Endocrine disrupting chemicals

Author(s): Telma Encarnação, Alberto ACC Pais, Maria G Campos and Hugh D Burrows
Source: Science Progress (1933-) , March 2019, Vol. 102, No. 1 (March 2019), pp. 3-42
Published by: Sage Publications, Ltd.

Stable URL: https://www.jstor.org/stable/10.2307/26873467

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826802
research-article2019
SCI0010.1177/0036850419826802Science ProgressEncarnação et al.

Article

Science Progress

Endocrine disrupting chemicals: 2019, Vol. 102(1) 3­–42

© The Author(s) 2019
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DOI: 10.1177/0036850419826802
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environment

Telma Encarnação,
Alberto ACC Pais, Maria G Campos
and Hugh D Burrows
CQC, Department of Chemistry, University of Coimbra, Coimbra, Portugal

Abstract

Endocrine disrupting chemicals are a group of pollutants that can affect the endocrine system and
lead to diseases and dysfunctions across the lifespan of organisms. They are omnipresent. They
are in the air we breathe, in the food we eat and in the water we drink. They can be found in
our everyday lives through personal care products, household cleaning products, furniture and
in children’s toys. Every year, hundreds of new chemicals are produced and released onto the
market without being tested, and they reach our bodies through everyday products. Permanent
exposure to those chemicals may intensify or even become the main cause for the development
of diseases such as type 2 diabetes, obesity, cardiovascular diseases and certain types of cancer. In
recent years, legislation and regulations have been implemented, which aim to control the release
of potentially adverse endocrine disrupting chemicals, often invoking the precautionary principle.
The objective of this review is to provide an overview of research on environmental aspects of
endocrine disrupting chemicals and their effects on human health, based on evidence from animal
and human studies. Emphasis is given to three ubiquitous and persistent groups of chemicals,
polychlorinated biphenyls, polybrominated diphenyl ethers and organochlorine pesticides, and
on two non-persistent, but ubiquitous, bisphenol A and phthalates. Some selected historical
cases are also presented and successful cases of regulation and legislation described. These led
to a decrease in exposure and consequent minimization of the effects of these compounds.
Recommendations from experts on this field, World Health Organization, scientific reports and
from the Endocrine Society are included.

Keywords

Endocrine disruption, human health, children, environment, policy, precautionary principle

Corresponding author:
Telma Encarnação, CQC, Department of Chemistry, Faculdade de Ciências e Tecnologia, University of
Coimbra, Rua Larga, 3004-535 Coimbra, Portugal.
Email: tencarnacao@qui.uc.pt

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4 Science Progress 102(1)

Figure 1. Production of chemicals considered hazardous to health in European Union 28

countries (EU-28), between 2004 and 2016 (million tons). Consumption does not differ
significantly from production. However, consumption is generally higher than production, due
to importation.
Source: Eurostat.

Introduction
Some of the biggest problems that humankind faces are climate change and global warm-
ing, biodiversity loss, ocean dead zones, achieving energy sustainability, increasing pop-
ulation, which is estimated to exceed nine billion in 2050,1 overconsumption of resources,
waste management, air, soil and water pollution. These are posing dramatic challenges
that can jeopardize our future. A myriad of synthetic chemicals has been released into the
environment, especially since World War II, and some in large quantities. In 2015, the
total production of chemicals within the 28 member states of European Union (EU) was
323 million ton, 205 million ton of which were considered hazardous to health.2 Figure 1
presents the production of chemicals hazardous to health, over the last 12 years, accord-
ing to five toxicity classes. The production rate does not necessarily translate into the
release into the environment and human exposure, but it is, nevertheless, an indicator of
the potential impact on human health and on the environment.
Concerns regarding exposure to these chemicals and potential adverse effects are due,
in part, to the increasing number of reports of their role as their endocrine disrupters. In
the last 20 years, a large number of research papers have been published, which address
various aspects of endocrine disrupting chemicals (EDCs), including environmental
occurrence, ecological effects and consequences of human exposure.
In 1996, with support from the European Commission, the World Health Organization
(WHO), Organization for Economic Co-operation and Development (OECD) and other
national authorities, the international meeting, ‘The impact on the endocrine disrupters

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Encarnação et al. 5

on human health and wildlife’, appealed for a better understanding of epidemiological

aspects, and to the needs of identification, monitoring and the development of methods
to test and screen EDCs (The Weybridge Report).3 This meeting considered that meas-
ures to reduce exposure to these chemicals should be made according to the Precautionary
Principle (1992 Rio Declaration) (Rio Declaration, 1992 Principle 15:

In order to protect the environment, the Precautionary Approach shall be widely applied by
States according to their capabilities. Where there are threats of serious or irreversible damage,
lack of full scientific certainty shall not be used as a reason for postponing cost-effective
measures to prevent environmental degradation.

In a Judgement (C180/96, point 99), on 5 May 1998, the Court of Justice, has said that
‘where there is uncertainty as to the existence or extent of risks to human health, the
Commission may take protective measures without having to wait until the reality and
seriousness of those risks become apparent’). The Precautionary Principle arose from
environmental considerations and can be viewed as an ethical ideal. Another outcome of
this international meeting was the definition of EDCs: an EDC was defined as an ‘exog-
enous substance or mixture that alters function(s) of the endocrine system and conse-
quently causes adverse health effects in an intact organism, or its progeny, or (sub)
populations’. Also, ‘a potential endocrine disrupter is an exogenous substance or mixture
that possesses properties that might be expected to lead to endocrine disruption in an
intact organism, or its progeny, or (sub)populations’4 (WHO, International Programme
on Chemical Safety).5
In 2009, The Endocrine Society published the first Scientific Statement on EDCs
addressing the concerns to public health, based on evidence from animal models, clinical
observations and epidemiological studies.6 The statement includes evidence of the effects
of endocrine disrupters on male and female reproduction, breast development, prostate
and breast cancer, neuroendocrinology, thyroid, metabolism and obesity, and cardiovas-
cular endocrinology, and calls for an increased understanding of the effects of EDCs,
with the involvement of individual and scientific society stakeholders in communicating
and implementing changes in public policy and awareness.6 In 2013, the WHO released
The State of the Science of Endocrine Disrupting Chemicals - 20127 expressing concern
on the impact of EDCs; this was supported by extensive research that improved the
understanding of the mechanisms involved in endocrine disruption and stated that there
is ample evidence attesting to the impacts of EDCs on human and wildlife health.7 Even
after decades of research on EDCs, and the two decades since the Weybridge Report,
there is still no consensus on EDCs among scientists, regulators and activists, either
within the EU or at the international level. On 16 December 2015, a judgement of the
General Court of the Court of Justice of the EU declared that the European Commission
‘unlawfully failed to adopt delegate acts concerning the scientific criteria for the deter-
mination of endocrine properties’ (Case T-521/14).8 The European Commission was
expected to deliver, before December 2013, scientific criteria for the definition and iden-
tification of chemicals that may possess endocrine disrupting properties, and to adopt
and delegate acts according to such criteria.9 In October 2017, the member states’ repre-
sentatives rejected the Commission’s definition on EDCs, and, 1 year later, there is still

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6 Science Progress 102(1)

