Endocrine-disrupting chemicals and risk of diabetes: an evidence-based review

Abstract

The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection of environmental endocrine-disrupting chemicals (EDCs) with diabetes and impaired glucose metabolism. The review summarises the literature on both cross-sectional and prospective studies in humans, as well as experimental in vivo and in vitro studies. The findings were subjected to evidence grading according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) classification. We found >40 cross-sectional and seven prospective studies regarding EDCs and risk of diabetes. Taken together, there is moderate evidence for a relationship between exposure to dichlorodiphenyldichloroethylene (p,p′-DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane, and diabetes development. Regarding polychlorinated biphenyls (PCBs), it is likely that the rodent models used are not appropriate, and therefore the evidence is poorer than for p,p′-DDE. For other EDCs, such as bisphenol A, phthalates and perfluorinated chemicals, the evidence is scarce, since very few prospective studies exist. Brominated flame retardants do not seem to be associated with a disturbed glucose tolerance. Thus, evidence is accumulating that EDCs might be involved in diabetes development. Best evidence exists for p,p′-DDE. For other chemicals, both prospective studies and supporting animal data are still lacking.

Electronic supplementary material
The online version of this article (10.1007/s00125-018-4621-3) contains a slide of the figure for download, which is available to authorised users.

Full text

REVIEW
Endocrine-disrupting chemicals and risk of diabetes:
an evidence-based review
P. Monica Lind
1
&Lars Lind
2
Received: 13 February 2018 /Accepted: 19 March 2018 /Published online: 9 May 2018
#The Author(s) 2018
Abstract
The purpose of this study was to review the epidemiological and experimental evidence linking background exposure to a selection
of environmental endocrine-disrupting chemicals (EDCs) with diabetes and impaired glucose metabolism. The review summarises
the literature on both cross-sectional and prospective studies in humans, as well as experimental in vivo and in vitro studies. The
findings were subjected to evidence grading according to the Grading of Recommendations Assessment, Development and
Evaluation (GRADE) classification. We found >40 cross-sectional and seven prospective studies regarding EDCs and risk of
diabetes. Taken together, there is moderate evidence for a relationship between exposure to dichlorodiphenyldichloroethylene
(p,p′-DDE), a metabolite of the pesticide dichlorodiphenyltrichloroethane, and diabetes development. Regarding polychlorinated
biphenyls (PCBs), it is likely that the rodent models used are not appropriate, and therefore the evidence is poorer than for p,p′-
DDE. For other EDCs, such as bisphenol A, phthalates and perfluorinated chemicals, the evidence is scarce, since very few
prospective studies exist. Brominated flame retardants do not seem to be associated with a disturbed glucose tolerance. Thus,
evidence is accumulating that EDCs might be involved in diabetes development. Best evidence exists for p,p′-DDE. For other
chemicals, both prospective studies and supporting animal data are still lacking.
Keywords Bisphenol A .BPA .Chemicals .DDE .DDT .Diabetes .EDCs .Endocrine-disrupting chemicals .Pesticides .
Review
Abbreviations
BFR Brominated flame retardant
BPA Bisphenol A
DDT 1,1,1-Trichloro-2,2-bis (p-chlorophenyl)ethane
DEHP Di(2-ethylhexyl) phthalate
EDC Endocrine-disrupting chemical
GRADE Grading of Recommendations Assessment,
Development and Evaluation
p,p′-DDE Dichlorodiphenyldichloroethylene
PCB Polychlorinated biphenyl
PFAS Perfluoroalkyl and polyfluoroalkyl substance
PFNA Perfluorononanoic acid
PFOS Perfluorooctane sulfonic acid
POP Persistent organic pollutant
PPAR Peroxisome proliferator-activated receptor
TCDD 2,3,7,8-Tetrachlorodibenzo-p-dioxin
Introduction
The prevalence of diabetes is increasing in all countries and the
disease is becoming a substantial public health concern world-
wide. During the last decade, numerous studies have proposed
links between endocrine-disrupting chemicals (EDCs) and dis-
turbances in glucose metabolism. The present review will fo-
cus on a representative selection of groups of environmental
EDCs and use a well-known system to grade the evidence. We
searched PubMed for publications with the search terms con-
taminant/pollutant/name of the chemicals included in the re-
view [AND] diabetes/glucose/insulin, including both human
and experimental studies.
