Reported low-dose effects for EDCs have come under intense
more poorly defined mechanism involving the hypothalamic- scrutiny regarding the question of the adequacy of traditional
pituitary-gonadal axis. Another example is the ability of the DDT toxicology testing paradigms for detecting low-dose effects. A recent
metabolite DDE to act as an antiandrogen by inhibiting workshop on this issue (NTP, 2001a) concluded that although low-
testosterone binding with the androgen receptor, but these dose effects may be occurring, those effects often are not replicated

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IPCS GLOBAL ASSESSMENT OF EDCS

consistently, and the toxicological significance of the reported active, and these can be detected in people and wildlife as well as in
effects is not known. Dose–response issues should be explicitly environmental samples. Some of these persist in the environment
considered when studies are designed for risk evaluation for health and others do not. Some are lipophilic, sequestered in adipose tissue
or wildlife effects. Of particular relevance is the issue of dose and secreted in milk, and others may only be present for short
selection. Ideally, the doses used should span a wide range to periods of time but at critical periods of development. Our
identify both toxic and mechanistic end points. The issue of dose knowledge about the magnitude of human or wildlife exposure
selection has become critical to the current controversies remains very limited. Most of the more definitive studies on
surrounding the issue of biphasic dose–response curves for EDC chemically mediated effects, including those on EDCs, have been
effects on end points such as prostate weight. Although there may conducted on highly exposed groups in various occupations or from
never be complete knowledge on the mechanism(s) of action for accidental exposures. In only a few cases, appropriate exposure
any chemical, some knowledge of key events could help clarify information is available from lower level environmental exposures
dose–response relationships. because of analytical sensitivity and the latency in outcome after
Timing of exposure is also critical to the understanding of exposure has occurred.
dose–response relationships for EDCs. Numerous examples exist in Hormonally active environmental chemicals are
the literature where age at exposure is a known risk factor. For extraordinarily diverse in their structure and potency. For example,
example, endocrine disruption of the developing brain can some organohalogens, such as the PCBs, DDT, PCDDs, and
permanently alter behavior, whereas similar exposures to a fully PCDFs, are suspected endocrine-disrupting agents, but various
differentiated brain could be without effect. Ecological and wildlife members of these groups of chemicals exhibit profound differences
effects are also strongly influenced by the timing of exposure (e.g., in potency, biological and ecological persistence, and mechanisms
during the breeding season). of action. For example, 75 PCDD congeners and 135 PCDF
Population heterogeneity is another important factor in congeners vary tremendously in their potency to exhibit TCDD-
dose–response evaluation. For human health, a number of factors like activity (see Chapter 6). This kind of diversity creates obvious
contribute to a wide range of risks, including genetic problems in human and ecological health assessments, and it also
predisposition, age, gender, diet, disease conditions, and past increases the complexity and costs of analyzing for concentrations
exposures. The range of risk modulators may be even greater for of these chemicals in biological samples. In addition to the PCBs,
complex ecosystems, but little information is available in this area. PCDDs, and PCDFs, many other kinds of chemical modulators of
Evaluation of the dose–response relationships for health and endocrine function are examined in this report. These include
environmental effects of endocrine disruptors will be most credible phthalate acid esters, DDT and DDE, alkylphenols,
when information is available from several sources (e.g., toxicity methoxychlor, bisphenol, diethylstilbestrol, estradiol as an
studies, mechanistic and epidemiological studies, and field studies). ecological contaminant, the fungicide vinclozolin, and several
There are a number of issues that are helpful to consider when other synthetic chemicals that are reported to interact with various
embarking on dose–response assessment. These include, but are not components of the endocrine system.
limited to, 1) the adequacy of relevant experimental models for Synthetic chemicals are not the only exogenous agents that
evaluating potential human effects of low-dose exposure to endocrine have caused health concerns because of their hormonelike activity.
disruptors, 2) state of knowledge concerning quantitative relationships Of particular interest are the phytoestrogens (such as genistein and
among the various processes maintaining homeostasis for the tissue, equol) and the fungal estrogens (such as zearalenone). The
organ, or function being studied, 3) how perturbations in homeostasis phytoestrogens and fungal estrogens are diverse in structure,
lead to disease or dysfunction, 4) whether these changes can be undergo complex metabolic processes, and are ubiquitous in the
quantified, 5) an understanding of the mechanisms through which environment. They can be found in blood and urine samples of
endocrine disruptors perturb homeostasis and endocrine function and virtually every person and animal on this planet, often in high
alter the risks from that of normal levels of endogenous hormones, 6) concentrations. They pose difficult analytical issues, yet if
consideration of how differences in lifestyle factors (diet, nutrition, exposure–response relationships for the phytoestrogens remain
etc.) affect sensitivity to endocrine disruption, 7) an understanding of uncertain, health assessments for many endocrine-disrupting
how the age of the endocrine system alters sensitivity to endocrine agents, particularly the environmental estrogens, will also remain
disruption, and 8) how interindividual differences (based on genetic uncertain. This is because several of the phytoestrogens, mostly
variation) in constituents of endocrine pathways (e.g., receptor notably genistein and its analogs, possess binding affinities for the
variants) alter responses to endocrine-sensitive end points caused by ER far greater than many of the EDCs of concern, such as the
exposure to EDCs. Most of these considerations are relevant to both alkylphenols, bisphenol A, and DDE. From a potency standpoint,
human and wildlife effects of EDCs. the phytoestrogens exert a far greater impact on human exposure to
A common dose–response relationship for all effects and for exogenous estrogens than do the synthetic chemicals. This does not
all endocrine disruption mechanisms should not be expected. mean that we should not be concerned about synthetic estrogens,
This conclusion is based on the knowledge that there are many but it does emphasize that exposure assessments for EDCs need to
different kinds of hormonal actions of chemicals categorized as consider both the magnitude of exposure and relative potencies of
endocrine disruptors. These activities include estrogenic, the array of EDCs that may be encountered in the home,
antiestrogenic, antiandrogenic, growth factor modulation, workplace, and general environment.
cytokine and thyroid modulation, modulation of hormone Information is needed to more accurately quantify the human,
metabolism, among many others. wildlife, and environmental burden of hormonally active
environmental chemicals so that quantitative comparisons can be
2.5 Exposure Issues made between body levels of natural and exogenous hormones
There are numerous chemicals in the environment (e.g., pesticides, based on potency, not just absolute amount. This kind of
industrial chemicals, and natural products) that are hormonally information is essential if we ever hope to properly evaluate

