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Phthalates: On The Issue of Sources, Human Uptake, Time Trends and Health Effects
Phthalates: On The Issue of Sources, Human Uptake, Time Trends and Health Effects
Phthalates
On the issue of sources, human uptake,
time trends and health effects
Phthalates
On the issue of sources, human uptake,
time trends and health effects
Huan Shu
Huan Shu
Huan Shu
DOCTORAL THESIS
urn:nbn:se:kau:diva-62637
ISSN 1403-8099
Distribution:
Karlstad University
Faculty of Health, Science and Technology
Department of Health Sciences
SE-651 88 Karlstad, Sweden
+46 54 700 10 00
WWW.KAU.SE
Dedication
1
Abstract
The thesis shows that PVC flooring in the home is a source for human
uptake of phthalates, that replacement of phthalates in soft PVC
products have an impact on human uptake of these chemicals, and that
exposure for phthalates in early life increase the risk for airway
disorders in children.
2
Contents
DEDICATION ............................................................................................... 1
ABSTRACT ................................................................................................. 2
CONTENTS ................................................................................................. 3
PREFACE .................................................................................................... 5
LIST OF PAPERS ....................................................................................... 6
ABBREVIATIONS ....................................................................................... 7
INTRODUCTION ......................................................................................... 8
ENDOCRINE DISRUPTING CHEMICALS ............................................................ 8
PHTHALATES: A HUNDRED YEAR OLD STORY .................................................. 9
Phthalates is a high production volume group of chemicals ...... 9
Human exposure to phthalates ................................................ 10
Global health concern for phthalate exposure ......................... 12
The current regulation on phthalates ....................................... 13
Replacements and phthalate alternatives ................................ 14
THE FULL CHAIN MODEL ............................................................................. 14
RESEARCH QUESTIONS FOR THE THESIS ..................................................... 15
AIM OF THE THESIS ................................................................................ 16
METHOD ................................................................................................... 16
THE DBH-STUDY ..................................................................................... 16
THE SELMA STUDY ................................................................................. 18
Questionnaires ........................................................................ 19
Biomarkers in prenatal urine and serum .................................. 19
BIOSTATISTICAL ANALYSES AND MODELING ................................................. 21
ETHICAL APPROVAL................................................................................... 23
RESULT AND DISCUSSION..................................................................... 23
PVC FLOORING MATERIALS IN THE HOME AS A SOURCE FOR HUMAN UPTAKE OF
PHTHALATES ............................................................................................ 23
TIME TRENDS FOR HUMAN LEVELS OF PHTHALATES ...................................... 28
EARLY LIFE EXPOSURE TO PHTHALATES AND AIRWAY PROBLEMS IN CHILDREN 32
PVC flooring and incidence of asthma ..................................... 33
Prenatal phthalate exposure and croup during infancy ............ 35
OVERALL DISCUSSION OF THE FINDINGS...................................................... 37
Leakage of phthalates from PVC to indoor dust ...................... 40
3
Phthalates in indoor air and dust and the relation to human
urinary levels ........................................................................... 41
Phthalates in indoor dust and the association to airway
problems in children ................................................................ 41
The full chain for BBzP ............................................................ 42
ETHICS CONSIDERATION ............................................................................ 43
A PUBLIC HEALTH CONCERN ...................................................................... 43
CONCLUSION ........................................................................................... 44
ACKNOWLEDGEMENTS.......................................................................... 46
4
Preface
5
LIST OF PAPERS
II. Shu, H., Jönsson, B. A., Lindh, H., Nånberg, E. and Bornehag,
C.-G., PVC flooring at home and uptake of phthalates in
pregnant women in the Swedish SELMA study.
In manuscript
III. Shu, H., Jönsson, B. A., Genning, C., Svensson, Å., Nånberg,
E., Lindh, C., Knutz, M., Takaro, T. and Bornehag, C.-G.,
Temporal Trends in Phthalate Exposures in Swedish
Pregnant Women.
IV. Shu, H., Wikström, S., Jönsson, B. A., Svensson, Å., Nånberg,
E. and Bornehag, C.-G., Prenatal Phthalates Exposure and the
Association to Infants Croup in the Swedish SELMA Study.
6
ABBREVIATIONS
7
Introduction
8
Therefore, exposure to chemicals with endocrine disrupting properties
is a growing concern for the fetus, infants, children and adults alike.
One group of EDCs is phthalates.