Electronic supplementary material The online version of this article
(https://doi.org/10.1007/s00125-018-4621-3) contains a slide of the
figure for download, which is available to authorised users.
*Lars Lind
lars.lind@medsci.uu.se
1
Occupational and Environmental Medicine, Department of Medical
Sciences, Uppsala University, Uppsala, Sweden
2
Cardiovascular Epidemiology, Department of Medical Sciences,
Entrance 40, Uppsala University, 751 85 Uppsala, Sweden
Diabetologia (2018) 61:1495–1502
https://doi.org/10.1007/s00125-018-4621-3
Content courtesy of Springer Nature, terms of use apply. Rights reserved.

Overview of EDCs
An EDC has been defined as ‘an exogenous agent that inter-
feres with synthesis, secretion, transport, metabolism, binding
action or elimination of natural blood-borne hormones that are
present in the body and are responsible for homeostasis, re-
production and developmental process’[1]. EDC was origi-
nally a term devoted to disruption of the reproductive system
but has now been broadened to include disturbances in other
hormonal systems.
Some EDCs are lipophilic, such as polychlorinated biphe-
nyls (PCBs), dioxins, organochlorine pesticides and brominated
flame retardants (BFRs); they accumulate in the food chain and
are ingested by humans. These chemicals are stored in adipose
tissue and generally have very long half-lives (months to many
years). Perfluoroalkyl and polyfluoroalkyl substances (PFASs)
comprise another class of EDCs, the members of which are
non-lipophilic and are transported bound to albumin and stored
in the liver in humans. PFASs also accumulate in the food chain
and, depending on the length of their carbon chain, also have
very long half-lives (months to years) in humans. Together,
these types of chemicals accumulating in humans are denoted
persistent organic pollutants (POPs).
However, not all EDCs are persistent and not all accumu-
late to a major degree in humans. Bisphenol A (BPA), a well-
known plastic hardener, has a very short half-life (hours) in
humans but detectable levels are nevertheless found in most
humans in the industrialised world due to exposure on a more-
or-less daily basis. The phthalates are another huge group of
EDCs with short half-lives (hours to days) but ubiquitous ex-
posure. These chemicals are used as plasticisers and solvents.
The present review will focus on selected EDCs—those
able to be analysed in a valid way either in plasma/serum or
in urine, thereby enabling evaluation of the health effects of
exposure in epidemiological studies.
Please see Table 1for the groups of EDCs mentioned in
this review.
Epidemiological studies
Some studies have shown that high POP levels are associated
with diabetes; the study that induced a major interest in this
topic was conducted by D.-H. Lee and D. R. Jacobs Jr. and
colleagues in 2006 [2]. In that cross-sectional study, they used
the USA National Health and Nutrition Examination Survey
(NHANES) database to show that six different POPs, including
PCBs, dioxins and organochlorine pesticides, were related to
prevalent diabetes.
Following that landmark study, >40 cross-sectional studies
have been published, showing a link between EDC levels and
prevalent diabetes in different countries. However, since
cross-sectional studies are clearly prone to reverse causation
and other biases, prospective studies are warranted.
A meta-analysis of the cross-sectional and prospective
studies, published in 2016, showed that in the cross-
sectional setting significant relationships were found between
levels of dioxins, PCBs, organochloride pesticides and BPA
and prevalent diabetes, while the relationship for phthalates
was of borderline significance [3]. The results of this meta-
analysis are summarised in Fig. 1. For the seven prospective
studies included in the meta-analysis, data were only available
for PCBs and organochlorine pesticides but, as seen in the
cross-sectional studies, increased levels of these two classes
of contaminants were significantly related to incident diabetes.
