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Faculty of Social and Life SciencesPublic Health Sciences
DISSERTATION Karlstad University Studies
2010:32
Malin Larsson
Indoor Environmental Factors and Chronic Diseases in
Swedish Pre-School ChildrenRisk factors and methodological issues investigated
in a longitudinal study on airway diseases and autism spectrum disorders
Karlstad University Studies2010:32
Malin Larsson
Indoor Environmental Factors and Chronic Diseases in
Swedish Pre-School ChildrenRisk factors and methodological issues investigated
in a longitudinal study on airway diseases and autism spectrum disorders
Malin Larsson. Indoor Environmental Factors and Chronic Diseases in Swedish Pre-School Children - Risk factors and methodological issues investigated in a longitudinal study on airway diseases and autism spectrum disorders
DISSERTATION
Karlstad University Studies 2010:32ISSN 1403-8099 ISBN 978-91-7063-324-9
© Author
Distribution:
Karlstad University
Faculty of Social and Life SciencesPublic Health SciencesS-651 88 Karlstad+46 54 700 10 00
www.kau.se
Print: Universitetstryckeriet, Karlstad 2010
5
ABSTRACT
Research has shown a considerable increase in asthma and allergies during the past
40-50 years. Along with this increase, a heightened awareness regarding different
neurodevelopmental disorders such as autism spectrum disorders has occurred and
it has been proposed that such disorders are also on the increase. It has been
suggested that environmental factors, especially in the indoor environments, may
be associated with the increase in asthma and allergy, especially among children,
who spend more than 90% of their time indoors and environmental exposures are
on the list of potential causal factors for neurodevelopmental disorders as well.
The aim of this thesis has been to investigate certain environmental factors in
homes and their impact on asthma, rhinitis, eczema as well as autism spectrum
disorders in children, and to identify certain methodological difficulties in
epidemiological investigations.
The articles in this thesis are based on data from the Dampness in Buildings and
Health (DBH) study which started in the year 2000 in the county of Värmland,
Sweden. This thesis is based upon findings from questionnaire data from the first
phase of the DBH-study, which was a baseline questionnaire study in 2000 to the
parents of 14,077 children aged 1-5 years, and data from the third phase of the
study, which was a five year follow-up questionnaire study carried out in 2005.
Estimating the incidence of allergic symptoms and disease from questionnaire
studies can be assessed by the use of data from birth cohort studies as well as from
cohorts established later on in life. When not using birth cohort data the estimated
incidence rates are strongly dependent of how the baseline population’s health is
defined and how the studied health outcome at follow-up is defined. We found
that the mean incidence rate per year for doctor diagnosed asthma was in the range
of 0.6 to 2.4% and for doctor diagnosed rhinitis in the range of 1.1 to 3.7%
depending on different definitions at baseline and health outcome at follow-up.
The incidence rate of eczema ever was 2.7%.
Our results show that the associations between parental reported moisture
problems in the home and asthma in children, that were revealed in cross-sectional
6
analyses, decreased or disappeared when longitudinal data were used. Our results
therefore indicate that associations between parental reported moisture problems
and asthma from cross-sectional questionnaire studies should be interpreted with
caution due to the risk for reporting bias.
Finally, our results indicate that children who were living in homes with PVC-
flooring in the bedroom when they were 1-3 years of age were more likely to
develop asthma during the following 5-year period compared with children living
in homes without such flooring material. A similar association was found for
children with autism spectrum disorders, where children who were living in homes
with PVC-flooring in the bedroom when they were 1-3 years of age were more
likely to have a diagnose of autism spectrum disorders five years later when
compared with children living in homes without such flooring material. These
results indicate that building materials including suspected endocrine disrupting
chemicals e.g. phthalates might be of importance for the development of these
chronic diseases. Further studies are needed to explore the early life exposure and
the mechanisms and contribution of phthalates for the development of chronic
diseases.
7
SAMMANFATTNING
Astma och allergier har ökat under de senaste 40-50 åren. Under samma tidsperiod
har troligen olika neuropsykiatriska tillstånd också ökat, även om en del av
ökningen kan bero på mer uppmärksamhet och förbättrad diagnostik. Barn idag
tillbringar mer än 90% av tiden inomhus kan exponeringar i sådana miljöer ha
betydelse för astma och allergi men kanske även för autism och andra
autismliknande tillstånd.
