Endocrine-disrupting chemicals (EDCs) are defined as
chemicals, or mixtures of chemicals, that interfere with any
aspect of hormone action.1 These chemicals are designed,
produced, and marketed largely for specific industrial
purposes (plasticizers, pesticides, food-packaging, etc). They
are present in the environment, consumer products, food
storage containers, personal care products, and elsewhere.
Some EDCs are also found in certain natural foods and
may become further concentrated during processing.
Public interest in possible health threats posed by EDCs
has intensified in recent years, leading to the development
of policies, laws and regulations designed to mitigate EDC
related health risks. The European Union (EU) has introduced
specific legislative obligations aimed at phasing out endocrine
disruptors in water, industrial chemicals, plant protection
products and biocides.2 The European Commission is
charged with developing science-based criteria for endocrine
disruptors. However, the EU has struggled to define
criteria to identify EDCs, and EU laws governing EDCs are
inconsistent in their management of these chemicals.
The Endocrine Society wants to ensure that policies
governing EDCs consider the full body of research into
EDCs. As the largest global professional organization for
basic and clinical endocrine research and the treatment of
endocrine disorders, the Society counts among its members
the world’s leading experts in endocrinology, including
experts on EDCs and their effects. In its 2009 Scientific
Statement4 and its 2012 Statement of Principles,1 the
Society calls for greater research and updated regulatory
processes for the identification of EDCs, which overtly or
potentially, depending on the chemicals and endpoints, pose
a significant global public health threat. The evaluation of
chemicals for endocrine effects must take into account the
scientific issues of latent and transgenerational effects, lowdose
effects, non-monotonic dose responses, and mixture
effects. It is also critical that regulatory agencies understand that the consequences of EDC exposures depend upon the
timing of exposure. Developmental stages — from prenatal
life through adolescence — represent particularly vulnerable
periods during which irreversible damage can result from
exposure to even low levels of EDCs. These scientific issues
are not adequately addressed under the current Organization
for Economic Cooperation and Development (OECD) —
screening guidelines, which rely on outdated methodology
and insensitive endpoints for evaluating endocrine activity.5
For example, while the fish life-cycle toxicity test focuses
on GnRH development in brain after chronic exposure,
developmental neuroendocrine disruption may not alter
GnRH neuron proliferation or structure directly, but rather
through alteration of one or more neuromodulators controlling
GnRH secretion. We note that the primary aim of the
Endocrine Society is human health; however, this should not
be taken to mean that impacts on wildlife are not of concern.
The understanding that environmental chemicals can interfere
with hormone action has developed slowly over the past
half century. The European Union has been engaged in
policy work relevant to EDCs since the late 1990s.3 Some
milestones include Europe’s Strategy on EDCs6 (1999);
the Regulation on Registration, Evaluation, Authorization
and Restriction of Chemicals7 (REACH, 2007); pesticides
regulation8 (2009); and biocides regulation9 (2011). More
recently the European Parliament adopted a resolution on
the protection of public health from endocrine disruptors;10
the 7th Environmental Action Programme was published
in 2013 and calls for minimizing exposures to EDCs.
Currently, the European Commission seeks to define criteria
for the identification of substances as EDCs. Among these
criteria, “endocrine-mediated action” cannot be restricted to
perturbing a single class or system of hormones interacting
with a receptor, since a single chemical or class of chemicals
can interact with different endocrine pathways, and endocrine
systems are often linked. Therefore, “endocrine-mediated” should specifically indicate that the adverse outcome is
plausibly caused by a substance interfering with hormone
action. By “hormone action”, we mean “hormone receptor
activation”, recognizing that many hormones have multiple
receptor isoforms including nuclear and/or membrane or
other receptors that “transduce” hormone signals into cellular
actions that affect development and/or physiology. It should
also reflect the World Health Organization’s International
Program on Chemical Safety (WHO-IPCS) definition, which
encompasses all endocrine systems and effects including a)
receptor-mediated effects; b) interference with endogenous
ligand delivery to the receptor; and c) epigenetic effects.
SCIENCE OF EDC ACTIONS HAS ADVANCED.
EU policymakers are invested in protecting their constituents
from harmful chemical exposures, and they rely on scientific
experts to help them determine how best to do this.