In a 2013 US National Toxicology Program workshop re-
view of six studies (including two prospective studies) inves-
tigating associations between levels of BFRs and diabetes, no
clear association was found [4]. In a review of four cross-
sectional studies, no associations were seen between the two
most commonly investigated PFASs, perfluorooctane sulfonic
acid (PFOS) and perfluorooctanoic acid, and prevalent diabe-
tes, although in the only study investigating perfluorononanoic
acid (PFNA) a significant association was found [5]. This
relationship between PFNA and diabetes was confirmed in a
later cross-sectional study [6]. However, in two prospective
studies, PFNA and other PFASs were observed to have no
effect or even a protective effect [7,8].
Taken together, prospective evidence exists for associa-
tions between background exposures to PCBs and organo-
chlorine pesticides and incident diabetes. In addition, cross-
BPA (n=5)
Phthalates (n=4)
Dioxins (n=6)
Pesticides (n=11)
PCBs (n=13)
1 2 3 4
OR
1234
OR
Cross-sectional
PCBs (n=7)
Pesticides (n=5)
Prospective
ab
Fig. 1 Summary of a meta-analysis of available cross-sectional (a)and
prospective (b) studies on the association between environmental con-
taminants and diabetes published in 2016 by Song et al [3]. ORs (circles)
and 95% CI (horizontal bars) are shown and are based on comparisons
between the highest and lowest values presented in the different studies
underlying the meta-analysis. The number of studies concerning each of
the different chemical classes is shown in parentheses. This figure is
available as a downloadable slide
1496 Diabetologia (2018) 61:1495–1502
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Table 1 Overview of the groups of EDCs included in this review
Group Physical and chemical
properties
Example Common route of
exposure
Use in products Production/regulatory status Toxicity/mechanism of action
PCBs 209 congeners distinguished by number
and position of chlorine atoms
substituted on the biphenyl moiety
Resistant to acids, bases and heat
Most are lipophilic and very persistent
3,3′,4,4′,5-Pentachlorobiphenyl
(PCB-126)
High-fat food (dairy, meat,
fish)
Mixtures have been used in electrical
equipment, surface coatings, inks,
adhesives, flame retardants and paints
PCB production was banned by the US
Congress in 1979 and by the Stockholm
Convention on Persistent Organic
Pollutants in 2001
Due to their persistence in the
environment, there are still concerns
The chlorination pattern determines the
toxicity.
Mechanisms of action depend on chlorine
substitution pattern of congener:
oestrogenic, anti-oestrogenic, neurotoxic,
dioxin-like
Dioxin-like PCBs are ligands to the AH
receptor, while many non-dioxin-like PCBs
bind to PXR and CAR
Organochlorine
pesticides
Insecticidal properties
Highly lipophilic
Many are very persistent
DDT and its main metabolite
p,p′-DDE
Hexachlorobenzene
Several chlordanes
High-fat food (dairy, meat,
fish)
DDT was first used during World War II
to control lice-borne typhus
Subsequently, farmers used DDT to
control agricultural pests
DDT was banned in the USA in 1973
and also in some other countries but is
still in use in countries with malaria
Wide range of toxic effects
p,p′-DDE, the most environmentally
relevant DDT derivative, binds to androgen
receptor and has anti-androgenic properties
Dioxins A diverse range of chemical compounds
419 dioxins and related compounds have
been identified
Lipophilic
Some are very persistent
TCDD Soil, dairy, meat, seafood Not used in products
Formed during the combustion of wastes
or are undesirable byproducts in the
manufacture of herbicides, disinfectants
and other agents
Covered by the Stockholm Convention
on Persistent Organic Pollutants
Wide range of toxic effects, including
immune toxicity, developmental and
neurodevelopmental effects and changes in
thyroid and steroid hormones and
reproductive function
Only about 30 dioxins are considered to
have significant toxicity, with TCDD being
the most toxic
Mechanisms of action and toxicity vary
depending on the chlorine substitution
pattern of the congener: oestrogenic,
anti-oestrogenic, neurotoxic, dioxin-like
The dioxin-like effect is mediated by
activation of the AH receptor