Syftet med denna avhandling är att identifiera miljöfaktorer i bostaden under tidig
barndom som är associerade till utvecklandet av astma, rinit och eksem samt
autismliknande tillstånd hos barn samt att studera metodologiska svårigheter i
epidemiologiska studier som rör sjukdomsutveckling.
Avhandlingen är baserad på enkätdata från Bostad-Barn-Hälsa-studien (DBH) som
startade år 2000 i Värmland, Sverige. I den första fasen skickades en enkät ut till
alla föräldrar till 14 077 barn i åldern 1-5 år med en svarsfrekvens på 79%. Fem år
senare skickades en uppföljande enkät ut till föräldrarna till de tre yngsta
årsgrupperna där 73% svarade.
Våra resultat visade att den årliga incidensen av läkardiagnostiserad astma var
mellan 0,6 och 2,4%, incidensen av läkardiagnostiserad rinit mellan 1,1 och 3,7%
och incidensen av eksem var 2,7%, beroende på beräkningssätt. Beräknandet av
incidens, d.v.s. nyinsjuknande, påverkas av hur man definierar en frisk
baslinjepopulation samt hur man definierar sjukdom i den uppföljande studien.
De samband vi hittade mellan föräldrarapporterade fuktproblem i bostaden och
astma hos barnet i tvärsnittsdata minskade eller försvann när vi undersökte
longitudinella data från samma population. Slutsatsen är därför att samband mellan
föräldrarapporterade fuktproblem i bostaden och astma från tvärsnittsstudier ska
tolkas med försiktighet då denna typ av resultat kan vara behäftade med
systematiska rapporteringsfel.
PVC-golv i föräldrarnas eller barnens sovrum när barnen var 1-3 år ökade risken
för att barnet skulle utveckla astma under den följande femårsperioden jämfört
8
med barn som inte har PVC-golv i sovrummen. Ett liknande samband kunde ses
för barn med autismliknande tillstånd, där barn med PVC-golv i sovrummen när
barnen var 1-3 år rapporterade mer autismliknande tillstånd när barnen var fem år
äldre jämfört med barn utan dessa golvmaterial. Mjukgjord PVC är ett
byggnadsmaterial som innehåller och avger ftalater till inomhusmiljön vilka kan tas
upp av människan. Resultaten indikerar därför att misstänkt hormonstörande
kemikalier i byggnadsmaterial, t.ex. ftalater, skulle kunna vara en riskfaktor för
utveckling av astma och autism hos barn. Framtida studier bör undersöka
betydelsen av tidig exponering för ftalater under graviditet och spädbarnstid för
senare uppkomst av kroniska sjukdomar hos barnet.
9
CONTENTS
ABSTRACT.......................................................................................................5
SAMMANFATTNING......................................................................................7
LIST OF PAPERS ...........................................................................................11
ABBREVIATIONS .........................................................................................12
INTRODUCTION..........................................................................................13
Chronic disease of public health concern ............................................................................................ 14 Asthma, rhinitis and eczema ...................................................................................................................... 14 Autism spectrum disorders.......................................................................................................................... 15 Comorbidity ............................................................................................................................................ 15 Burden of disease ...................................................................................................................................... 16
World wide time trends ......................................................................................................................... 17 Increase in allergic diseases during the last decades............................................................................................ 17 Has autism spectrum disorders increased? ......................................................................................................22
Interaction between exposures and genetic predisposition................................................................ 22 Genetic predisposition ................................................................................................................................ 22 Environmental exposures ........................................................................................................................... 24 Psychological and social factors..................................................................................................................... 26
Indoor environmental risk factors ........................................................................................................ 27 Moisture related problems and asthma .......................................................................................................... 27 Chemical exposure and asthma.................................................................................................................... 29 Chemical exposure and autism spectrum disorders............................................................................................ 31
Methodological problems in epidemiology ......................................................................................... 32
AIMS AND OBJECTIVES ..............................................................................34
MATERIALS AND METHODS......................................................................35
The DBH-study ..................................................................................................................................... 35 DBH Phase I.......................................................................................................................................... 35 DBH phase II......................................................................................................................................... 36 DBH phase III ....................................................................................................................................... 36 DBH phase IV....................................................................................................................................... 36