Endocrinological research into EDCs over the past 20
years has revealed important issues that have not yet been
incorporated into testing paradigms, guideline studies, or
in regulatory analyses. It is now clear that multiple hormone
systems, including those involved in fetal development,
reproduction, metabolism, obesity, and brain development,
can be targets of EDCs. Furthermore, EDCs can produce
effects that do not exactly mimic those of natural hormones.4
EDCs can also act on multiple generations. For example,
exposure of pregnant women to EDCs will result in exposure
of the fetus through placental transfer, and exposure can
continue in the newborn through breast-feeding. Recent
biomonitoring studies from across Europe have shown that
people in the general population are typically contaminated
with several chemicals.11,12,13 As is the case in the US, it is likely
that nearly all babies born in the EU are exposed to industrial
chemicals and are potentially at risk for EDC hazards.14
Individuals exposed to EDCs in the womb face elevated risk
of disease later in life. Additionally, some EDCs have multigenerational
effects through modification of DNA and other
heritable mechanisms, thereby placing future generations at
higher risk of disease. In the case of the female fetus, germ
cell numbers are maximized by seven months gestation and
EDC exposure can alter the germ cells during this critical
developmental period. Therefore, the endocrine-disrupting
potential of a compound extends far beyond actions at
hormone receptors, and testing paradigms and public policy
must incorporate these aspects of EDC exposure. Regulatory paradigms must incorporate new endpoints that reflect the
sensitivity of organisms to endocrine disruption and are
relevant to disease states to which exposure has been linked.
EDC EFFECTS ARE SEEN AT LOW
LEVELS OF EXPOSURE.
Current EDC policy relies largely on data produced from
guideline studies examining the effects of high doses of
chemicals, relative to human exposure. A substance must
show evidence of a narrow set of adverse effects that
increase proportionally with dose in order to be considered
dangerous by classical standards. However, many EDC
effects occur at low doses irrespective of effects seen at
high doses. In fact, increasing amounts of hormone or a
hormone mimic can squelch a measured adverse effect by
overwhelming or down-regulating the endocrine system’s
ability to respond. In this circumstance, an effect seen at
low levels of exposure would not be observed at higher
levels of exposure. By eliminating low-dose studies from
policy considerations, the regulatory community may
be excluding crucial evidence of harmful EDC actions
that exhibit hormone-like dose-response profiles.
BASIC RESEARCH PREDICTS OR
CONFIRMS HUMAN DISEASE.
EDC effects may not be detectable until years after the initial
exposure occurs and may affect the offspring of the exposed
individual. This was first demonstrated for diethylstilbestrol
(DES), which was given to pregnant women in the mid-20th
century with the intention of preventing miscarriage. However,
DES caused male and female reproductive abnormalities.
Additionally, in early adulthood, the daughters of these
women were observed to develop a rare cancer at a higher
rate than women who had not been exposed to DES
before birth. The observation led to basic research studies
in animal models that confirmed the causal relationship of
prenatal DES exposure to the development of cancer later
in life. The confirmation of DES’ effects illustrates in reverse
the power of research in appropriate animal models.
WHAT CONSTITUTES “PROOF?”
Unlike pharmaceuticals, for which clinical trials are
undertaken to prove benefits and rule out adverse effects,
it would be unethical to perform human studies to uncover
harmful EDC effects. One cannot imagine a scenario in which
DES would have been given to pregnant women after animal
studies revealed its harmful effects. Thus, calls for “definitive
proof of harm to humans” present an unachievable goal.
It is therefore imperative that strong evidence from animal
models be heavily weighed in assessment paradigms.
Identifying direct links between EDC exposure and childhood
or adult disease is difficult for many reasons, including the
challenge of accurately assessing a lifetime of exposure to
a complex mixture of potentially harmful agents. However,
the reality is that humans and wildlife are already exposed
to many EDCs on a daily basis and their future health is in question today. It is therefore important to synthesize
information from animal model systems, detailed laboratory
analyses of EDC mechanisms, and epidemiological studies
to predict and quantify potential effects in humans so that
exposure reductions can be taken where needed.15
While a number of countries in North America and the
EU have banned baby bottles and other baby food
containers that contain bisphenol-A (BPA), a chemical
used in many polycarbonate plastics, based on in vivo
studies in humans and animals and other in vitro studies,
no measures whatsoever have been taken so far to
protect other vulnerable individuals such as pregnant
women and adolescents. Similar controversies exist
over other EDCs, such as perchlorate and phthalates.
There are likely to be a number of explanations to account
for the broadly divergent conclusions by different groups
of scientists on some issues, but the lack of representation
of endocrine scientists with expertise in hormonal action
and hormonal effects on EDC advisory groups is a
crucial consideration. Endocrine scientists have unique
expertise and experience in experimental endocrinology,
and this expertise is critical for high-quality evaluation
of endocrine studies which cannot be assessed by
scientists with different discipline-specific expertise.