BFRs Widely varying chemical properties
At high temperatures, BFRs have an
inhibitory effect on combustion
chemistry
Some are lipophilic and very persistent
Main classes are PBDEs,
HBCDDs, TBBPA and other
phenols, and PBBs
High-fat food (dairy, meat,
fish)
Used in plastics and textile applications,
electronics, clothes and insulation in
buildings and furniture
The use of certain BFRs is banned or
restricted in the EU
In the USA, the manufacture of PBB
wasbannedin1976
Due to the persistence of BFRs in the
environment, there are still concerns
Toxic effects, including teratogenicity,
carcinogenicity and neurotoxicity, have been
observed for some BFR congeners
(especially PBDEs)
There is evidence that some BFRs disrupt
the thyroid hormone system–most data are
available for the PBDE class
PFASs Hydrophobic and lipophobic
Some are resistant to environmental
degradation and are extremely persistent
Perfluorocarboxylic acids (e.g.
PFOA, sometimes called C8,
and PFNA) and
perfluorosulfonates (e.g. PFOS
and PFHxS)
Seafood, drinking water and
food contact material
Used in industry and consumer products
since the 1950s
Used in food packaging materials,
non-stick cookware, water-resistant
clothing, cleaning products, paints,
varnishes and sealants, firefighting foam
and cosmetics
Use of PFASs has been largely phased
out of food packaging materials
The European Parliament has approved
an EU directive (2006/122/EU) with
restrictions on marketing and use of
PFOS and PFOS-related substances
There is evidence that some PFASs disrupt
the thyroid hormone system.
Some PFASsbind to PPAR-αand to a lesser
degree to PPAR-γ.
Bisphenols Group of non-persistent chemicals with
two phenolic rings joined together by a
bridging carbon or other chemical
structure.
Bisphenol A (BPA;
4,4′-isopropylidenediphenol)
Ubiquitous Commonly used to produce plastics
BPA is used mainly in the manufacture
of polycarbonate and is also used in
other plastics as a hardener
Used in products such as DVDs, dental
materials and lunch boxes
Epoxy plastic can be used in electronics,
building materials, in the protective
lining in cans and in the relining of water
pipes
BPA is present in thermal paper
Controversial issue
BPA is banned in baby bottles
throughout the EU
In 2017, 5.4 million tons of BPA was
produced
Initially BPA was designed as a synthetic
oestrogenandhasbeenshowntobindto
oestrogen receptors (ERα,ERβ, and to the
membrane ER)
Emerging data shows that BPA interacts
with other hormone receptors, including
androgen receptors and the thyroid hormone
receptor
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Tab l e 1 (continued)
Group Physical and chemical
properties
Example Common route of
exposure
Use in products Production/regulatory status Toxicity/mechanism of action
Phthalates Esters of phthalic acid
Not persistent
DEHP Ubiquitous Used as plasticisers in the production of
plastics
Used in cosmetics, perfumes,
pharmaceutical tablets, medical tubing,
nutritional supplements, adhesives,
paints, food containers and wrappers,
toys and cleaning materials
Controversial issue
Some countries have banned their use in
children’stoys
Five million tons of phthalates are
produced annually
MEHP, a metabolite of DEHP, has been
found in exposed organisms and interacts
with all three PPARs
These EDCs were selected because they can be analysed in a valid way either in plasma/serum or in the urine, thereby enabling the evaluation of the health effects of exposure in epidemiological studies
Congeners: congeners are related chemical substances, related to each other by origin, structure, or function
AH, aryl hydrocarbon; CAR, constitutive androstane receptor; EU, European Union; HBCDD, hexabromocyclodecane; MEHP, mono-ethyl-hexyl-phthalate; PBB, polybrominated bisphenol; PBDE,
polybrominated diphenyl ether; PFHxS, perfluorohexasulfonate; PFOA, perfluorooctanoic acid; PXR, pregnane X receptor; TBBPA, tetrabromobisphenol A
1498 Diabetologia (2018) 61:1495–1502
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sectional evidence exists for relationships between dioxins
and BPA and prevalent diabetes, while there is no convincing
evidence for relationships between phthalates, BFRs or
PFASs and diabetes.