no defined strategy that addresses the challenges they pose. The regulation of chemicals
includes carcinogens, mutagens, teratogens and substances that disrupt reproduction.
EDCs represent a relatively new classification, involving different chemical classes that
are able to mimic or antagonize endogenous hormones. Although there is no consensus
on their regulation, EDCs are addressed in various cases in EU law, such as the Water
Framework Directive, Registration, Evaluation and Authorization of Chemicals
(REACH), Plant Protection Products Regulation (PPPR) and Cosmetic Regulation.
These will be described briefly below.
EDCs are found in many of our everyday products, for example, those that we use for
personal or domestic care, in the air we breathe, in the food we eat and in the water we
drink. The challenges that arise from the field of endocrine disruption are the immense
diversity of chemicals produced, but not tested, the mixtures and the unknown interac-
tions between them, together with their consequent effects. The lack of an effective and
strong legislation and regulation poses a significant threat to humans, animals and plants,
and contributes to the exposure to chemicals that may disrupt the endocrine system.
Since World War II, more than 140,000 synthetic chemical compounds have been
produced; about 1000–2000 new compounds are synthesized each year,10 and approxi-
mately 800 chemicals are known, or suspected, to interfere with endocrine system.11 The
increasing incidence rate of some medical conditions, such as breast and prostate cancer,
types 2 diabetes, cardiovascular diseases, in the last decades, and the higher rates
observed in the industrialized world cannot be explained only by genetic factors (see
Figures 2 and 3). Environmental factors, nutrition and lifestyle, viral diseases, are some
of the other variables in such a complex system.
In recent decades, several chemicals, such as polychlorinated biphenyls (PCBs),
polybrominated diphenyl ethers (PBDEs), dioxins, furans, pesticides, have been shown
to interfere with various metabolic pathways, leading to alterations in development,
growth and reproduction, and causing medical conditions which may not become evi-
dent until many years after exposure (see below). In 2005, the Environmental Working
Group (EWG) found an average of 200 industrial chemicals and pollutants present in
the umbilical cord blood, and tests revealing a total of 287 chemicals.13 Among
these were compounds banned by the Stockholm Convention. Of the total 287 chemi-
cals detected in umbilical cord blood, 180 are reported to cause cancer in humans or
animals, 217 are toxic to the brain and nervous system, and 208 cause birth defects or
abnormal development.14 Chemical exposure begins in the womb, even, potentially, in
pre-conception stages, and can have a dramatic effect later in life. Certain environmen-
tal chemical pollutants can cause such effects weeks, months or even years after expo-
sure (see below). Available data from these studies clearly indicate that the general
population is exposed to at least, some of these pollutants. Many chemicals present in
the environment originate in municipal wastewater. Several environmentally relevant
organic chemicals, such as pharmaceuticals, pesticides, plasticizers, persistent organic
pollutants (POPs), are not eliminated by conventional water treatment methods, and,
through the urban water cycle, can enter ground and surface waters (Table 1). In addi-
tion, these pollutants can persist in the environment, bioaccumulate through the food
chain and reach drinking water.

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Encarnação et al. 7

Figure 2. Trends in cancer incidence, in the selected countries, by year of diagnosis. Data on
trends in incidence for breast, prostate and all cancers excluding non-melanoma skin, for the
selected countries, were extracted from CI5plus-Cancer Incidence in Five Continents Time
Trends (http://ci5.iarc.fr/CI5plus/Default.aspx).

This review provides an overview of research on environmental aspects of endocrine

disrupters. Emphasis is given to three ubiquitous and persistent group of chemicals, for
example, PCBs, PBDEs and organochlorine pesticides (OCPs), together with two non-
persistent, but ubiquitous groups, bisphenol A (BPA) and phthalates, whose occurrence
and effects on human health and wildlife have been widely reported. Selected historical
cases are also presented to highlight the fact that, generally, human corrective actions
tend to appear only following catastrophes, and in turn, the importance of the precaution-
ary principle, a science-based approach that accepts uncertainty and requires action in
order to avoid and prevent harm. Some successful cases are described of regulation and
legislation that have prevented or decreased the exposure, and consequent effects, of
these compounds. Recommendations from WHO, scientific reports and from the
Endocrine Society are also included.

Understanding the processes involved

Our current knowledge of the mechanisms involved in the disruption of the normal
functions of cells by EDCs is still limited. Nevertheless, it is known that EDCs can

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 8

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Figure 3. Worldwide trends in the number of adults with diabetes by region (a) and decomposed into the contributions of population growth
and ageing, rise in prevalence and interaction between the two (b).12
Source: DOI: https://doi.org/10.1016/S0140-6736(16)00618-8 and Creative Commons Attribution Licence (CC BY).
Science Progress 102(1)
Encarnação et al. 9

Table 1. Endocrine disrupting chemicals found in consumption and surface waters.

Compound Adverse effects Occurrence Concentration Source

(ng L−1)
Perfluorooctanoic Carcinogenic, Consumption 43–519 15
acid (PFOA) endocrine disrupter, waters (Germany)
hepatotoxic
Carbamazepine Enzyme inhibition Consumption 2 16
epoxide in fish waters (Spain)
17α-ethinyloestradiol Endocrine disrupter Europe 0.3 17
Ibuprofen Surface waters 204.0 18
(River Minho,
Portugal)
Bisphenol A Endocrine disrupter, Surface waters 7.9–521.8 19
cardiovascular (Rivers Ave,
disorders, diabetes, Portugal)
infertility
17α-ethinyloestradiol Endocrine disrupter Surface water (Ria 14.4–25.0 20
Formosa Portugal)
Nonylphenol Oestrogenic Surface water (Ria 12.2–547 20
properties, Formosa Portugal)
endocrine disrupter

have multiple mechanisms of action, interact with different receptors and affect the
entire endocrine system. The majority of studies focus on the oestrogen, androgen and
thyroid receptors and their mechanistic pathways. Accordingly, this section will give
only a very brief description of the normal endogenous oestrogen pathway and their
disruption by oestrogenic EDCs. There are other mechanisms of action of EDCs
(Table 2), especially those involving the aryl hydrocarbon receptor (AhR) which reg-
ulates the expression of several genes, including the cytochrome P450 (CYP)-1 gene
family members and glutathione S-transferase M, which mediates many of the
responses to environmental toxic chemicals.34 An overview of some of the mecha-
nisms involved can provide insight for more comprehensive understanding of the
impact on human health. For additional background information, or detailed descrip-
tion of the endocrine events and their disruption by EDCs, several excellent reviews
are available in the literature that cover this broad and continually evolving research
field.21,35–38
The endocrine system is a complex network of glands that release specific hormones
into the blood stream. It controls growth, development, metabolism, circadian cycles,
glucose levels, sex hormones, T-cell development, calcium levels and many other
functions.39 The endocrine glands, located at various sites in the body, release certain
chemicals, the hormones, that affect specific cells, target cells and receptors. Other
chemicals can interfere with this hormone action. When they enter the body, EDCs
mimic or antagonize natural hormones, interacting with hormone receptors, and can
potentially disrupt the body’s normal functions.

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 Table 2. Human nuclear receptors, their function, some major target genes and important ligands. 10

NR Function Examples of target genes Examples of Examples of endocrine References

endogenous disrupting chemicals
ligand
Androgen (AR) Male sexual development Probasin, KGF, p21, maspin, Testosterone p, p′-DDE, pesticides, 21–24
PSA plasticizers, phthalates,
alkylphenols
Oestrogen (ER) Female sexual development IGFBP4 Oestradiol BPA, benzophenone 23,25,26
GREB1 derivatives, parabens,
CTSD pesticides, dioxins, furans,
heavy metals
Thyroid hormone Metabolism heart rate THRB Thyroid PCBs, BPA, dioxins, 23,27–29
(TR) hormones furans, PBDEs, phthalates
pesticides, perchlorates,
phytoestrogens
Progesterone Female sexual development Progesterone Musk compounds, BPA, 23,24
receptor (PR) herbicides, insecticides,
fungicides
Glucocordicoid Development metabolism Cortisol BPA, phthalates, PCBs, 23,24
receptor (GR) stress response DPCBs, methyl sulphones,

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tolylfluanid
Aryl hydrocarbon Proliferation and Cytochrome P450s (CYPs) Indol and PCBs, dioxins, herbicides, 23,24

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receptor (AhR) differentiation tryptophan indoles, pesticides,
Neurogenesis derivatives flavonoids
Circadian rhythm
Peroxisome Gluconeogenesis Cytochrome P450s (CYPs), Lipids BPA, organotins, phthalates 23,24
proliferator- Lipid, fatty acid and glutathione S-transferase Arachidonic
activated receptors cholesterol metabolism (GST) acid
(PPARs) derivatives
Linoleic acid
derivatives
Science Progress 102(1)
 Table 2. (Continued)

NR Function Examples of target genes Examples of Examples of endocrine References

Encarnação et al.

endogenous disrupting chemicals

ligand
Pregnane X Xenobiotic detoxification Cytochrome P450s (CYPs) 5 β- PCB, BPA 24,30–32
receptor (PXR) Glucose tolerance and CYP3A cholestane-
energy balance CYP2B 3α, 7α,
CYP2Cs 12α-triol
OATP2 steroids
MRP2
MDR1
GST-A2
BSEP
CYP7A
Retinoid X Cellular proliferation Retinoic acid Organochlorine 22,33
receptors (RXRs) Development, growth and pesticides, styrene dimers,

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homeostasis alkylphenols parabens,
organotins

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Constitutive Xenobiotic detoxification CYP2B Androstane PCB 24,32

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androstane CYP3A and
receptor (CAR) CYP2Cs derivatives
OATP2
MRP2
UGT1A1

DDE: dichlorodiphenyldichloroethylene.
11
12 Science Progress 102(1)