9
High molecular weight phthalates (HMW), including di-iso-
nonyl phthalate (DINP), di-iso-decyl phthalate (DIDP), and di-
2-propylheptyl phthalate (DPHP), have more than seven carbon
atoms in their main carbon chain and their water solubility is
very low (National Research Council (US) Committee on the
Health Risks of Phthalates, 2008).
Low molecular weight phthalates (LMW), such as butyl-benzyl
phthalate (BBzP), di-butyl phthalate (DBP), and di-ethyl-hexyl
phthalate (DEHP), have three to six carbon atoms, and their
water solubility is slightly higher than phthalates with higher
molecular weight (European Chemical Agency, 2016).
Other phthalates include a group of compounds with the lowest
molecular weight and less than three carbon atoms in the carbon
chain, such as di-ethyl phthalate (DEP). Based on the chemical
structure, this group tends to have a higher volatility and
solubility in water than the HMW and LMW groups (National
Research Council (US) Committee on the Health Risks of
Phthalates, 2008).
Since phthalates create weak chemical bonds when they are added into
different products, these compounds are readily leached into the
surrounding environment (Bertelsen et al., 2012). For several of the
phthalates, the major exposure route is via food ingestion (Colacino et
al., 2010; Meeker et al., 2009). Some phthalates have also been found
in fatty foods such as fish, oil and dairy products (Cheng et al., 2013;
Sharman et al., 1994). While other studies found phthalates in food that
have been contaminated with its packaging (Cirillo et al., 2011; Fierens
et al., 2012), phthalates (DEHP) have also been added purposely into
sports drink (Yang et al., 2013). Phthalates present in a mother’s body
10
can be transferred to young children via breast milk, while infant
formula contaminated with phthalates during production may also
contribute to infant phthalates exposures (Calafat et al., 2004b; Ge et
al., 2016; Mortensen et al., 2005; Zhu et al., 2006).
Table 1. Phthalate metabolites and its parent compounds, registered use in EU and
amount used in Sweden
Registered use in Amount used in
Molecular
CAS No. Compond Name Category EU Sweden
weight 1 2
(ton / year) (ton/in 2011)
84-66-2 Di-ethyl phthalate (DEP) 222.24 Other 1,000 - 10,000 12
84-74-2 Di-butyl phthalate (DBP) 278.34 1,000 - 10,000 0
LMW
85-68-7 Benzyl butyl phthalate (BBzP) 312.36 1,000 - 10,000 0
(Low molecular weight)
117-81-7 Di-(2-ethylhexyl) phthalate (DEHP) 390.56 100,000 - 1,000,000 446
68515-48-0 Di-isononyl phthalate (DiNP) 418.61 100,000 - 1,000,000 1895
HMW
68515-49-1 Di-isodecyl phthalate (DIDP) 446.66 100,000 - 1,000,000 4826
(High molecular weight)
53306-54-0 Di-(2-propylheptyl) phthalate (DPHP) 446.66 100,000 - 1,000,000 15398
1Europe commission database
2Swedeish Chemical Agency report 2015
Another source of exposure that also has come on the radar for
researchers is sex toys (Biesanz, 2007; KEMI, 2017). Unlike children’s
toy, sex toys are largely unregulated and untested (Biesanz, 2007).
Biesanz (2007) mentioned a study done in 2000 by German chemist
Hans Ulrich Krieg where 10 dangerous chemicals, including DEHP,
were found in sex toys that were available in Europe. DEHP phthalate
was also found in sex toys sold on the Swedish market (KEMI, 2017).
11
many enzymes and completely degraded into individual metabolites
(e.g., into monoesters) and further oxidation may also occur, resulting
in oxidative metabolites (Silva et al., 2006).
Major public health concerns regarding EDCs over the past three
decades have focused on phthalates. In animal tests, these chemicals
(DBP, BBzP, and DEHP) have been proven to have anti-androgenic
effects on offspring, which means that they block male hormones that
guide reproductive development (Borch et al., 2006; Braun et al., 2013;
Foster, 2006; Howdeshell et al., 2007). EDCs are suspected to be
associated with altered reproductive function in males and females,
increased incidence of breast cancer, abnormal growth patterns and
neuro-developmental delays in children, as well as changes in the
immune function (Eisenberg et al., 2011; Kim et al., 2009; Lopez-
Carrillo et al., 2010; Swan et al., 2010).
12
The current regulation on phthalates
In the European Union (EU), the use of some phthalates has been
restricted in children’s toys since 1999 with DEHP, BBzP, and DBP
restricted for all toys, and DINP, DIDP, and Di-n-octyl (DNOP)
restricted in toys that can be put into mouths (Johnson et al., 2011).