Experimental studies
Several studies indicate that Vietnam veterans exposed to Agent
Orange contaminated with dioxins have an increased risk of
incident diabetes (see [4] for review) but animal studies have
generally shown a hypoglycaemic response to the potent dioxin
2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [9]. Neither could
any consistent hyperglycaemic responses be seen in rodent stud-
ies exploring the effect of PCB exposure [10], except in one
study in which dioxin-like PCBs impaired glucose tolerance in
lean but not fat mice [11].
Regarding organochlorine pesticides, perinatal exposure to
1,1,1-trichloro-2,2-bis (p-chlorophenyl)ethane (DDT) induced
impaired glucose tolerance later in life in mice [12]. In addition,
adult rodents exposed to DDT later in life showed impaired
glucose tolerance and reduced insulin secretion [13].
Nadal and co-workers showed that mice exposed in utero to
BPA displayed impaired glucose tolerance and reduced insulin
secretion later in life [14]. In addition, long-term exposure of
BPA later in life induced impaired glucose tolerance in mice [15].
Taken together, in vivo animal studies do not support the
epidemiological evidence of a diabetogenic response to dioxins
or PCBs, while evidence in rodents supports an effect for DDT
and BPA.
Potential obesogenic role of contaminants
Based on the experimental finding that the organotin substance
tributyltin induced weight gain in mice and that this effect was
mediated by peroxisome proliferator-activated receptor
(PPAR)-γand involved reprogramming of mesenchymal stem
cells towards the adipocyte lineage [16], it has been proposed
that certain environmental contaminants could contribute to
the obesity epidemic seen worldwide, acting as so-called
‘obesogens’. Since obesity is the major risk factor for future
type 2 diabetes, it is of interest to investigate whether the
contaminants found to be related to diabetes might also induce
obesity.
The lipophilic POPs, such as dioxins, PCBs and organochlo-
rine pesticides, accumulate in adipose tissue to a major degree.
The degree of fat mass influences their circulating levels, making
it difficult to study the relationships between these compounds
and obesity in adults. However, mother–child cohorts, with mea-
surements in the pregnant mothers and follow-up of the weight
gain of the children, may provide evidence for the ‘obesogen’
hypothesis, since it has been suggested that exposure to
contaminants early in life would have the greatest impact on
future weight gain.
A recent meta-analysis of seven mother–child cohorts showed
a positive relationship between prenatal exposure to DDT/
dichlorodiphenyldichloroethylene (p,p′-DDE) and future weight
gain in the children [17].Thesedataaresupportedbyanexper-
imental study showing that prenatal exposure of mice to this
pesticide induced reduced energy expenditure and a transient
weight gain [12]. When given a high-fat diet, the mice developed
impaired glucose tolerance.
In a review from 2011, no convincing association was
found between exposure to other types of lipophilic POP
and future weight gain in mother–child cohorts [18].
In a recent review of more short-lived, less lipophilic EDCs,
prenatal exposure to phthalates and BPA, as well as childhood
exposure to these plastic-associated chemicals, was not consis-
tently associated with increased future body weight. In contrast,
most studies of PFASs in this context have shown a relationship
between prenatal exposure to PFASs and impaired weight gain
[19].