Nuclear receptors (NRs) are a class of proteins, transcription factors, that regulate
gene expression, and are activated by steroid hormones, such as oestrogen and progester-
one, in addition to other lipid-soluble signal molecules such as retinoic acid, oxysterols
and thyroid hormones.39 Some of these NRs are considered to be orphans, as their spe-
cific ligand or physiological functions remain unknown. So far, 48 NRs have been dis-
covered in humans through sequencing of the human genome.40 A review on the
mechanism of action of the NRs can be found in the paper of Gronemeyer et al.22 Steroid
hormone receptors, such as the oestrogen receptors (ERα and ERβ), progesterone recep-
tors and androgen receptors, are included in this NRs superfamily. Many EDCs exhibit
oestrogenic activity, targeting oestrogen receptors (ERs), in particular, ERα and ERβ.
EDCs that interfere with ER signalling generate biological responses via both genomic
(nuclear) and non-genomic (extranuclear) pathways.41
Oestrogen is not only a reproductive hormone, but also exerts effects on almost all
tissues of the body,35 and has been linked to the development of conditions such as can-
cer, endometriosis, obesity, insulin resistance as well as cardiovascular, autoimmune and
neurodegenerative diseases.35 Oestrogens act through three types of receptors, the classi-
cal ERs, the ERα and ERβ, and the recently discovered, non-classical, G protein-cou-
pled membrane receptor 30, GPR30. The GPR30 receptor is believed to react through
non-genomic mechanisms, as illustrated in Figure 4.
According to the proposed classical model of oestrogen action, following the binding
of oestrogen to the receptor in the cytoplasm, this complex dimerizes and translocates to
the nucleus where it binds to a specific oestrogen responsive element (ERE), located
within the promoter region of the target gene, to regulate gene transcription (Figure 4).35,42
The steroid hormone receptors are bound to protein chaperones, such as Hsp 70 and Hsp
90, which regulate their functions.43 Once the ligand binds to the receptor in the cyto-
plasm, the receptor is freed from the protein chaperone and the co-chaperone p23, allow-
ing homodimerization and movement towards the nucleus. The co-chaperone p23 is a
small protein, with a relatively simple structure, and is found in all eukaryotes, from
yeast to humans; it is best known as a co-chaperone of Hsp90. The p23 molecule is
involved in various cellular processes.44 Once in the nucleus, the oestrogen–ER complex
recruits transcriptional coactivator proteins and components of the ribonucleic acid
(RNA) polymerase complex that induce the transcription of target genes in response to
the particular ligand.35
Some EDCs, such as alkylphenols, BPA, dioxins, furans, heavy metals, and halogen-
ated hydrocarbons,36 can cross the cell membrane and bind directly to these receptors,
either activating them by acting as agonists, or inhibiting them and acting as antagonists
to the NRs. Thus, either a new protein is synthesized or messenger ribonucleic acid
(mRNA) transcription is terminated.
This NR activation can occur with picogram quantities and nanomolar concentrations40
of EDCs and, as with the steroid hormones, these can have an impact at similar very low
doses.40,45,46
In the genomic pathway, EDCs bind to ERs, in particular ERE in the nucleus, affect-
ing the transcription of target genes in the nucleus. The non-genomic pathway of EDCs
may occur through the binding of GPR30, located in the cytoplasmic membrane, and
consequently triggering subsequent stimulation of protein kinase activation and

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Encarnação et al. 13

Figure 4. Representation of endocrine disruption by EDCs.

ER: oestrogen receptor; ERE: oestrogen response element; CoA: coactivators; P: phosphorylation; TF:
transcriptional factor.

phosphorylation, affecting the transcription of target genes, by the ERE or by interaction

between ERs with other transcriptional factors. The interaction between ERs and GPR30,
in gene expression and intracellular signalling, can result in a cellular response, which
may lead to adverse effects on organs, for example, carcinogenesis.

Persistent EDCs
POPs
POPs constitute a class of chemicals that share similar properties, such as persistence in
the environment, high toxicity and half-life times of years or even decades before their
degradation into less toxic forms (Table 3). They bioaccumulate through the food chain,
and their lipophilicity means they will accumulate in fatty tissues, and thus pose a threat
to human health and wildlife. Bioaccumulation leads to biomagnification, as POPs are
absorbed by lower trophic organisms, such as phytoplankton, that are consumed by zoo-
plankton, and accumulates in the fatty tissues of the organisms that are then eaten by
higher organisms. This possibly magnifies the effect of POPs up the food chain. This
concentration effect reaches its maximum level in top predator species, such as humans
and other mammals. POPs have moderate volatility and are chemically and environmen-
tally stable. Because of these characteristics, they may travel long distances and may be
found everywhere, including the Arctic, Antarctica and even remote Pacific Islands.73

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 14
Table 3. Examples of EDCs with widespread distribution in the environment and their reported health effects.

Endocrine Used for Found in Biological EDCs Reported health impact References
disrupting half life (in
compound humans)
-1
Bisphenol A Plasticizer Weak bond 6h 2.04 µg L for Oestrogenic effect 46–50
Improvement of polycarbonate children (n = 653) Increase prostate, child
physical, thermal Epoxy resins 1.88 µg/L for behaviour problems,
and mechanical Food and drink adults (n = 639) breast cancer, metabolism
properties packaging and breast cancer risk
Anti-androgen
Child behaviour problems
17-α Synthetic hormone Rivers, groundwaters 17 h Mimic the endogenous 17,51
ethynyloestradiol used as contraceptive and superficial waters oestrogen
pills
Polybrominated Flame retardants in Environment, human 2–16 years 1.80–16.5 ng g−1 in Increase cell proliferation, 52–57
diphenyl ethers furniture, textiles, blood, placenta, foetal human biological carcinogenic,
(PBDEs) plastics, electronics, cord blood, urine and samples neurodevelopment deficit
etc. breast milk, children,
fish, marine mammals

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and eggs
-1

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PCBs Dielectric fluids Environment and Few years to 140 ng L of PCB- Intellectual impairment in 58–63

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in capacitors and wildlife, human breast 35 years 153 in cord serum young children
transformers, milk, human blood Immunotoxicity,
additives and ectodermal defects,
plasticisers in paints, development delay,
plastics and rubber behavioural problems
sealants, pesticides, and poor cognitive
etc. development,
neurotoxicity, cancer
Science Progress 102(1)
 Encarnação et al.

Table 3. (Continued)

Endocrine Used for Found in Biological EDCs Reported health impact References
disrupting half life (in
compound humans)
Phthalates Plasticisers in plastic, Environment, human 36 h 2 × 10−9– Low sperm counts, 48,64–67
PVC baby toys, biological fluids 8 × 10−6 M metabolism, birth defects,
flooring, perfume, asthma, neurobehaviour
etc. problems, cryptorchidism,
hypospadias
TCDD Pesticides, unwanted Environment, wildlife, 5–10 years 2 ρg g-1 body fat Changes in the sex ratio, 56,66–69
by-products of food chain chloracne, porphyria,
thermal and industrial transient hepatotoxicity,
processes and peripheral and central

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neurotoxicity
-1
Triclosan Disinfectant and Environment, wildlife, 21–96 h 1.65 µg L Biocidal effects and 48,70–72

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antiseptic used in human biological fluids in human estimate of urinary contributes to bacterial
soaps, toothpastes, plasma concentration resistance, dermatitis, skin
kitchen utensils, toys, per unit dose of irritation. Triclosan react
bedding, clothes triclosan with chlorinated water
producing chloroform

EDC: endocrine disrupting chemical; TCDD: 2,3,7,8-tetrachlorodibenzo-p-dioxin.

15
16 Science Progress 102(1)

POPs that are deposited and accumulated in the soil and water can evaporate or subli-
mate to the atmosphere and travel long distances, to condensate again, for example, in
these remote regions.74,75 Through this cycle, these pollutants can contaminate indige-
nous people and wildlife in such regions, by entering in the food web or through inhala-
tion.74 Because of their genetics and lipid accumulation, indigenous people often have
the highest levels of contamination with POPs, even though they did not produce or
directly consume the products. POPs include polyhalogenated industrial chemicals, such
as PCBs, polybrominated biphenyls (PBBs), OCPs such as dichlorodiphenyltrichloro-
ethane (DDT), aldrin and heptachlor, and industrial by-products such as polyaromatic
hydrocarbons (PAHs) (Figure 4 and Table 5). They were banned by the Stockholm
Convention, which became international law in 2004. However, some are still used.
Mosquitoes that spread malaria are responsible for significant morbidity and the deaths
of one million people each year, mostly children, and the solution for this problem is not
clear. DDT is effective in killing and repelling the mosquitoes that transmit malaria.
Although DDT is highly toxic to health and to the environment, in some countries,
mainly in Africa, the benefit of using this pollutant to tackle malaria may compensate for
the risk.
Some pollutants are granted exemptions for use, such as DDT in certain countries
where malaria poses a major health threat, or some PCBs used in old electric transform-
ers and capacitors in developing countries, where the alternatives are too expensive or
too complicated to produce.