This restriction also states that the amount of these phthalates may not
exceed 0.1% mass percent of the plasticized part of the toy (Cate, 2009).
They will be restricted from 22 July 2019 for all electrical and electronic
equipment, except from Category 8 (medical devices) and Category 9
(monitoring and control equipment), which will have an additional two
years to comply, by 22 July 2021 (European Union, 2015).
13
Replacements and phthalate alternatives
14
Figure 1. The life cycle of an endocrine disruptor from source to environmental
exposure to biomarkers, and to human health risks.
15
Aim of the thesis
Method
The DBH-Study
This current thesis included data from 3,228 children and their
families with data drawn from three datasets: the baseline (DBH I), the
5-year follow-up (DBH III), and the 10-year follow-up (DBH IV) as
shown in Figure 2. By including DBH III in this thesis, we identified
subjects who developed asthma after the 5-year follow-up.
Questionnaires
20
In these serum samples, cotinine levels were measured. Cotinine is
commonly used as a biomarker for tobacco smoke exposure. If cotinine
levels were below 0.2 ng/mL, subjects were categorized as non-smoker;
if cotinine levels were greater than 15 ng/mL, subjects were considered
as active smokers; and while in between, subjects were considered as
passive smokers (Jefferis et al., 2010).
21
Associations between different environmental and health effects were
estimated by crude and adjusted odds ratios (ORs and aORs). Logistic
regression analysis was carried out using SPSS for Windows (V.19.0;
IBM Corp, Armonk, NY, USA) for Paper I and PROC LOGISTIC in SAS
version 9.3 of the SAS System for Windows. Copyright © 2012, SAS
Institute Inc. Cary, NC, USA.
22
Because of potential correlations between different phthalate
metabolites that occur together, traditional regression methods may
suffer from collinearity effects, when compounds are investigated one
by one. Such correlation can be because the same metabolites share
various sources (e.g., consumer products and articles). In order to solve
this problem, we used weighted quantile sum (WQS) regression, which
is a recently proposed method by Carrico et al. (2015). The benefit of
using WQS is that while considering the correlation between
compounds, generalized inference about the mixture effect can be
made and individual chemicals with the most significant contributions
can be identified. WQS regression was used in paper IV. The analysis
was conducted using PROC GLM in SAS version 9.3 of the SAS System
for Windows. Copyright © 2012, SAS Institute Inc. Cary, NC, USA.
Ethical approval
23
flooring can be warrantied for up to 30 years or more (The European
Council of Vinyl Manufacturers, n.d.).
The Swan is the official Nordic ecolabel, which was introduced by the
Nordic Council of Ministers. As per its document about floor covering,
wood flooring and plastic flooring are the most popular flooring types
in Sweden (The Swan ecolabel, 2014). In 2012, 5.7 million plastic
flooring were sold in Sweden, however, most of the production of the
flooring industry has shut down in Sweden and just one large flooring
manufacture remains (KEMI, 2015a). Our data in DBH and SELMA
shows that approximately 30 - 40% of the homes (between 2000 and
2010) have PVC flooring in at least one of the bedrooms of the home
(paper I and paper II).
The association between type of flooring in the home and urinary levels
of phthalate metabolites were analyzed for pregnant women in a cross-
sectional design including 1,658 women for which we had data for all
included variables for the biostatistical modeling.
24
Figure 3. Least square geometric mean levels (95% CI) of MnBP, MBzP, and
MECPP in urine (log scale) in relation to flooring material in 1,658 homes.
Adjustments made for mother’s age, mother smoking status, education,
dwelling type, marital status and creatinine. Adjusted overall significance
for trends is marked with a p-value (*<0.05, **<0.01, ***<0.001).
25
Our results show that analyses with a traditional logistic regression
model with a compound by compound approach, and with a mixture
model conducted in a WQS regression model revealed similar results
regarding PVC flooring as a determinant for urinary levels of MBzP.
The importance for DEHP metabolites, however, was disappearing and
the DINCH metabolite appeared in the WQS analyses.
Table 3. Correlations between urinary levels of phthalates and phthalate
alternative metabolites expressed as Pearson correlation coefficient and
significance level (p-value) calculated on log transformed urinary
concentrations controlled for creatinine (N=1,658).