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 CHAPTER 2: INTRODUCTION/BACKGROUND

exposure–response relationships in field and epidemiology studies epidemiological, and experimental studies. Internal measurements
and to use those relationships to produce credible risk assessments. are often confounded by the rapid metabolism of some EDCs
Data on historical and geographic trends of exposure to EDCs are (Elsby et al., 2001). This means that quantification of metabolites
generally lacking. Knowledge of the fate and transport of new and or degradation products in biological samples is necessary for
existing chemicals is also limited, particularly among the different endocrine disruptor research. Some of the rapidly metabolized
environmental compartments (water, sediment, and biota). chemicals reviewed in this document are the phthalate acid esters,
Exposure assessment, particularly as it involves human health, alkylphenols, diethylstilbestrol, some PCBs, phytoestrogens, and
must focus on vulnerable groups, in terms of both life stage and methoxychlor.
lifestyle. Exposure assessment for the critical development stages Other complications in exposure assessment include time lags,
remains a high research priority. These stages include gestation, seasonality, and multiple chemical exposures. a) Time lags between
lactation, adolescence, and senescence. The endocrine system, exposure and effect: The transgenerational nature of some EDC
through a developmentally regulated pattern of expression, controls effects may be the single most complicating factor. All of the
the pathways essential for cell proliferation, differentiation, and potential latent effects that may occur from short-term exposures
organ development, so it is not surprising that perturbations of the during critical development windows have not yet been identified.
endocrine system during critical windows of sensitivity create the b) Seasonality: Because of the sensitivity of reproductive stages to
greatest potential for adverse health effects. EDCs, seasonality will be extremely important to wildlife. In
Vulnerability of different groups in the population will be addition, the association of EDCs with the aquatic environment is
affected by lifestyle factors (e.g., subsistence hunting and fishing, complicated by seasonal rainfall, storm runoff, and water releases.
and avid sportsmen who consume fish and wildlife), genetic factors c) Multiple chemical exposures: This, too, is a factor for any toxic
(e.g., metabolic differences that can determine sensitivity), special chemical, but it is especially identified here because of the potential
dietary habits, and age (e.g., the types and rates of food for effect modification (e.g., synergy, additivity, or antagonism).
consumption in children). Although there is general agreement that The most critical need on status and trends is for the
diet would likely be the major exposure route for exposure to the continuation and improvement of monitoring of the environment
EDCs, an approach based on integrated exposure assessment needs for the presence and magnitude of contaminants. Although
to be taken. All routes should be examined (e.g., dermal, inhalation, environmental and tissue levels of certain EDCs (e.g., PCBs) have
and ingestion). Examining the exposure of humans or wildlife to declined in some countries in response to regulations, they remain
multiple chemicals (especially for chemicals with a common mode of concern in other countries, and uncertainty still exists regarding
of action and/or common target sites) that may function as EDCs future trends. For most EDCs, data on trends are not available.
is also critical. Long-term data using harmonized collection and analysis methods
Exposure assessment encompasses both external measurements are needed. Existing programs that furnish repeated measures of
(levels in air, water, soil, food, etc.) and internal measurements chemical contamination in the environment or in food provide our
(levels in blood, urine, and tissue samples). Both kinds of only indication of whether exposure is increasing or decreasing, and
measurements provide critical information for wildlife, to what magnitude.

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