PCBs. PCBs constitute a class of chemically stable aromatic compounds in which 1

to 10 chlorine atoms are attached to a biphenyl backbone, allowing for, theoretically, 209
different congeners. PCBs were widely used in agriculture and in a number of industrial
applications during the past decades. Their applications included dielectric fluids in capaci-
tors and transformers, hydraulic fluids, their use in building materials, such as additives
and plasticisers in paints, plastics and rubber sealants, copying paper, adhesives, pesticides.
Due to their widespread use and careless disposal over several decades, PCBs have become
widely distributed in the environment; although bans and restrictions exist on them at the
global level, they are still found in the atmosphere, rivers, fish, other wildlife, human breast
milk and other biological samples and in ecosystems. The toxic impact of PCBs on human
health and on the environment was first recognized in the 1960s, in particular with the
Yusho incident in Japan, and later, with the Yu-Cheng accident in Taiwan.
PCBs exhibit endocrine disrupting effects, such as ERs’ transcriptional activity
and breast cancer cell line MCF-7 proliferation, and affect enzymes mediated
by thyroid hormone.76 In addition to the bioaccumulation and biomagnification char-
acteristics of PCBs, these chemicals have also been passed to the future generations
through pregnancy and breastfeeding, thus exposing the most vulnerable in the womb
and infancy during critical stages of development, where the disruption can have a
dramatic effect later in life. Because of the strong evidence for them inducing cancer
in humans and in animals, PCBs were classified in 2013, by the International Agency
for Research on Cancer (IARC), as carcinogenic to humans (Group 1).59–61

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Encarnação et al. 17

Figure 5. Molecular structures of common endocrine disrupters.

PBDEs. PBDEs constitute a class of polyhalogenated aromatic compounds with

a basic structure consisting of two phenyl rings linked by an oxygen atom, with a
variable number of from 1 to 10 bromide atoms, allowing for 209 different possible
congeners, which depend on the number and position of the bromine atoms (Figure
5). Only a few of the 209 different combinations are commercially available, and
their toxicity depends on the specific bromine substitution. The congener deca-BDE
is poorly absorbed and rapidly eliminated.53 In contrast, the congeners tri- to hexa-
BDEs are strongly absorbed, slowly eliminated and strongly bioaccumulative.53
PBDEs are widely used as brominated flame retardants, and are present in a number
of consumer goods, plastics, electronics, furniture and textiles. Although PBDEs have
been gradually phased-out worldwide (in the EU they were banned in 2004 and 2008),
biomonitoring studies indicate that they are still ubiquitous in human blood and breast milk
worlwide.77 A number of older products, particularly e-wastes, such as obsolete electronic
and electrical items, contain significant amounts of these pollutants that are still being
released into the environment, leading to contamination of ecosystems. PBDEs have been
found in fish, eggs, human breast milk and in infants and toddlers, probably as a result of
contamination via house dust. The highest concentrations are found at the top of the food
chain, indicating biomagnification53. The exposure routes include diet, ingestion, inhala-
tion of indoor dust and dermal contact.
Certain PBDEs and their mixtures have been shown to disrupt the thyroid hormone
thyroxine and have been associated with neurodevelopment deficits in rats and humans.
Mixtures of PBDEs have increased cell proliferation in human breast cancer cell lines,
and also carcinogenic effects in humans.52–55

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18 Science Progress 102(1)

OCPs. OCPs are a ubiquitous, diverse group of POPs. Representative members of this
group include DDT, mirex, dieldrin, chlordane, heptachlor, endrin, hexachlorobenzene
(HCB), aldrin and toxaphene, which are listed in the so-called dirty dozen, banned by
the Stockholm Convention. These pesticides were extensively used in agriculture and as
insecticides for mosquito control between the 1940s and 1970s. Although banned, as a
result of their strong persistence in the environment and bioaccumulation, the principal
metabolites of DDT are detectable in more than 25% of the general population.78,79 The
adverse health effects of OCPs on animals and human health have been extensively
reported in the literature and linked to diabetes, cancer, neurodevelopment problems in
children, miscarriages and many other health outcomes. Due to agricultural activities,
traces of OCPs and their metabolites have been found in both surface and groundwater.
The presence of OCPs in groundwater has been associated with increased risk of cancer
among people consuming the contaminated supplies. The presence of these pollutants
in several shallow groundwater samples and the corresponding potential health hazards
were recently discussed.80 In this study, HCB, hexachlorocyclohexane (HCH), result-
ing from the degradation of lindane, and p, p′-DDE (dichlorodiphenyldichloroethylene),
a DDT metabolite, were detected, several years after their use. When the OCPs reach
groundwater, they may remain there for several years. Human exposure towards OCPs
includes the consumption of food and water contaminated with residues and their degra-
dation products, dermal contact and inhalation. As with the other POPs, OCPs are char-
acterized by their persistence, bioaccumulation and biomagnification, lipophilicity, and
they may be transported over long distances by winds and ocean currents.

Non-persistent EDCs
BPA
BPA, with its full IUPAC name, 4-(2-(4-hydroxyphenyl) propan-2-yl)phenol, is an
important monomer, used for the production of polycarbonates, epoxy resins, polyesters,
polysulfones and polyether ketones and is also applied as polymer additive in plasticizers
and halogenated flame retardants. It is present in a wide range of applications including
baby bottles and linings for metal-based food and beverage cans, ophthalmic lenses,
medical equipment, consumer electronics and electric equipment.
BPA was first synthesized by the Russian chemist Aleksandr P. Dianin in 189181 who
reacted phenol with acetone in the presence of an acid catalyst. In 1905, Theodor Zincke
also reported its synthesis.82 In the 1930s, BPA was found to have oestrogenic activity,
but, because of the development in 1938 of the more powerful synthetic oestrogen,
diethylstilbestrol (DES), which is stronger than natural oestrogen, BPA was ignored for
this application. In 1953, the Bayer chemist Hermann Schnell synthesized polycarbon-
ates by reacting BPA with phosgene. The new material produced was clear, strong and
stable and could be heated in microwave ovens without deformation. The production of
new polycarbonates reached industrial levels in the 1960s and BPA production has
increased greatly since then. In 2015, the production of BPA was estimated at more than
4.5 million ton.83,84 Each year, more than 100 ton is released into the atmosphere and is
found in air, drinking water, house dust, food, lakes, sea and soil. BPA is ubiquitous.

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Encarnação et al. 19

Human exposure occurs through food, drinking water, household products, cosmetics,
medical equipment, dental materials and occupational sources.85 The polymerization
of polycarbonate plastics is not 100% complete, and, as consequence, the unbound
monomer, or the additives, can easily leach out of the products into the environment.86
Prompted by the broad applications of BPA, several studies have demonstrated continu-
ing exposure of the general population to this chemical.
Although the oestrogenic activity of BPA is lower than that of natural estrogens,47,87
its prevalence at high concentrations in the environment, including surface, ground and
drinking waters, poses a potential risk to human health.
In humans, after exposure, almost 100% of BPA is eliminated in the urine, excreted
mainly as BPA-glucuronide.88 In contrast to PCBs, which can persist in the human body
for decades,89 BPA has an average half-life of approximately 6 h in humans.47 However,
in spite of this short half-life, BPA can be considered as persistent due to its widespread
occurrence and the continuous exposure that the population receives. There are several
studies reporting the presence of BPA in urine samples of children and adults.47,88,49 BPA
is found in the amniotic fluid, providing evidence for its passage through the placenta.90
Its presence has been reported in maternal and foetal serum and amniotic fluid, indicat-
ing significant exposure during the prenatal stage.90 In a biomonitoring study, 100% of
the 81 children examined revealed the presence of BPA in their urine samples. The
median intakes estimated for dietary ingestion, nondietary ingestion and inhalation were
109, 0.06 and 0.27 ng/kg/day, respectively.88
A European level project on biomonitoring measured the BPA levels of 653/639
child–mother pairs and determined the mean values of 2.04 µg/L for children and
1.88 µg/L for mothers. Environmental, geographical and life style and dietary habits
were considered factors that could predict exposure to BPA.49
Numerous studies of human biomonitoring of BPA exposure in the global population
have been reported. These studies reveal the exposure of more than 90% of the world’s
population and demonstrate that there are no differences in the BPA levels between coun-
tries or continents, and that the urinary levels among the youngest groups tend to be
higher than in the older ones.49
Following from the restrictions imposed on the use of BPA in many countries, BPA
analogues, such as the most common substitutes bisphenols F and S, have been synthe-
sized and have replaced BPA in numerous consumer products.91 Sixteen bisphenol ana-
logues have been documented and are used commercially in thermal papers, food
containers, toys lacquers, dental sealants, personal care products and in many other
applications.91 These analogues are now frequently detected in biomonitoring studies
and in the environment92 and also exhibit endocrine disrupting activity, cytotoxicity,
genotoxicity, reproductive toxicity and neurotoxicity.91,92