The scientific controversy over EDCs has stimulated scientists
to raise new questions and to accumulate evidence that
can no longer be denied by the scientific community or
by policymakers. The Endocrine Society encourages
further research to resolve scientific discrepancies and
uncertainty, and recommends that policymakers consider
taking a precautionary approach when developing policy
about chemicals that may be harmful to the public. When
conclusive evidence is lacking, but sound scientific studies
indicate a strong possibility for adverse health effects, it is
the responsibility of the government to adopt measures that
protect people from the risk of exposure to certain chemicals.
Furthermore, while some chemicals have been shown to have
endocrine-disrupting activity, there are no data on the vast
majority of the thousands of compounds in use and in the
environment today. Thus, appropriate testing strategies must
be developed to consistently and comprehensively examine
all chemicals for potential EDC activity. Widely applicable,
science-based criteria for identification of EDCs are required.
As more information about endocrine disruptor effects
and mechanisms becomes available, it will be increasingly
important to carefully assess the extent of human exposure to EDCs and assess the inherent risk in that exposure as far as this is possible. Additionally, it will
become increasingly necessary to provide research
funding so that scientists can further examine EDC effects,
in particular those already manifesting in people.
To better inform EU guidelines, endocrine research is needed
to further elucidate the mechanisms whereby EDCs interfere
with endocrine systems necessary for normal development
and physiology. Toxicologic research is needed to understand
the dose-response relationship between general endpoints
of toxicity and chemical exposures that typically involve
doses higher than those which alter endocrine systems.
Epidemiologic research is needed to identify and quantify
levels of human exposure that correlate with disease
development. Environmental science is needed to identify
sources of exposure. All disciplines must work together with
policymakers, non-governmental organizations, scientific
societies, and other stakeholders in order to ensure that a
comprehensive examination of EDC exposure and its effects
on human health are used as the basis for policy decisions.
The Endocrine Society is concerned that the European public
may be placed at risk because critical information about
potential health effects of endocrine-disrupting chemicals
is being overlooked in the development of guidelines and
regulations. EDC effects know no disciplinary boundaries.
Teams of scientists, including endocrine scientists,
toxicologists, epidemiologists, environmental scientists and
others, must work together to inform EDC-related policies.
Legislators, regulators, and others involved in EDC-related
policies must develop comprehensive programs for all
chemicals and regulations governing EDCs in manufactured
products, the food supply, and the environment.
Therefore, the Endocrine Society supports the
Rigorous standards and protocols should be
developed for characterization of study populations
and collection, storage, and processing of biological
samples for measurements of EDCs and byproducts.
Regulations should be designed to protect
the most vulnerable populations — including
but not limited to fetuses, children, and
adolescents — from irreversible effects.
Definition and criteria for EDCs should be sciencebased,
not economics-based, and should
be applicable across all potential EDCs.
The Endocrine Society opposes the inclusion
of a “potency” cutoff as an element of hazard
characterization because the concept as it is applied
in this context is inconsistent with endocrine science
and fails to account for developmental windows
or whether the appropriate endpoint is used.16
It cannot be assumed that there are thresholds
below which EDC exposures are safe.
Policy should be based on comprehensive data covering
both low-level and high-level exposures, including
cumulative and mixture effects. This includes synthesizing
basic science (comprising animal and in vitro studies),
clinical observations, and epidemiological data.
Consistent with the current state of the art of endocrine
science, the default approach to assessing potential
EDCs must include low-dose studies relative to
human exposures and below those dose ranges used
for traditional toxicity testing. Assessments should
take into account that there may be no detectable
threshold below which EDC can be presumed to
be safe, and that potency is an inaccurate predictor
for toxic effects, due to variations depending on
hormonal systems and many other factors.
Tests and screens used to determine EDC activity
should be balanced between those that examine
simple mechanisms and others that measure integrated
biological outcomes at different periods of life, thereby
encompassing both known and unknown effects.
EDC identification methods should incorporate
the most sensitive endpoints, and endpoints
relevant to human and ecological health.
All processes governing the identification of EDCs
should ideally include endocrine scientists with
expertise in the biological systems and mechanisms
at play to ensure comprehensive understanding
of the effects and endpoints to be examined.
The results of EDC identification processes
should be transparent and publicly available.
The European Commission and agencies should
support further research into EDCs, including the
development of high-throughput assays that would
allow the testing of many chemicals for EDC activity
at a full range of concentrations and in both males
and females. Such assays must be anchored to
biologically relevant endpoints that reflect actual
effects on human health and the environment.
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