The study population............................................................................................................................. 37
10
Descriptions of the used questionnaires .............................................................................................. 39
Estimation of incidence rates for asthma, rhinitis and eczema.......................................................... 42
Statistical methods................................................................................................................................. 43
Ethics...................................................................................................................................................... 44
RESULTS AND DISCUSSION .......................................................................45
Prevalence and incidence rates of asthma, rhinitis and eczema ........................................................ 45 Health status at baseline and follow-up and incidence rates ................................................................................ 46 Incidence of asthma ................................................................................................................................... 47 Incidence of rhinitis and eczema ................................................................................................................... 48 Factors associated with incidence of asthma, rhinitis and eczema ......................................................................... 49
Moisture related problems indoor and asthma .................................................................................... 51 Moisture related problems and incidence of asthma ........................................................................................... 53 Can cross-sectional associations be due to reporting bias? ................................................................................... 55
PVC-flooring and development of asthma ........................................................................................... 58
Autism spectrum disorders and indoor environmental factors........................................................... 61
Similarities in risk pattern for asthma and autism spectrum disorders ............................................. 64
Limitations in the current study ........................................................................................................... 65
Further studies ....................................................................................................................................... 67
MAIN CONCLUSIONS AND RECOMMENDATIONS .................................70
ACKNOWLEDGEMENTS .............................................................................72
REFERENCES...............................................................................................74
11
LIST OF PAPERS
This thesis is based on the following original publications, referred to in the text by
Roman numerals (I-IV).
I. Larsson M, Hägerhed-Engman L, Sigsgaard T, Janson S, Sundell J,
Bornehag CG. “Incidence rates of asthma, rhinitis and eczema
symptoms and influential factors in young children in Sweden”
Acta Paediatrica 2008: 97: 1210-1215
II. Larsson M, Hägerhed-Engman L, Moniruzzaman S, Janson S, Sundell J,
Bornehag CG. “Can we trust cross-sectional studies when studying the
risk of moisture related problems indoor for asthma in children?”
International Journal of Environmental Health Research 2010 (in press)
III. Larsson M, Hägerhed-Engman L, Kolarik B, James P, Lundin F,
Janson S, Sundell J, Bornehag CG. “PVC – as flooring material – and its
association with incident asthma in a Swedish child cohort study”
Indoor Air 2010 (in press)
IV. Larsson M, Weiss B, Janson S, Sundell J, Bornehag CG. “Associations
between indoor environmental factors and parental-reported autistic
spectrum disorders in children 6-8 years of age”
NeuroToxicology 2009: 30: 822-831
Reprints have been made with prior permission of the publishers.
12
ABBREVIATIONS
aOR Adjusted Odds Ratio
ASD Autism spectrum disorders
ASSQ Autism Spectrum Screening Questionnaire
CI Confidence interval
DBH The Dampness in Buildings and Health study
DSM-IV The Diagnostic and Statistical Manual of Mental Disorders, 4th
Revision
EDC Endocrine Disrupting Chemical
ETS Environmental tobacco smoke
HDM House dust mites
IAQ Indoor air quality
ICD-10 The International Statistical Classification of Diseases and Related
Health Problems, 10th Revision
IgE Immunoglobulin E
IOM The Institute of Medicine
ISAAC The International Study of Asthma and Allergies in Childhood
OR Odds Ratio
PCB Polychlorinated biphenyls
PGEs Propylene glycol and glycol ethers
P-value A measure of probability that a difference between groups during an
experiment happened by chance
PVC Poly Vinyl Chloride
SBS Sick Building Syndrome
SELMA Swedish Environmental Longitudinal, Mother and child, Asthma
and allergy study
SES Socio Economic Status
SPSS Statistical Package for the Social Sciences, a computer program for
analyzing statistics
WHO World Health Organization
13
INTRODUCTION
During the last decades there has been a remarkable increase of different chronic
diseases such as asthma, allergies, obesity, diabetes, male reproductive and
neurodevelopmental disorders (Stahlhut et al. 2007, Hertz-Picciotto et al. 2009,
Han et al. 2010, Main et al. 2010) where causes are largely unknown but
environmental factors are suspected. Part of this increase is probably an artefact
based on better diagnostic methods and more attention, but the main increase is
believed to be real.