Phthalates
Phthalates are a group of multifunctional industrial chemicals and are used in a wide
range of consumer products. They are used as plasticisers, to improve flexibility in
plastics, such as polyvinyl chloride (PVC), or as additives in the textile industry, and as
carriers in pesticide formulations. They are added to pharmaceuticals as coatings in

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20 Science Progress 102(1)

time-release pharmaceuticals and are also used as industrial solvents and lubricants.
Phthalates are frequently added to consumer and personal care products, such as cos-
metics, perfume, deodorants, hair sprays, skin cleansers, to retain colour or fragrance,
and are used in medical devices, toys and fuels to enhance performance. They are
diesters of phthalic acid (1,2-benzenedicarboxylic acid) and an alcohol moiety. The
phthalate products display different properties which depend on the length and degree
of the branching of the side chain. The branched chain di-(2-ethylhexyl)-phthalate
(DEHP), with eight carbon atoms in the alkyl side chain, is one of the most commonly
used phthalates worldwide. Between 2012 and 2018, the global consumption of
DEHP exceeded 3000 thousand metric tonnes.93
The polymer cellulose nitrate was synthesized in 1833 by Pelouze, while preparation of
cellulose acetate was reported by Schutzenberger in 1865 and that of PVC by Baumann in
1872.94 However, these polymers were too intractable to be processed and needed addition
of substances, plasticisers, to soften them. Gum copal, natural rubber, linseed oil, castor oil
and camphor were some of the substances tested to overcome the inherent intractability of
these polymers.94 The high volatility, flammability and unpleasant odour of the most com-
monly used plasticiser, camphor, triggered the search for alternatives. As a consequence, in
the 1900s, diphenyl and dicresyl phthalates, and phthalic esters in general, were patented
as plasticisers which avoided these problems. Phthalates became commercial during the
1920s and 1930s, along with a number of new thermoplastic polymers.
The first reports of the adverse effects of phthalates on animals date from 1945.95
Since then, several reports have been published associating phthalates with a wide range
of health outcomes (Table 3).
Phthalates are not covalently bonded to the polymeric matrix and, as such, may be
easily and continuously released from the polymer chains to the surrounding environ-
ment, during their life cycle. Consequently, human exposure is widespread. Exposure
is primarily through ingestion, inhalation and skin contact. As with BPA, phthalates are
ubiquitous and the continuous exposure of general population to them has been dem-
onstrated in various biomonitoring studies.96,97 The Scientific Committee on Toxicity,
Ecotoxicity and the Environment (CSTEE) NOAEL (No-Observed-Adverse-Effect-
Level) identified values for four phthalates di-isononyl phthalate (DINP), di-octyl
phthalate (DNOP), di-2-ethylhexyl phthalate (DEHP), di-isodecyl phthalate (DIDP),
which settled concerns with the so-called phthalate syndrome. The phthalate syndrome
is the variety of effects observed in rat experiments and is characterized by malforma-
tions of their reproductive organs, reduced anogenital distances and nipple reten-
tion.98,99 Evidence of the human analogue of the ‘phthalate syndrome’ has been reported
in recent years and has demonstrated the disruption of the androgen signalling path-
way.65,100,101 Phthalates have been implicated in various male malformations of exter-
nal genitalia, such as cryptorchidism and hypospadias. Reports on the effects of
prenatal exposure to phthalates in humans showed that birth outcomes and reduced
anogenital distance were associated with high levels of phthalate esters, notably DEHP,
in the urine of the mothers during pregnancy.102,103 The incidence of these genital mal-
formations is increasing in male new born babies.103 In a recent study, the levels of
phthalates in urine from 1170 peripubertal girls were measured. Concentrations of

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Encarnação et al. 21

phthalates ranged from <1 to 10,000 µg/L and associations between phthalates expo-
sure and puberty age were estimated.65
Phthalates have been found in several consumer products, and in food, milk, and
drinking water. Although the exposure to a single phthalate below a certain threshold
does not produce any evident effect, the mixture of several phthalates could exhibit tox-
icity in the exposed individual.99

Impact on human health

Although strong and robust evidence is mounting on the adverse effects of EDCs on
human health, there is still considerable controversy surrounding this area.7,104–110 The
complexities of the multiple causes and effects that lie behind the mode of action of
EDCs, coupled with scepticism, denial machines, and industrial interests, contrarian sci-
entists with their argumentum ad hominem, have all fuelled this controversy. In addition,
some concepts can be difficult to accept or assimilate.
There is considerable evidence of adverse effects of EDCs in animal models. However,
the evidence of their effects on human health is more controversial and challenging. The
outcomes of exposure to certain environmental pollutants may only be evident years or
decades later. Another difficulty, when assessing the consequences of EDCs on human
health, is that humans are exposed to a large number of chemicals; each has specific
modes of action, while interactions between them may lead to different results than with
the individual compounds.111
The phrase ‘the dose makes the poison’ is a traditional toxicological assumption
first proposed by Paracelsus, where larger doses have a greater impact than lower ones.
However, with EDCs, the dose no longer makes the poison, and understanding their
toxicity is not a trivial process. Very low doses of some chemicals can have a greater
impact on health than much higher ones. At low doses, they can bind to the receptors
and induce a biological response. In contrast, higher doses can saturate the same recep-
tors and inhibit the correspondent pathways.110,112 Long-term exposure of some chemi-
cals at extremely low doses can have adverse health effects. The timing of exposure
can also be a crucial factor. The toxicity of EDCs is a time-dependent process, and
exposure to them during critical stages of development can have dramatic effects later
in life.113

Some historical cases

The historical case of DES is an example of how exposure of a foetus to synthetic oes-
trogen can adversely impact health later in life. DES was synthesized in 1938 by the
biochemist Charles Dodds.114,115 Between the 1940s until the early 1970s, DES was pre-
scribed to millions of American and European women, initially to treat the symptoms of
the menopause, and later prescribed to pregnant women to prevent miscarriage, although
there is no clinical evidence or adequate testing that supported such a claim. In 1971,
Herbst et al.113 demonstrated that DES causes a rare vaginal cancer in young woman,
who were the daughters of mothers who had been exposed to the synthetic oestrogen.

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22 Science Progress 102(1)

Since then, various other reports have been published demonstrating adverse outcomes
associated with DES.116–118
Thalidomide, α-phthalimidoglutarimide, was synthesized by Chemie Grunenthal in
West Germany in 1954. This company was searching for low-cost production of antibiot-
ics from peptides and, when they failed to demonstrate any antibiotic activity, they decided
to explore the potential of this new molecule as a sedative in humans.103 After the tests in
mice, rats, guinea pigs, rabbits, cats and dogs have not apparently revealed no toxicity or
side effects, Chemie Grunenthal distributed free samples to doctors in West Germany and
Switzerland. In 1957, after the company created its own tests, the ‘jiggle cage’, to demon-
strate to the licensing authorities the efficacy of thalidomide as a sedative, it was com-
mercialized, first in Germany and later in other European countries. The drug rapidly
became a success and, soon after, was sold in 46 countries. Although studies of the effects
on foetus were never performed, the company wrote in 1958 to all German physicians
advising the prescription of thalidomide to pregnant women for morning sickness and
nausea.119 In 1961, reports started to appear, linking thalidomide with a variety of birth
defects, including the rare malformation phocomelia. Between 1957 and 1961, thousands
of babies were born worldwide with severe congenital malformations. Widukind Lenz, a
German paediatrician, found that the administration of the drug between the 20th and 36th
day of gestation could lead to the development of malformations in the foetus. Although
the link with these birth defects precludes its prescription to pregnant women, currently,
the drug thalidomide is used with an enormous success in various medical conditions,
including erythema nodosum leprosum, immune system disorders, multiple myeloma,
cancer and in many other examples.119–121
Another important historical case occurred in Japan in 1968; a rice cooking oil pro-
duced by Kanemi Company was accidentally contaminated with PCBs, polychlorinated
dibenzofurans (PCDFs), polychlorinated quaterphenyls (PCQs) and other compounds
from heat exchangers.122,123 Over 1800 people presented a range of symptoms, including
dermal lesions, pigmentation of the skin, nails and conjunctiva, numbness of the limbs,
irregular menstrual cycles; more than 500 have died from exposure to this contaminated
oil. The incident is known as the Yusho oil disease, and clinical and epidemiological
studies from it are extensively documented.122–124 From 2001 to 2003, measured mean
blood levels of total dioxins and 2,3,4,7,8-penta-chlorodibenzofuran (PeCDF) in Yusho
patients revealed that 36 years after the exposure, those levels were 3.4–4.8 and 11.6–
16.8 times higher than in a control, providing evidence that PCBs and dioxins persist for
many years in the human body.89
In 1979, a similar case occurred in Taiwan, the ‘Yu-Cheng’ incident, in which 2000
people had consumed PCB- and PCDF-contaminated rice cooking oil. The symptoms
were similar to those in the Yusho victims. High mortality from liver diseases was
reported within 3 years after the incident125 and children born to exposed mothers were
found to have ectodermal defects, development delay, behavioural problems and poor
cognitive development up to 7 years.58,126 A higher prevalence in type 2 diabetes among
the Yu-Cheng cohort was also reported.127
These historical cases drew attention to the possible dramatic consequences to human
health and the environment, arising from the production and use of untested and unregu-
lated synthetic chemicals, particularly in critical stages of development.