MEP MBP MBzP MEHP MEHHP MEOHP MECCP MCMHP MHiNP MOiNP MCiOP MHiDP MCiNP
1
DEP MEP
0.13 1
DBP MBP
***
0.06 0.54 1
BBzP MBzP
** ***
0.09 0.37 0.34 1
MEHP
*** *** ***
0.10 0.40 0.35 0.83 1
MEHHP
*** *** *** ***
0.09 0.42 0.37 0.83 0.99 1
DEHP MEOHP
*** *** *** *** ***
0.07 0.35 0.32 0.78 0.92 0.93 1
MECCP
*** *** *** *** *** ***
0.07 0.25 0.23 0.68 0.87 0.85 0.85 1
MCMHP
*** *** *** *** *** *** ***
0.07 0.19 0.16 0.32 0.40 0.39 0.39 0.28 1
MHiNP
*** *** *** *** *** *** *** ***
0.08 0.25 0.20 0.39 0.46 0.45 0.45 0.32 0.95 1
DiNP MOiNP
*** *** *** *** *** *** *** *** ***
0.05 0.13 0.09 0.24 0.31 0.30 0.37 0.27 0.91 0.90 1
MCiOP
* *** *** *** *** *** *** *** *** ***
-0.02 0.16 0.13 0.21 0.23 0.23 0.19 0.13 0.21 0.24 0.18 1
DIDP MHiDP
0.36 *** *** *** *** *** *** *** *** *** ***
/
-0.01 0.06 0.07 0.12 0.16 0.15 0.25 0.20 0.47 0.43 0.57 0.13 1
DPHP MCiNP
0.60 ** *** *** *** *** *** *** *** *** *** ***
-0.02 0.16 0.13 0.21 0.23 0.23 0.19 0.13 0.21 0.24 0.18 1.00 0.13
DINCH MOiNCH
0.36 *** *** *** *** *** *** *** *** *** *** *** ***
26
York City found that children from homes with PVC or linoleum
flooring had significantly higher urinary MBzP concentration than
other children Just et al. (2015). To our knowledge, there is no study
focusing on the importance of PVC for uptake of DINCH.
This is the first study where the associations between urinary phthalate
metabolite levels and the existence of PVC flooring at home were
examined with both a traditional compound by compound approach,
as well as a mixture (WQS) method. By using WQS method, this
approach addressed issues that arise with the correlated factors.
Our finding that PVC flooring may be a source for uptake of BBzP
metabolites in pregnant women raise concern for several reasons. First,
BBzP is under regulation and is classified as reproduction toxic
category 1B (i.e., substances presumed to have carcinogenic potential
for humans). Furthermore, BBzP cannot be used for any application
within the EU without permission after 2015 (ECHA, 2016). Another
concern is that PVC flooring material is very common in Sweden
(around 30% - 40% of Swedish homes have PVC flooring). However,
while the use of BBzP as a plasticizer is most likely on the decrease,
27
time trend data in human urinary levels of MBzP does not show that
trend (see chapter 4.2 below). It is notable that PVC is not overly
popular in other countries in North America and Europe. However, one
global commonality is the usage of such flooring material in public
facilities such as health care unit, schools, and daycare centers because
of its unique properties such as durability, long lasting, and easy to
clean (The European Council of Vinyl Manufacturers, n.d.).
One limitation with these analyses is that we do not have data on the
age of the PVC flooring. This means that we cannot distinguish between
the PVC floorings with older phthalates such as DEHP and PVC
floorings and newer phthalates, such as DINCH. Since phthalates are
SVOCs, one of many properties of SVOC is that SVOCs tend to be in the
absorbed phase, and not in gas phase. Therefore, while with the unique
properties of added phthalates in the PVC flooring, the high material
phase concentration and low emission rate make the PVC flooring
relatively constant and stable over time. With newly installed PVC
flooring in a home, the emission is slow. Over time the concentration
of emitted phthalate indoors will plateau. Plasticizers such as DEHP
inhibit the degradation of the PVC polymer when they migrate to the
surface. When it is absorbed by other material, PVC discolors and fall
apart. This raises the concern of long-term human phthalate exposure
with intact aged PVC floorings in home.
28
Since 1999, regulations around phthalates have been closely followed
by the global market. As mentioned earlier, in the European market,
the HMW phthalates (e.g., DiNP, etc.) currently dominate and they
have in several applications replaced the LMW phthalates (e.g., DBP,
BBzP, DEHP) (KEMI, 2015b). Many Swedish companies have replaced
DEHP with DIDP, DINP, and DPHP (KEMI, 2015b). In 2006, the
European Food Safety Authority (EFSA) approved DINCH for a wide
variety of food contact applications. DINCH compounds have been
used to replace DEHP and DINP (Crespo et al., 2007).