Asthma and allergies are one of the most common chronic diseases in children - at
least in western societies - and the prevalence of such diseases has increased
considerably over the past 40-50 years (Beasley et al. 2000, Pearce et al. 2007, Lai
et al. 2009). Simultaneously, an increased awareness regarding different
neurodevelopmental disorders such as autism spectrum disorders (ASD) has
occurred (Fombonne 1999, Newschaffer et al. 2003, Rutter 2005). Recent research
has proposed that these disorders are also increasing (Hertz-Picciotto et al. 2009).
It has been suggested that indoor environmental factors may be of relevance for
the rise in asthma and allergies as well as ASD, not at least due to the fact that we
spend most of the time in the home.
During the last decades there has been an increase in exposure for certain
industrial chemicals in the general population. Several chemicals found in many
common consumer products, such as plastics, toys, cleaning products, cosmetics
and building materials, have been shown or are suspected to impact human health
(Weschler et al. 2006, Rudel et al. 2009, Bornehag et al. 2010). An interaction
between a genetic predisposition and environmental factors (exposures) is
suspected to play an important role for these diseases, but the biological
mechanisms are poorly understood.
The current thesis concerns certain environmental factors in the dwelling and their
impact on children’s health, in terms of the development of asthma, rhinitis and
eczema as well as autism spectrum disorders.
14
Chronic disease of public health concern
A chronic disease is a condition that persists over a long period, usually more than
three months (Groholt et al. 2003). Asthma, allergies and neurodevelopmental
disorders, which are in focus in this thesis, are included in such a definition
(Lindbaek et al. 2005). Asthma, rhinitis, eczema, and ASD, are conditions that may
lead to long-term health effects. Children who suffer from these conditions may
experience frequent exacerbations, leading to interrupted development, missed
education, stress and strain on family and community resources. ASD, in
particular, is considered a highly debilitating and life-long condition.
Understanding risk factors associated with these diseases can help identify
effective treatments, and prevention programmes, leading to a better quality of life
for affected children, their families, and the communities as a whole (Gillberg et al.
2006, Shaaban et al. 2008).
Asthma, rhinitis and eczema
Asthma is a chronic inflammatory disease in the airways which causes recurrent
episodes of wheezing, breathlessness, chest tightness, and coughing. Rhinitis
symptoms can be hay fever with blocked nose and/or runny eyes, sneezing and
increased mucus secretion. Such symptoms can be seasonal and due to pollen
exposure. Eczema is a local inflammation of the skin leading to recurrent itching
(Johansson et al. 2004).
Asthma, rhinitis and eczema can either be allergic or non-allergic depending on
whether specific immunologic mechanisms are initiating the reaction or not. An
immunological reaction means that a person becomes sensitized with a production
of IgE-antibodies after contact with certain allergens. The most common allergens
in Scandinavia are from cats, dogs, and pollen while allergens from house dust
mites and mold spores are quite rare. Allergic diseases can therefore be seen as a
hypersensitivity reaction initiated by specific immunologic mechanisms (Johansson
et al. 2004).
Sensitization can be influenced by adjuvant factors. An adjuvant is an agent that
may stimulate the immune system and increase the response to an allergen,
without having any specific antigenic effects in itself. Typical adjuvant agents
include certain chemicals, where several studies have investigated exposure to
15
phthalates in combination with well known allergens, with the aim to examine if
the chemical exposure increase the sensitization effect compared with exposure to
only allergens (Larsen et al. 2007).
Autism spectrum disorders
Autism spectrum disorders is a developmental disorder that commonly involves
impairments in social, communicative and behaviour development and is
accompanied by abnormalities in cognitive functioning, learning, and sensory
processing and is generally regarded as a life-long disorder. Over the past few
decades, our understanding of the genesis and character of autism has undergone a
series of transformations. It is now viewed, not as a single disorder, but as one with
multiple dimensions (hence the term ASD), with sufferers exhibiting a range of
severity. Autism spectrum disorders is sometimes a composite diagnosis including
one or more other diagnoses, including infantile autism/autistic disorder, Asperger
syndrome, disintegrative disorder, other autistic-like conditions and severe autistic
features (Gillberg et al. 2006).