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Encarnação et al. 23

Exposure to EDCs, and growth, development and health of children

Foetuses, infants and children are particularly vulnerable to contaminants. Various envi-
ronmental chemicals, including pesticides, PCBs, methyl-mercury, are known to be neu-
rotoxic and may alter brain development. Neurodevelopment is a complex process that
begins at conception with the formation of a primitive neural tube, the first stage of brain
development, followed by a differentiation of the cells and the formation of the central
nervous system. During the first two trimesters of foetal development, the basic structure
of the brain is formed. Changes in neural connectivity and function occur in the last tri-
mester and the first few postnatal years. Synaptogenesis and myelination, the most pro-
longed changes, occur in the last trimester and continue postnatally into adulthood.128,129
The disruption of these complex processes could lead to neurodevelopmental disorders,
such as attention-deficit hyperactivity disorder (ADHD), autism spectrum disorder
(ASD), schizophrenia, intellectual disabilities and neurological disorders, such as Rett
syndrome (Table 3). The prenatal or early life exposure to EDCs can have repercussions
on brain functions later in life. The POPs are of particular concern, due to their chemical
structure, persistence and lipophilicity. They are widely dispersed into the environment,
accumulate in organisms and can lead to biomagnification in the food chain. PCBs are
among the most extensively studied environmental contaminants in terms of their effects
on neurodevelopment and cognitive functions. Several reports have revealed PCBs
adverse effects of these compounds, which include immunotoxicity, endocrine disrup-
tion, neurotoxicity and cancer.
The parental exposure to certain EDCs has been linked with a higher risk of congeni-
tal malformations in future progeny and changes in the sex ratio of the offspring. For
example, the exposure of men to the dioxin 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)
is linked to the decrease of the sex ratio in their offspring. The Seveso disaster occurred
in 1976 with the release of the TCDD and resulted in the exposure of the population to
this dioxin. It was observed that the children born from parents with the highest exposure
to TCDD, in the first decade after the exposure, were all female.68,69 Many epidemiologi-
cal studies are underway to study the long-term adverse health effect of this dioxin.
Another example of the effects of pre-conception stages is related with occupational
exposure; the pre-conception exposure of parents to pesticides is linked to the develop-
ment of congenital malformations of their offspring.130–132
Since 1970, childhood cancer has been rising in Europe and United States by 1% per
year, and the data show evidence for an increase in this trend.133,134 The causes of most
childhood cancer are largely unknown. A few causes have been established, such as
exposure to radiation and carcinogens, timing of exposures and genetic susceptibility to
development of cancer, but only a limited number of chemical compounds have been
directly linked to childhood cancer.

EDCs in indoor air and dust

New sources of human exposure to EDCs have been identified in indoor environments,
such as homes and the workplace. Over the last decades, there has been a marked increase
in new materials for building construction, furnishings, carpets, textiles, electrical and

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24 Science Progress 102(1)

electronic appliances, and many other consumer products that are present in indoor envi-
ronments. These lead to common classes of chemicals, such as formaldehyde, pesticides,
phthalates, PCBs, brominated flame retardants, alkylphenols (e.g. nonylphenol, alkyl-
phenol ethoxylates) and parabens, being found in indoor air and dust. Advances in tech-
nologies to improve thermal comfort have decreased the ventilation rates of indoor
spaces and have, consequently, led to a decline in the quality of air inside the buildings.
This has repercussions on health. Respiratory illness, sick building syndrome, allergies
and loss of productivity are some the health implications reported.135–137
We spend about 90% of our life in enclosed spaces, particularly the home and work-
place, and in cars138; indoor air quality (IAQ), therefore, has a considerable impact on our
exposure to contaminants. A number of major studies have been conducted on air and
dust pollution of indoor environments (Table 4). The samples collected in these studies
were found to have high levels of contaminants, and, in general, their concentrations in
indoor air exceed those in outdoor air, and they are considered as ‘one of the most serious
environmental risks to human health’.139,142,143
Children are at greater risk than adults since their normal behaviour, such as playing
close to the ground, and considerable hand-to mouth and object-to-mouth contacts,
increases the exposure through inhalation and ingestion routes. Physiological factors,
such as the small body mass, weaker detoxification capabilities, and rapid growth and
development, also contribute to the increased risk of health outcomes.144 The process of
ventilation dilutes and removes the chemicals produced by the daily activities and released
from indoor sources. However, the removal of the sources of these chemicals would be a
more effective way to decrease the exposure to pollutants.

Government policies
As mentioned above, the phrase ‘the dose makes the poison’ has been the basis for imple-
mentation of public health policies and imposition of thresholds regulations. However,
when dealing with EDCs, the adage should be ‘the dose no longer makes the poison’. For
example, studies of the effect of phthalates in animal models have shown that although
the doses of each phthalate individually were below the ‘adverse effect threshold’, the
mixtures of phthalates exhibited testicular toxicity,64,111 which raises concerns when
humans are exposed to a panoply of chemicals every day.
As in many other fields of science, one reason for scepticism among the public on
EDCs comes from the influence of predominantly industry backed lobbies. Although
there are notable examples of very positive participation of certain individuals in indus-
try, in general, this negative influence can weaken policies, and delay, or even put at risk
their implementation protecting human health and the planet. The current legislation
and regulations are ineffective to safeguard human population, nature and ecosystems.
The tendency has been for the majority of industrial chemicals to go to the market with-
out being extensively tested, and it is only when any adverse effects are dramatically
evident, or when major accidents happen, that they are banned or regulated. In contrast,
pharmaceuticals are subject to an intense, and very expensive, testing procedure before
they can be released on the market. Even when they have shown to be safe, there may
always be some secondary effects that could arise, and in such cases, the risk/benefit

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 Encarnação et al.

Table 4. Organic chemicals detected in indoor air and dust.

Samples Number of organic Number detected per Most abundant organic Concentrations References
(homes) chemicals identified home chemicals identified

Air Dust Air Dust Air Dust

120 52 66 13–28 6–42 Phthalates, 50–1500 ng m-3 139
alkylphenols,
brominated flame
retardants, pesticides
2 PCBs PCBs (52, – – PCBs (52, 105 and 153) 8–35 ng m−3 21–190 µg g−1 140
105 and 153)

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congeners congeners

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50 63 – – – Phthalates, >1 µg m−3 – 142

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alkylphenols, PAHs

PCB: polychlorinated biphenyl; PAH: polyaromatic hydrocarbon.