Taken together, the best evidence for EDCs inducing obe-
sity that might cause diabetes is present for the pesticide DDT.
Mechanistic studies
Insulin secretion and insulin sensitivity are the two main charac-
teristics determining glucose tolerance. In a recent study, the early
and late insulin response was modelled using data obtained at a
2 h OGTT [20]. Both the dynamic first-phase and the static
second-phase insulin response were impaired in non-diabetic in-
dividuals with high levels of organochlorine pesticides, while the
association with PCBs was weaker. When the proinsulin-to-
insulin ratio was used as a proxy for a disturbed beta cell func-
tion, high levels of some phthalates and some PFASs were asso-
ciated with this ratio [6,21].
In experimental studies, the potent dioxin TCDD has been
shown to influence insulin secretioninaratinsulin-secretingbeta
cell line and in isolated rat pancreatic cells [22]. TCDD has also
been reported to induce pancreatic cell death by auto-
phagy in the beta cell line INS-1E [23]. In insulin-sensitive
tissues such as liver, skeletal muscle and adipose tissue from
the guinea pig, TCDD induced insulin resistance [24], possibly
by downregulation of glucose transporters [25]. The insecticides
malathion and diazinon have been reported to influence insulin-
secreting beta cells [26,27], partly by downregulation of musca-
rinic receptors. Prenatal exposure of rats to di(2-ethylhexyl)
phthalate (DEHP) has been shown to induce hyperglycaemia,
hyperinsulinaemia and a reduced beta cell mass [28]. In vitro,
organochloride pesticides reduced insulin secretion in pancreatic
INS-1E beta cells [20].
Using the HOMA index of insulin sensitivity in humans, a
prospective study showed insulin sensitivity to be impaired in
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middle-aged individuals who 20 years earlier showed high
levels of organochlorine pesticides [29]. Other cross-sectional
studieshave linked levels of PCBs and, especially, organochlo-
rine pesticides to insulin sensitivity [20]. Although some
phthalates and PFASs have been linked to impaired insulin
sensitivity in humans, some studies have failed to reproduce
the link between PFASs and insulin resistance [6,7,21,30].
Experimental prenatal exposure to PFOS, as well as to DDT,
phthalates and BPA, resulted in impaired insulin sensitivity and
glucose intolerance [12,14,31]. In addition, exposure to a mix-
ture of PCBs, or a mixture of 23 lipid-soluble POPs, induced
glucose disturbances and insulinresistanceinvivoinmice[32,
33]. The effect of a mixture of POPs has also be observed in vitro
in cultured adipocytes [33].
Taken together, many of the EDCs investigated have been
shown to impair insulin secretion and sensitivity in both hu-
man and experimental studies.
Discussion and future perspectives
Ideally, large prospective studies are needed to investigate wheth-
er fetal and prenatal exposure to EDCs induces obesity and later
type 2 diabetes. Unfortunately, those studies are not likely to be
conducted for practical reasons. Since an ideal study would take
60–70 years to accomplish, most of the chemicals used at the
initiation of the study would probably not be in use at the time
when the results became available. Thus, in practice, we do have
to rely on results from studies not covering the whole lifespan.
Currently, results of a moderate number of prospective studies
involving PCBs and organochlorine pesticides are available. It is
reassuring that the results of a meta-analysis of these studies are
in line with results from a much larger number of cross-sectional
studies on the same EDCs. Firm experimental data also exist to
support a causal relationship between DDT/p,p′-DDE exposure
and diabetes development. According to the well-established
Grading of Recommendations Assessment, Development and
Evaluation (GRADE) criteria used for reviewing evidence
(http://www.gradeworkinggroup.org), moderate evidence exists
of a true relationship between DDT/p,p′-DDE exposure and
diabetes development. To achieve a high degree of evidence,
randomised trials are needed but will never be accomplished in
the field of EDC research. Regarding dioxins and PCBs, it is
likely that the rodent models used are not appropriate due to the
large discrepancy in sensitivity of the aryl hydrocarbon receptor
between humans and rodents and therefore there is less evidence
than for DDT/p,p′-DDE. For other EDCs, the evidence is low,
since we do not have enough prospective data.