Old phthalates that have been used for long time, such as DEHP,
DBP, and BBzP;
Newer phthalates that were introduced (in the late 1990s) in
order to substitute the old phthalates, such as DINP, DIDP, and
DPHP; and,
Non phthalate compounds (phthalate replacements) were
introduced around 2005, such as DINCH.
The study population for the current analysis is 1,651 women for which
we have data for all included variables in the biostatistical modelling,
where we have used LSGM analyses adjusted for potential confounding
variables.
29
including DEHP metabolites, while the newer phthalates are increasing
including DiNP and DiDP/DPHP metabolites, and the phthalate
replacement is also increasing with an even faster rate, including the
DINCH metabolite MOiNCH. More specifically, we found:
When analyzing the metabolites of DEP (MEP), DBP (MBP), and BBzP
(MBzP) we could not find any significant changes during the 2.5-year
period.
30
Figure 5. Urinary levels of phthalate metabolites (estimated by LSGM with 95%
CIs) during four periods from 2007 to 2010 in 1,651 pregnant women in the
SELMA study; 271 samples were included from 2007, 683 samples in 2008,
593 samples in 2009 and 104 samples in 2010. The model adjusted for
urinary creatinine, mothers age (years), season (winter vs. summer),
mother’s education (university vs. other), and PVC flooring in a bedroom
(yes vs. no). DEHP metabolites trend (p<0.001) are in red, DiNP
metabolites trend (p<0.01) are in yellow, and the DINCH metabolite trend
(p<0.001) is in blue.
lists. Other studies found the significantly negative temporal trends for
MnBP, and MBzP (Gyllenhammar et al., 2017; Zota et al., 2014). One
reason for this difference could be the use of a shorter sampling period
in our data.
Our findings regarding DEHP, DiNP and DINCH are in line with the
current regulation patterns in Sweden, as reported by KEMI (2011).
The usage of DEHP and DiNP in PVC was changed between 2002 and
2005. The production of DEHP was reduced from 12,272 tons in 1999
to 2,732 tons in 2002, while DiNP increased from 452 tons to 8,246
tons during the same period. This substitution process has continued
throughout the past several years, although to a much lower extent. The
use of DINCH in Sweden increased by 47 times between 2011 and 2012,
31
from 427 tons to 20 077 tons (KEMI, 2014). In 2012, the registered
amount of DINCH according to the product register was only 40
percent lower than the total amount of phthalates recorded (KEMI,
2014). However, KEMI (2011) report that the usage of BBzP in PVC has
reduced from 1,268 in 1994 tons to 19 tons in 2008, which was not
reflected in our time trend data.
32
disease during infancy. Assessments of environmental exposures
could, therefore, be extended from relationships with asthma to
include other clinical measures in early life. Wheeze is such a
recognizable clinical symptom that also has been shown to be
associated with the development of asthma later in life (Jackson et al.,
2008). Other inflammatory morbidities and early life conditions
providing relevant proxies of significant airway inflammatory response
may include viral croup and otitis media, which are upper respiratory
tract infections (Cetinkaya et al., 2001; Janson et al., 2007; Moussa et
al., 1996; Nicolai et al., 1996; Van Bever et al., 1999).
The following results from two studies are presented: one relating to
the importance of PVC flooring in childhood and development of
doctor diagnosed asthma during 10 years with data from the DBH-
study (Paper I), and one study on prenatal exposure for phthalates and
the importance for airway symptoms/diseases such as wheezing and
croup in infants in the SELMA study (Paper IV).
Subjects who had PVC flooring in the parents’ bedrooms, but not the
child’s bedroom at baseline were at higher risk of developing asthma
compared to subjects who had PVC flooring in child’s bedrooms but not
in parents’ bedroom. One possible explanation of this association with
parents’ bedrooms could be that the flooring in the parents’ bedroom
at the time of the baseline questionnaire in most of the cases represents
the situation during the pregnancy period. This could then indicate the
exposure situation for the pregnant women. For the children who at
baseline had lived in the same location since birth, PVC flooring in the
parents′ bedroom was significantly associated with having doctor-
33
Figure 6. Association between parental reported doctor-diagnosed asthma at
follow-ups (5 and 10 years) and PVC flooring in the home in childhood at
baseline, extracted by rooms and expressed as adjusted odds ratio and 95%
CI.
diagnosed asthma, whereas this association was not seen for the child’s
bedroom.