The average age at diagnosis has been shown to be 2-4 years for children with
autism (Fombonne 2003, Mandell et al. 2005) while Asperger in general is
diagnosed later, often when children reach the age of 6-8 years.
Comorbidity
Comorbidity between asthma, rhinitis and eczema is frequently found. More than
half of the population in U.S. suffering from allergic rhinitis also has asthma.
Rhinitis and asthma have similar pathogenic mechanisms and similar treatments
(Spector 2001). Comorbidity of asthma with eczema was diagnosed in one third of
children in a recent study (Yuksel et al. 2008).
Children who have an allergic predisposition are frequently seen to get eczema in
early childhood. Children with eczema are frequently diagnosed with asthma
within a few years of age. Later in their childhoods, vulnerable school age children
may experience allergic problems that involve symptoms from the nose and eyes,
called rhinitis. This process is called “the atopic march” or “the allergic march”
and is described in Figure 1 (Spergel 2010).
16
Some studies have suggested that there might be a relationship between ASD and
allergic diseases, including asthma. Becker et al. (2010) found that both diseases
share particular aspects of disease etiology, including skewed sex bias towards boys,
early childhood age-of-onset, increasing prevalence in the population, and shared
molecular and genetic markers. A modest association between autism in the child
and maternal asthma and allergy diagnoses recorded during the second trimester
has been showed (Croen et al. 2005). These findings raise the question whether
gene-environment interactions may be involved in both disorders (Becker et al.
2010).
Early childhood Childhood School age
EczemaAsthma
Rhinitis
Early childhood Childhood School age
EczemaAsthma
Rhinitis
Figure 1. An overall picture of allergic disease development in children that most often starts with eczema and followed by asthma and rhinitis later on in life (Spergel 2010)
Burden of disease
In Sweden, asthma and allergies have high prevalence rates, especially among
children. In childhood, boys are consistently reported to have more asthma and
rhinitis than girls (Anderson et al. 1992, Peroni et al. 2003). However, in the
teenage there is a shift towards more asthma diagnosed in girls (Larsson 1995).
Almost one third of all children between the ages of 4 to 12 years suffer from
asthma or allergies which make this an essential public health problem (Wickman
2009). In Sweden, prevalence rates of 8% of ever having asthma and 6.9% of
current rhinoconjunctivitis have been found (Asher et al. 2006). Furthermore, in
2009, 22.3% children were reported to have current eczema and 38.6% were
reported to have ever been diagnosed with eczema, which is one of the highest
rates in the world (Odhiambo et al. 2009).
17
ASD is not as commonly diagnosed as allergic diseases, with about 1% of the
children in Sweden having this diagnosis (Gillberg et al. 2006), compared with a
Norwegian study found 1.8% (Posserud et al. 2006).
There are heavy economic burdens associated with asthma, allergy and ASD. For
asthma and allergies the most obvious cost is medication and hospitalization, but
these conditions also lead to costs related to work and school losses (Bahadori et
al. 2009). The costs are greater than supposed, due to comorbidity of asthma,
rhinitis and eczema. These diseases may also contribute to decreased physical and
social functioning, such as disrupts in sleep, leading to fatigue, irritability, memory
deficits and depression (Shaaban et al. 2008). For a child with ASD, the health and
medical costs are only a small part of the total economic burden, which include
costs for community support and schooling (Jarbrink 2007). ASD also affects the
family because it is a lifelong and complex disorder which involves difficulties in
social, behavioural and sometimes physical development (Levy et al. 2009).
It is essential to develop both primary and secondary prevention strategies for
asthma, allergy and ASD. The primary prevention targets the incidence of these
diseases and would optimally occur at the prenatal, perinatal and postnatal stages,
where avoidance or limited exposure of different risk factors decreases the risk of
affecting the developing immune system of the fetus, and decreases the likelihood
of symptoms to arise after infants are born. The secondary prevention is aimed to
reduce the risk for children who are already sensitized to develop symptoms. The
tertiary prevention is focused on reducing complications caused by severe disease
and also to minimize the need of medication (Lorente et al. 2007, StoLoff 2008).
When greater understanding about risk factors at each level of disease prevention
are understood, this knowledge can be translated into public health policy and
clinical practice (Milgrom 2006).