A very important future aim is to gain prospective data in
population-based studies with a high number of incident out-
comes. The major hurdle in achieving that goal is not the lack
of such cohorts but rather that the volume of blood/urine needed
for analysis of EDCs is still too large. Only when it is possible to
measure EDCs in <100 μl of plasma at a reasonable cost will
biobanked plasma from large cohorts be used for this purpose.
Although analytical chemistry has improved over the years re-
garding the volumes needed for proper analyses, the advance-
ment of the field is heavily dependent on further developments.
Another area in need of improvement is the study of mixture
effects. Nowadays, the relationships between EDCs and diseases,
such as diabetes, are usually studied either by the sum of con-
centration of the chemicals in a certain class or by simply
analysing the contaminants one by one. One exception to this
rule is the use of toxic equivalents, based on binding to the aryl
hydrocarbon receptor, but this ‘pharmacological approach’is
only applicable to dioxins and other dioxin-like chemicals. In
other instances, sophisticated statistical methods are needed to
study mixture effects and some examples of using those methods
to study mixture effects have been published [34,35]. It is also
possible to use less sophisticated methods to estimate the effects
of multiple EDCs once they have been identified one by one, as
exemplified by our recent estimation in the Prospective
Investigation of the Vasculature in Uppsala Seniors (PIVUS)
study that the population attributable risk for diabetes for the
combination of 2,2′,4,4′,5,5′-hexachlorobiphenyl (PCB-153),
p,p′-DDE, monoethylphthalate and PFNAwas 13%. The impact
of these contaminants was estimated to be related to a yearly
healthcare cost of diabetes in Europe of €4.51 billion [36]. This
is in line with the findings of an expert panel, based on several
published studies, who concluded that the cost of obesity and
diabetes caused by EDCs was €18 billion a year [37].
Since it is impossible to obtain the highest degree of evidence
by performing randomised clinical trials with environmental con-
taminants, it is essential to support epidemiological findings with
animal data to establish causality. Therefore, use of relevant
models using animals having similar sensitivity to the different
chemicals as humans is critical to increase the level of confidence
in human findings.
At first glance it seems contradictory that aryl hydrocarbon
receptor activation (dioxins), androgen receptor antagonism
(p,p′-DDE) and PPAR-γbinding (phthalates and PFASs) all
could lead to disturbed glucose metabolism but it must be re-
membered that a number of pharmaceutical drugs with different
modes of action can also impair glucose tolerance (e.g. β-
blockers, thiazide diuretics and neuroleptic drugs). Several down-
stream effects of the agonistic/antagonistic actions on the recep-
tors described above, such as mitochondrial dysfunction [38],
inflammation [39], oxidative stress [40] and alterations in thyroid
and cortisol pathways [41], comprise possible mediating path-
ways linking different EDCs to glucose disturbances.
In conclusion, several epidemiological studies have pointed to
an association between EDCs and diabetes. According to the
principle of REACH, a European Union regulation of chemicals
(no. 1907/2006) designed to ensure a high level of protection of
human health and the environment, this might be enough for
regulatory authorities to regard this problem as serious. The best
1500 Diabetologia (2018) 61:1495–1502
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evidence for an association between EDCs and diabetes, graded
as moderate, is found for DDT/p,p′-DDE. A lower grade of
evidence is found for PCBs, since supporting experimental data
are lacking. For other EDCs, prospective studies are needed to
support the findings of existing cross-sectional studies.
Duality of interest The authors declare that there is no duality of interest
associated with this manuscript.
Contribution statement Both authors were responsible for drafting the article
and revising it critically for important intellectual content. Both authors ap-
proved the version to be published.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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