In this study (paper IV) we have used data from the SELMA study
including 1,062 children with data on prenatal phthalate exposure and
parental reports of airway problem when they were 12 months old.
Approximately, 9.5%, 29.6% and 15.4% of the SELMA children were
reported to suffer from croup, wheezing, and otitis media respectively
during their first 12 months of age, and boys were reported to exhibit
more croup, wheeze and otitis media than girls have.
The prevalence of croup (9.5%) during the child´s first year of the
current study is slightly lower than the approximately 15% that were
reported in other studies (Bjornson et al., 2013; Charles et al., 2010;
Everard, 2009). However, this difference could be due to the fact that
children in the referred studies were slightly older; in the range of 6 to
36 months with a peak during the second year of life (Everard, 2009).
Our results indicate that prenatal exposure for phthalates can be a risk
factor for airway inflammatory response to viral infection during
infancy in offspring. However, to our knowledge no other studies have
focused on this issue and the biological mechanisms behind such a
potential association are largely unknown. Reinforcing the importance
36
of our present findings, other studies showed an association between
early life infections or inflammatory responses (including croup) and
asthma later in childhood (Nicolai et al., 1996; Van Bever et al., 1999).
Van Bever et al. (1999) investigated the cumulative incidence of croup
and recurrent croup by using ISAAC questionnaire in a group of 5,756
of 5-8-year-old children in Antwerp, Belgium. Van Bever et al. (1999)
reported croup and recurrent croup are associated with bronchial
asthma, where the association essentially based on the presence of
hyperactive airways.
Even if the picture is quite unclear for croup, more data have found an
association between prenatal exposure for BBzP and asthma and other
allergic problems in children. Compared to children of mothers with
MBzP concentrations in the first tertile, Whyatt et al. (2014) found
relative risk for a history of asthma-like symptoms among those in the
second tertile was 1.25 (95% CI: 0.94, 1.65). Just et al. (2012) reported
that MBzP was associated positively with any report of eczema by 24
months (RR = 1.52; 95% CI: 1.21, 1.91; p < 0.001, n = 113/376) after
adjusting for specific gravity, sex, and race/ethnicity. Ku et al. (2015)
identified that in boys, there was a significant association between the
prevalence of ever wheezing and a maternal MBzP concentration
greater than the 80th percentile (aOR = 4.95; 95% CI: 1.08–22.63). Hsu
et al. (2012) showed that urinary metabolite, MBzP, was found to be
higher in asthmatics compared to that of control subjects.
This thesis identified soft PVC used in flooring material as a source for
uptake of BBzP in pregnant women (Paper II), a finding supported by
several other studies. The thesis further revealed that substitution of
phthalates in soft PVC has an impact on urinary levels of such phthalate
metabolites (Paper III), also reported in other studies. Finally, this
thesis showed the use of PVC flooring in childhood to be a risk factor
37
Figure 8: Three papers of the thesis are put into the full chain model following
phthalates (mainly BBzP) from sources over environmental exposures to
human levels and finally to airway problems in children.
for the development of asthma during the following 10 years (Paper I),
and that prenatal exposure for BBzP and DEHP was related to croup in
infants (Paper IV). The finding that the use of PVC can be related to
airway problems in children has been reported by others, and some
studies have also reported prenatal BBzP exposure to be associated to
airway problems in children.
Using the earlier introduced full chain model, we will hereby put the
thesis results into a larger context to discuss how chemicals in a
building material – exemplified here by PVC flooring – can be related
to health outcomes in children (Figure 8). We will focus on BBzP since
this compound has been identified as a critical phthalate in several
aspects in the thesis. The scientific knowledge is consistent with the
basic structure of the full chain model:
38
Sources: By far, evidence has shown that BBzP is extensively
used as plasticizers in soft PVC such as flooring materials, toys,
etc., to improve the flexibility and workability of the material
(Akovali, 2007; Koch et al., 2005; National Toxicology, 2003;
Wittcoff et al., 2013; Yeang et al., 2010).