25
26 Science Progress 102(1)

must be debated. Should not the release of industrial chemicals to the market be subject
of similar rigorous procedures? The regulatory process must not be just at the national
level, but, instead, a global agreement must be the goal, since some EDCs do not respect
barriers or frontiers. POPs, for example, can evaporate from hotter regions and travel
thousands of miles around the planet to condensate again in the polar and/or mountain-
ous regions in the so-called grasshopper effect. As stated, the inhabitants in these places,
such as the indigenous people from the Arctic regions, have some of the highest values
of POPs, and they are far away from where those chemicals were produced or used.145
Several European and International environmental treaties already exist on EDCs.
In 1999, the European Commission’s Scientific Committee on Toxicity, Ecotoxicity
and the Environment (CSTEE) and the European Parliament presented the Community
Strategy for Endocrine Disrupting, whose objective was to identify the problem of
endocrine disruption, its causes and consequences, and to define appropriate policy
action to be taken by adopting a strategy in line with the precautionary principle ‘ful-
filling the Commissions obligation to protect the health of the people and the
environment’.146
On 22 May 2001, in what can be considered a major achievement, governments of the
whole world met in Sweden to sign and adopt an international treaty concerning POPs,
and consider the view that they can pose significant threats to health and the environ-
ment. This is the Stockholm Convention on POPs. The convention is a global treaty,
signed by 152 nations and administrated by the United Nations Environment Programme,
with the purpose of protecting human health and the environment from POPs. It com-
prised five essential aims: ‘eliminate dangerous POPs, starting with the 21 listed in the
Convention, support the transition to safer alternatives, target additional POPs for action,
clean-up old stockpiles and equipment containing POPs, and work together for a POPs-
free future’.73 The treaty requires Parties to take measure to eliminate or reduce the
release of POPs into the environment. It started with 12 substances, ‘the dirty dozen’,
which included eight chlorinated pesticides (aldrin, dieldrin, endrin, mirex, chlordane,
heptachlor, DDT and toxaphene), two industrial chemicals (PCBs and HCB) and two
by-products (PCDFs and polychlorinated dibenzo-p-dioxin). The convention entered in
force and became international law on 17 May 2004. In May 2009, nine more substances
were added. Table 5 lists the POPs banned or restricted under the Stockholm Convention.
As of March 2018, the Convention has 182 Parties as signatories.148
Other important international agreements include the Basel International Convention
and the Rotterdam Convention that regulate chemicals, pesticides and hazardous wastes at
the global level.149 The PPPR (No. 1107/2009) and the Biocidal Products Regulation (No.
528/2012 - BPR) both banned substances with endocrine disrupting properties and estab-
lished that EDCs should be regulated on the basis of hazard and without a specific risk
assessment, in addition to providing scientific criteria to identify endocrine disrupters.
EDCs are considered to be of similar regulatory concern as substances of very high
concern in the REACH regulation (No. 1907/2006), which should be regulated on a
specific case, case-by-case basis.
Other relevant EU legislation on EDCs includes the Water Framework Directive
(2000/60/EC), Regulation 1272/2008 on the classification, labelling and packaging of
substances and mixtures, the Toy Safety Directive (2009/48/EC) and the Cosmetics
Regulation 1223/2009.

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 Table 5. Persistent organic pollutants listed in Annexes A, B and C in the Stockholm Convention.

Chemical Use Molecular formula Chemical structure

Annex A (Elimination) Aldrin Pesticide Organochlorine insecticide C12H8Cl6

α-hexachlorocyclohexane Pesticide/by- Organochloride insecticide C6H6Cl6

Encarnação et al.

product By-product of lindane (for each ton

of lindane produced, 6–10 ton of α-
hexachlorocyclohexane are also obtained)
β-hexachlorocyclohexane Pesticide/by- Organochloride insecticide C6H6Cl6
product Same properties as α-hexachlorocyclohexane

Chlordane Pesticide Used extensively to control termites pesticide C10H6Cl8

for corn and citrus crops, environmental half-
life of 10–30 years
Chlordecone Pesticide Chlorinated pesticide and by-product of C10Cl10O
Mirex

Dieldrin Pesticide Organochloride pesticide

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C12H8Cl6O

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Endrin Pesticide Insecticide C12H8Cl6O

Heptachlor Pesticide Insecticide. Can persist in the environment C10H5Cl7

for decades

Hexabromobiphenyl Industrial chemical Flame retardant C12H4Br6

27

(Continued)
 Table 5. (Continued)
28
Chemical Use Molecular formula Chemical structure
Hexabromodiphenyl ether Industrial chemical Flame retardant C12 H(0-9)Br(1-10)O
and heptabromodiphenyl Theoretical number of possible congeners is
ether (commercial 209147
octabromodiphenyl ether)
Hexachlorobenzene (HCB) Pesticide/industrial Used as fungicide in food crops C6Cl6
chemical

Lindane Pesticide Organochlorine pesticide C6H6Cl6

Mirex Pesticide Organochloride pesticide C10Cl12

Pentachlorobenzene Pesticide/industrial By-product of the manufacture of carbon C6HCl5

chemical tetrachloride and benzene, intermediated in
the production of pesticides

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Polychlorinated biphenyls Industrial chemical Used in agriculture and in a number of C12H10-nCln
(PCBs) industrial applications electric transformers

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and capacitors

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Tetrabromodiphenyl ether and Industrial chemical Additive flame retardant C12H6Br4O
pentabromodiphenyl ether C12H5Br5O

Toxaphene Pesticide Pesticide used on cotton, crops and C10H8Cl8

vegetables. Half-life of up to 12 years
Science Progress 102(1)
 Table 5. (Continued)

Chemical Use Molecular formula Chemical structure

Annex B (restriction)
DDT Pesticide Pesticide used in agriculture and to control C14H9Cl5
Encarnação et al.

malaria
Perfluorooctane sulphonic Industrial chemical Man-made fluorosurfactant, used in C8HF17O3S
acid (PFOS), its salts and impregnation formulations for textiles, C8F18O2S
perfluorooctane sulphonyl leather, paints, varnishes, carpets, etc.
fluoride (PFOS-F)

Annex C (unintentional production)

Dioxins By-product 75 congeners C12 H9-nClnO2
PCDDs
Furans By-product 135 congeners C12 H9-nClnO
PCDFs
HCB By-product By-product from the manufacture of certain C6Cl6

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chemicals that can give rise to dioxins and
furans

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PCBs By-product Besides being industrial chemicals, are also C12H10-nCln
by-products

Pentachlorobenzene By-product Unintentionally produced during combustion, C6HCl5

thermal and industrial processes
29
30 Science Progress 102(1)

Figure 6. Timeline of lead poisoning prevention policies and blood lead levels in children aged
1–5 years, by year – National Health and Nutrition Examination Survey, United States, 1971–
2008.150–152
Available at https://phil.cdc.gov. Accessed 19 November 2018.
The symbol ‘*’ denotes National estimates for GM BLLs and prevalence of BLLs ⩾10 µg/dL, by NHANES
survey period and sample size of children aged 1–5 years: 1976–1980: N = 2372; 1988–1991: N = 2232;
1991–1994: N = 2392; 1999–2000: N = 723; 2001–2002: N = 898; 2003–2004: N = 911; 2005–2006: N = 968;
2007–2008: N = 817.
The symbol ‘†’ denotes NHANES survey period.

The European Commission Directive 2011/8/EU banned, on the basis of the precau-
tionary principle, the production and sale of baby bottles and food-related products for
children containing BPA (for more detailed information on European laws and regula-
tions, readers are referred to the EUR-Lex (https://eur-lex.europa.eu)). BPA has been
restricted since 2011, in the European Union, United States and other countries, because
of its endocrine disrupting properties. As a consequence of these bans, the total exposure
to BPA has effectively decreased, and BPA levels in the population of children showed a
marked decrease from 2000 to 2008.47
In Figure 6, the lead blood levels in young children are shown and are linked to the time-
line of policies on lead poisoning prevention in United States. Before the implementation
and intervention of policies, millions of children suffered from neurological effects and
diminished intelligence capacity due to lead exposure from gasoline, paints and other con-
sumer products.150,153,154 There is no threshold or safe level of lead in blood. Strong and
decisive evidence revealed that the cognitive deficits and behavioural problems can occur at
blood levels below 5 µL/dL.155,156 After the first policies were introduced, from 1976 to
1994, the lead blood levels dropped from 13.7 to 3.2 µL/dL and continued to decrease as
policies were implemented.

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Encarnação et al. 31

These, and the historical cases presented previously, indicate the limitations of sci-
ence, policies and the actions of the common citizens to avoid and prevent irreversible
damages but, at the same time, demonstrate that the concerted international effort, cou-
pled with scientifically informed political decisions, can have a tremendous impact and
effectiveness, through well-conceived policies and regulations, on the environment and
human health.

Some recommendations to minimize exposure to EDCs

In what follows, we present a brief summary of recommendations issued by the Endocrine
Society, WHO and the United Nations Environment Programme, and from experts in the
field.7,157–159

•• It is preferable to opt for fresh food instead of processed and canned foods

Food contact materials (FCMs) are a significant source of contamination. In general, the
FCMs are made of plastics that can contain additives, plasticizers and monomers that can
leach and migrate to food. Several reports have been published on this subject.69,160–163
Metal cans are normally coated inside with a thin layer of epoxy resin, which is made
from BPA.