World wide time trends
Increase in allergic diseases during the last decades
Although asthma patterns are varying around the world, there is considerable
evidence that there has been an increase globally in both the prevalence and
severity of asthma over the recent decades (Pearce et al. 2000, Bach 2002).
18
Figure 2 shows the increasing prevalence of asthma from 1956 to 2000. While the
studies referenced to in this figure use disparate methodology, the combined
evidence shows that increasing trends over time amongst populations in countries
of widely differing lifestyles and ethnic groups is generally consistent (Beggs et al.
2005). Studies have also shown that there has been an increase in the prevalence of
both rhinitis and eczema (Bach 2002, Beasley 2002). Industrialised countries have
mainly been the settings for research on asthma and allergies in children, but
during the last decade studies have shown an increase in developing countries as
well (Lai et al. 2009).
Figure 2. Changes in asthma point prevalence observed since 1956. Different studies for the same nation are distinguished by a, b, c and d. Data from Pearce et al. (2000), figure from Beggs et al. (2005)
19
One of the most comprehensive estimates of world wide asthma and allergies is
the International Study of Asthma and Allergies in Childhood (ISAAC), which is
mainly based on parental reports. With high response and participation rates,
ISAAC studies have provided valuable data on the prevalence of asthma and
allergies for international comparisons from countries all over the world,
incorporating responses from populations with different socioeconomic
backgrounds and over different points of time (Asher et al. 1995).
The first phase of the ISAAC study was conducted during the early to mid 1990s
using a questionnaire measuring the prevalence of asthma and allergies in more
than 700 000 school-children aged 6-7 and 13-14 years in more than 50
international settings (Asher et al. 1995). In a second phase, a more extensive
medical and technical investigation was conducted including 30 000 children, with
more detailed questionnaires, blood sampling, skin-prick testing of sensitization
and indoor environmental sampling (Weiland et al. 2004). The third phase was
conducted 5-10 years after the first questionnaire. The aim of this last study was to
investigate time trends in the prevalence of the three conditions in a population of
1.2 million children and to include new centers in this investigation, in order to
expand the coverage of world prevalence studies (Ellwood et al. 2005).
Broadly speaking, the results of the first ISAAC study, assessing children ages 6
and 7, found that the prevalence of asthma was highest in English speaking
countries, such as Australia, United Kingdom, New Zealand and Canada. The
study also found high prevalence in some countries in the Latin America (Costa
Rica and Panama). Among the non-English-speaking European countries, the first
ISAAC study found that asthma prevalence was higher in Western Europe
compared to populations living in Eastern and Southern Europe. Furthermore,
Africa and Asia showed generally low asthma prevalence rates (Asher et al. 1998).
The countries showing the highest prevalence rates for rhinitis were found in
different parts of the world, while the highest prevalence rates for eczema was
generally found in countries lying on high altitude, such as New-Zealand, Eastern
Europe and Scandinavia (Asher et al. 2006).
Figure 3 show a general picture of the changes of the prevalence rates for asthma,
allergic rhinoconjunctivitis, and eczema in children aged 6–7 year from phase one
to phase three in the ISAAC study with data from 64-66 centers. The figure show
20
that asthma has increased in 25 centers (mainly in East Mediterranean and Western
Europe) with a decrease seen in 14 centers (mainly in Asia Pacific) and no major
changes in 27 centers. The figure shows that over time, countries with lower mean
prevalence rates of asthma were likely to experience increases in mean change
while higher prevalence centers showed a lower mean change (Asher et al. 2006).
Prevalence rates for allergic rhinoconjunctivitis increased in 44 centers and a
decrease in nine centers. No major changes were seen in 13 centers. The same
trend was seen for eczema symptoms where an increase in prevalence was
reported in 44 centers and a decrease in eight centers and no major change in 12
centers (Asher et al. 2006).
There are speculations that the asthma prevalence has leveled out or plateaued in
the past ten years (Anderson et al. 2004, Robertson et al. 2004). If so, these results
would indicate that the saturation point for diagnoses has been reached. Regardless
of increase or not during recent years, asthma rates in particular are high in most
countries (Burr et al. 1989, Yunginger et al. 1992, Asher et al. 1995, Burr et al.
2006, Pearce et al. 2006, Lai et al. 2009) and in many cases one of the most
common health problems in children and young adults.