Environmental exposures: Consistent global data have
shown that independent of where a dust sample is collected
indoors, BBzP and other phthalates will be present. Numerous
studies have shown that BBzP and other phthalates can be
identified in both dust and air in homes and other environments
such as day care centers and schools. Sarka Langer et al. (2010)
analyzed dust samples collected from 500 bedrooms and 151
daycare centers of children (ages 3 to 5 years) in Denmark, and
found that BBzP was detected in 82% of the bedrooms and in
96% of the daycare centers. Furthermore, Adibi et al. (2003)
indicated BBzP was 100% detectable in personal air samples of
two populations of pregnant women in New York (N=30) and
Krakow (N=30). Just et al. (2015)found that BBzP was found in
100% of the dust samples from 239 children in New York City.
In the Swedish DBH study, it was found detectable levels of BBzP
in 79% of 346 dust samples (Bornehag et al., 2005).
Human uptakes (biomarkers): Consistent global data is
showing that metabolites from BBzP and other phthalates can be
identified in the urine of the general population, including
pregnant women, infants, children, and adults. Data from 2,540
NHANES subjects, which focused on the U.S. general population
greater than 6 years of age, found that phthalate metabolites
were 97% detectable (Silva et al., 2004). In Australia, Gomez
Ramos et al. (2016) reported that phthalate metabolites MBzP
were 100% detected in their pooled urine samples where
subjects’ age ranged from 0 to >60. Shu et al. (In Manuscript)
reported that MBzP was detected 70% in urine samples from 3
months old infants in Canada. In Sweden, MBzP was detected in
100% of the urine samples from 83 children age groups of 2 and
6 months (Carlstedt et al., 2013). Despite this, the most common
method of identifying recent exposures to phthalates was using
urine samples (studies have also measured phthalate
metabolites in breast milk). Main et al. (2006) examined 130
39
breast milk samples, which were collected from a prospective
Danish–Finnish cohort study (1997 – 2001) and found that
MBzP metabolites were detected in 100% of the samples. In a
Swedish study of 42 mothers who delivered their first child at the
University Hospital in Lund, Sweden, it was found that MBzP
metabolite were detected in 100% of the samples (Hogberg et al.,
2008). Phthalates have also been found in cord blood, amniotic
fluid and saliva (Silva et al., 2005; Tranfo et al., 2014). Silva et
al. (2005) showed that saliva contains enzymes capable of
hydrolyzing phthalate di-esters into their respective monoesters,
and that MBzP was 44% detectable in 39 saliva samples and 30%
of 155 serum samples from adults in U.S. Analyses of amniotic
fluid samples (N=70) that were donated by pregnant women
undergoing routine amniocentesis in Italy, showed that MBzP
metabolites were detected in 79% of the samples (Tranfo et al.,
2014).
Our finding in paper II that the use of PVC flooring relates to urinary
levels of BBzP metabolites in the pregnant women (Figure 8) can most
likely be explained by leakage of the compound from PVC materials to
the surrounding environment (and therefore found in indoor air and
dust), and then taken up by humans (Bi et al., 2015). The Swedish
DBH-study showed that PVC flooring in the home was significantly
related to levels of BBzP in indoor dust, with the more rooms with PVC
materials on the floors in the home, the higher levels of BBzP in the
indoor dust (Bornehag et al., 2005). Another study from Bulgaria
showed that the use of polishing products was also significantly
associated with the concentration of BBzP in the indoor dust (Kolarik
et al., 2008).
40
Phthalates in indoor air and dust and the relation to human levels
When the data in the current thesis is put into greater perspective by
using the full chain model in described in Figure 8, and in the context
of other available evidence, the following is suggested;
If early life exposure for phthalates and especially BBzP and DEHP are
risk factors for development of airway diseases in children, it is of
course of the greatest importance to understand which biological
mechanism that can explain such associations. Several phthalates, and
especially BBzP and DEHP have been found to have anti-androgenic
properties, meaning that they may interact with the natural hormone
system in humans and animals with adverse health effects as a possible
result; however, it is not clear if that is a mechanism of relevance for
airway diseases in children. With the current thesis as a ground, we
have no possibility to examine this issue. The result presented in this
thesis, calls for further research into possible biological mechanisms.
The thesis have shown that we can follow at least one phthalate, butyl
benzyl phthalate, from sources to environmental exposures in indoor
air and dust, and further to uptake in humans and measured as urinary
levels, and finally to airway problems in children by the use of a full
chain model. The thesis further reports that substitution of chemicals
in soft PVC where e.g., DEHP have been replaced by other phthalates
such as DiNP and DiNCH can be reflected as changes in urinary levels
42
in pregnant women over time. We have finally reported that exposure
for phthalates in early life may increase the risk for airway disorders in
children, and discussed that indoor air and dust may play a role for
such associations. However, the biological mechanism explaining why
such exposure should be related to airway problems in children is
unclear and was not the focus of this thesis.