•• It is preferable to opt for added chemicals-free food

Exposure to pesticides is linked to many diseases. Organic food may also be contami-
nated with pollutants because of the effects of the entire food chain and whole environ-
ment; however, this exposure is far less than conventional food. The option for organic
food could be more expensive, but as the consumption increases (the organic food mar-
ket is growing at a compound annual growth rate (CAGR) of around 14.56%, between
2017 and 2024), the prices of organic food products have tended to decrease.

•• Food in plastic containers should not be heated in a microwave oven. Plastic con-
tainers can be replaced by glass or ceramic ones.

The migration of the FCMs to foodstuffs can be accelerated by increasing the tempera-
ture. Some plastics, such as polycarbonate, may leach BPA. BPA analogues, such as
bisphenols F and S, which were synthesized, have replaced BPA in numerous consumer
products.91 These analogues also exhibit endocrine disrupting activity, cytotoxicity, gen-
otoxicity, reproductive toxicity and neurotoxicity.91,92

•• The consumption of fat dairy or meat products should be reduced.

POPs bioaccumulate through the food chain, and their lipophilicity means they accu-
mulate in fatty tissues. Bioaccumulation leads to biomagnification. POPs are absorbed
by lower trophic organisms, such as phytoplankton, that are consumed by zooplank-
ton and then by fish. They accumulate in fatty tissues of the organisms that are eaten

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32 Science Progress 102(1)

by other organisms, thus magnifying their effect up the food chain. This concentration
effect reaches maximum levels in top predator species, such as humans and other
mammals.

•• Products such as makeup, perfume and skin care should be free of phthalates,
parabens, triclosan and other chemicals.

Products with fragrances generally contain phthalates as carriers. Products that are
labelled ‘antibacterial’ generally contain triclosan. Information about ingredients of cos-
metics can be found in databases such as the EWG’s Skin Deep Cosmetics Database.

•• It is preferable to opt for ecological household cleaning products

Human exposure to BPA, phthalates and triclosan occurs, besides food, water and con-
sumer products, through households cleaning products. The use of household cleaning
products during pregnancy, at least once per week, was associated with 10%–44% greater
levels of phthalate metabolites in urine.164

•• Flame retardant treated furniture should be avoided

PBDEs are widely used as brominated flame retardants in furniture. These have been
gradually phased-out worldwide since 2004; however, biomonitoring studies indicate
that they are still ubiquitous in human blood and breast milk worlwide.77 A number of
older products contain significant amounts of these pollutants that are still being released
into the surroundings environment. PBDEs have been found in human breast milk and in
infants and toddlers, probably as a result of contamination by house dust.

•• Indoors environments should be ventilated regularly

It is estimated that the major source of contamination comes from indoor environments,
since we spend about 90% of our life in enclosed spaces, particularly home and work-
place, and also the car. Therefore, the IAQ has a considerable impact on our exposure to
contaminants and poses a risk to human health.138,139,142,143

•• Alternatives to plastic toys are preferred

Children toys and teething items are generally made of plastics that contain additives
which are intended to modify the properties of the polymer. The most common additives
or plasticizers, added to increase flexibility, durability and so on, have been phthalate
esters. Children’s normal behaviour, such as hand-to mouth and object-to-mouth contacts,
increases the exposure through inhalation and ingestion routes. Phthalates have been
implicated in various male malformations. Reports on the effects of prenatal exposure to
phthalates in humans showed that birth outcomes were associated with high levels of
phthalate esters in the urine of the mothers during pregnancy.102,103 Although EU has
imposed a limit of 0.1% (W/W) of phthalates in toys, these have been found in much
higher concentrations (from 0.1% to 63.34%).165

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Encarnação et al. 33

Concluding remarks and future perspectives

The exposure to EDCs begins before we are born, and even before conception. The
extent of our chemical burden is unknown; every year, hundreds of new chemicals are
produced and released onto the market without being tested, and reach our bodies
through everyday products. The omnipresence of this exposure may have affected us
all; we are not the same today as we were three centuries ago, before the invention of
synthetic chemicals. We have opened Pandora’s box, and because of the overwhelming
consequences of our actions, may be destroying our planet and our future. But the situ-
ation is not hopeless. A shift in lifestyles and consumption patterns is needed. We want
to live our lives in the comfort that the modern age has brought to us, but we can aim
for a more sustainable and ‘green’ future. One that provides health and wellbeing and
preserves the only home we have, Earth. By changing habits of consumption, we influ-
ence commerce, industry and national and international policies. In this context, it is
noteworthy that there are some significant shifts in policies and citizen’s thinking and
choices that may have, if the trend persists, an important impact on our planet. This
proenvironmental behaviour has increased considerably in recent years; the global
organic food and beverages industry has grown at a compound annual growth rate
around 14.56% between 2017 and 2024.166 The worldwide number of electric vehicles
increased from 2012 to 2017 from 110 thousands to 1.9 million.167 The global renew-
able power capacity has grown from around 850 GW in 2000, to 1829 GW in 2014,168
just to mention a few examples. International politics must also be influenced.
However, this it is not a trivial process, since each country has different declared and
other interests. For example, countries which have significant heavy chemicals indus-
try are more hostile to changes towards a greener chemicals production. Hope also lies
in the cooperation between countries, such as the Basel, Rotterdam and Stockholm
Conventions. These have raised awareness of the problem and have led to worldwide
efforts to enforce laws and regulations to protect the planet, and to protect us. There is,
therefore, some hope that it might be possible to see all countries in the world working
together on a solution to this global problem.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship
and/or publication of this article.

Funding
The author(s) received financial support for the research, authorship and/or publication of this
article: The authors acknowledge Fundação para a Ciência e a Tecnologia (FCT), Portuguese
national funding agency for science, research and technology, for the PhD research grants to
SFRH/BD/81385/2011. The authors are also grateful for support from the Coimbra Chemistry
Centre, which is funded by the FCT, through the projects PEst-OE/QUI/UI0313/2014 and
POCI-01-0145-FEDER-007630.

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Author biographies
Telma Encarnação holds a Master’s degree in Chemistry (2009) and a First Degree in Industrial
Chemistry (2007), both from the University of Coimbra. She is finishing her PhD on novel value
added fine chemicals using microalgal biomass and isotopic labelling. Her research focuses on biore-
mediation using algae and in the sustainable transformation of emerging pollutants for producing
bio-based products.

Alberto ACC Pais received his PhD in Chemistry in 1993 and is currently Full Professor at the
Department of Chemistry of the University of Coimbra. His research focuses on Molecular
Simulation, Chemometrics and Pharmaceutics. He was a guest editor for Advances in Colloid
and Interface Science, Pharmaceutics, and co-editor of the book ‘Simvastin delivery: challenges
and opportunities’. He is member of the section board for ‘Materials Science’ of the International
Journal of Molecular Sciences. He is co-author of ca. 170 ISI articles, a book and several book
chapters, ranging from molecular physics to food safety.

Maria G Campos completed her PhD in 1997 from Coimbra University Portugal followed this with
postdoctoral studies in 2000 at Industrial Research, Ltd, Lower Hutt, New Zealand. She is Auxiliary
Professor in the Faculty of Pharmacy, University of Coimbra, Director of Observatory of Herbal-
Drug Interactions, Head of the project IciPlant at the Oncological Hospital of Coimbra, and team
leader of the International Bee pollen Working Group at IHC. She is co-author of 3 books, 16 book
chapters and 94 scientific papers. She is also a member of the editorial board member of six scien-
tific journals.
Hugh D Burrows is Professor in the Department of Chemistry, University of Coimbra, Portugal.
He is a native of England and did his first degree (University of London) and PhD (University of
Sussex) there. He has since worked in Universities in the United Kingdom (Warwick), Israel (Tel-
Aviv), Nigeria (Obafemi Awolowo) and Portugal (Coimbra). He has been in Portugal for over
35 years, and his research has concentrated on various aspects of materials chemistry, polymers
and photochemistry. Much of his current interests concentrate on interactions between light and
molecules, particularly photophysical and aggregation behaviour of conjugated materials for
applications in sensing, nanostructuring, illumination and artificial photosynthesis. He is Sócio
Correspondente of the Academia de Ciências de Lisboa and Fellow of the Royal Society of
Chemistry. He is author/co-author of 7 books, 14 book chapters, around 400 scientific articles and
2 Portuguese and 1 European patents. He is also the Scientific Editor of the IUPAC journal Pure
and Applied Chemistry.

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