Ethics consideration
Since 2012, the SELMA study research team has organized annual open
houses with the purpose to better communicate research information
to participants. Such events can bring the individual-level awareness of
environmental chemicals, allowing individuals the opportunity to
discuss and seek the answers for the questions they may have.
Our data indicates that policy can predict exposure. For many long-
term disease (e.g., asthma) that has no current cure, minimizing
exposure of EDCs such as phthalates could decrease the disease
burden.
Conclusion
44
Living in a fast-paced life, we have unknowingly exposed ourselves and
our children to chemicals that may harm human health. Our senses are
not geared toward detecting the underlying dangers, but there are
things we can do that can better protect ourselves and our next
generation:
45
ACKNOWLEDGEMENTS
46
I will forever be thankful to my former Canadian supervisor (during my
undergraduate and graduate school period), Dr. Tim K. Takaro, who
lead me here. Tim has been helpful in providing advice many times
during my graduate school career. He was and remains my best role
model for a scientist, researcher, mentor, and teacher. I still think
fondly of my time as a research assistant in his lab. His enthusiasm and
quest for knowledge is contagious. Thank you for always being there
for me. You're always there when I need a hand pushing me, helping
me.
I would also like to thank Dr. Sverre Wikström, who provided tons of
much needed medical guidance in one of the manuscripts.
Completing this work would have been all the more difficult were it not
for the support I received from physician, nurses, and emergency
attendances at Vancouver General Hospital (VGH), Vancouver, Canada
in 2014 and 2015. As well as the aftercare and support I received from
Landstinget i Värmland, Karlstad, Sweden. Thank you all for the care
and support.
I also thank the wonderful staff in the Public Health as well as in other
departments at Karlstad University for always being so helpful and
friendly. People here are genuinely nice and want to help me out and
I’m glad to have interacted with many. If I have forgotten anyone, I
apologize.
I also thank my friends (too many to list here but you know who you
are!) for providing support and friendship that I needed. I would like
to thank my dearest colleague and friend Dr. Malin Knutz (AKA:
Mother ) for being supportive throughout my time here and for
checking up on me regularly. I think of her and her family as my
“Swedish family”. I will never forget our New York, Copenhagen, and
Spain trips, I’m sure there will be more laughs to come in the future. I
would especially like to thank Pyry Hämäläinen, the “flower boy”,
workout buddy, event planning buddy…, It was such an honored for me
47
to be a part of your wedding day. Thank you for always being there for
me, during the ups and downs. I am very thankful for Dr. Daniel
Nyqvist’s quick advice and suggestions on this thesis with a short
timeline. Thank you Daniel for the memorable trip to China, where I
learned so much about fish . A special appreciation to Jason Curran.
Jason was the one who was there for me during the thesis writing hell
to help me quickly proofread and give suggestions. I truly thank Daniel
Meron, who provided me with the ability to find the “sanctuary” as an
escape from stress out of my control. Thank you for not only teaching
me to swim, but also making me a better person. I would especially like
to thank Jane and Steve. Thank you Jane for giving me those
memorable trips we had, I can’t wait to have more adventures with you
again. Thank you Steve for provide me with this great book cover with
minimum verbal information. You are very talented artist who can read
my mind.
48
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61
Human health depends on a well-functioning endocrine system to regulate hormone
release for normal bodily functions. Endocrine disrupting chemicals (EDCs) constitutes
a group of chemicals, included in many commonly used products, (e.g., PVC flooring),
with properties proven or suspected to interact with the natural hormone system in
humans and animals.
One type of widely concerning EDC is phthalates. Since phthalates create weak
chemical bonds when they are added into different products, they readily leach into the
surrounding environment. Phthalate metabolites can therefore be frequently measured in
human biological samples. Major public health concerns regarding EDCs over the past
three decades have focused on phthalates resulting in implementation of regulations.
The thesis shows that PVC flooring in the home is a source for human uptake of phthalates,
that replacement of phthalates in soft PVC products have an impact on human uptake of
these chemicals, and that exposure for phthalates in early life increase the risk for airway
disorders in children. This means that regulation and consumers’ product choices can
lead to changes in uptake of EDCs of importance for human health. Philosophically, we
all have a responsibility to protect future generations from dangerous chemicals.
ISBN 978-91-7063-806-0
ISBN 978-91-7063-902-9
ISSN 1403-8099