Incidence of allergic diseases
In contrast to the well documented prevalence of asthma, there are less data on the
incidence of asthma. The incidence of a disease is measured by how many new
persons develop the disease under a certain period of time in a specified
population (Bonita et al. 2006). International studies have shown an incidence rate
for asthma in the range of 1.3-2.6 children/100 children/year (Anderson et al.
1992, Dik et al. 2004, Jaakkola et al. 2005).
Studies in Sweden have showed a yearly incidence rate for asthma of 1.1% in
young adults aged 16-19 years (Larsson 1995), with the same rate found in another
study of children aged 7-13 years old (Smedje et al. 2001). Another Swedish study
of children aged 7-9 years, an incidence rate of 0.9% was found for doctor
diagnosed asthma. This study also estimated an incidence rate of 1.6% for a child
reporting ever asthma (Rönmark 2002). While rhinitis and eczema are known to be
co-morbid conditions, unfortunately, there is a lack of valid information on
incidence rates of these conditions in children.
21
Figure 3. Mean change in prevalence per year of symptoms of asthma, allergic rhinoconjunctivitis, and eczema for children aged 6-7 years versus mean prevalence of ISAAC phase one and phase three for each center (Asher et al. 2006)
22
Has autism spectrum disorders increased?
There are suspicions that ASD has increased during recent decades (Rutter 2005).
ASD prevalence rates from international studies published before 1990 are ranged
from 0.4-0.5% (Yeargin-Allsopp et al. 2003, Rutter 2005), while more recent
studies have shown higher prevalence estimates in the range of 0.3 to 1.2%
(Bertrand et al. 2001, Fombonne 2005, Baird et al. 2006, Gillberg et al. 2006).
Scandinavian studies have shown prevalence rates of 0.2 to 0.8% (Kadesjo et al.
2000, Kielinen et al. 2000, Gillberg et al. 2006, Atladottir et al. 2007).
It is highly controversial if ASD has actually increased or not. Increased awareness
of the disorder, changes in definitions, more complete diagnostic criteria, younger
age at diagnosis, greater funding for services and an increased desire of parents to
seek services for affected children may have confounded the interpretation of
prevalence estimates in studies of ASD. However, recent publications argue that
the huge increase in the number of children born with ASD can not be attributed
simply to changes in diagnostic criteria or record-keeping. Such a large increase
could only possibly account for a quarter of the published increase in ASD with
the remaining increase based on real growth in this diagnosis category (Rutter
2005, Hertz-Picciotto et al. 2009).
Interaction between exposures and genetic predisposition
Human health is affected by different types of exposures from the environment
and from psychological and social factors (Figure 4). There is a general
understanding that such factors interact with our genetic disposition influencing
human health (Martinez 2008).
Genetic predisposition
The risk with different kinds of environmental exposures to lead to adverse health
effects, such as asthma, allergy and ASD, is most probably influenced by genetic
predisposition. Multiple studies have found that genetic factors (often expressed as
asthma and allergic problems in the family) is the strongest individual risk factor
for the development of asthma and allergies in children (Åberg 1993, Norrman et
al. 1998, Rönmark 2002, Peroni et al. 2003, Jaakkola et al. 2005). It has been
estimated that the odds of having a child with asthma were three times higher in
23
families with one asthmatic parent, and six times higher in families with two
parents with allergic symptoms, compared to those families without allergic
symptoms (Litonjua et al. 1998). Although a family history of asthma is a strong
risk factor, it is neither sufficient nor necessary cause for the development of
asthma (Burke et al. 2003).
Health effectsAsthmaRhinitisEczema
Autism spectrumdisorder
GeneticPredisposition
(Heredity)
ExposuresEnvironmental
Different environments• Outdoor• Occupational • Indoor
Specific exposures• Microbes• Chemicals• Radiation
Psychological• Stress• Depression• Psychiatric illness
Social • Socio economic status
Health effectsAsthmaRhinitisEczema
Autism spectrumdisorder
GeneticPredisposition
(Heredity)
ExposuresEnvironmental
Different environments• Outdoor• Occupational • Indoor
Specific exposures• Microbes• Chemicals• Radiation
Psychological• Stress• Depression• Psychiatric illness
Social • Socio economic status
Figure 4. Interaction between different kind of exposures and genetic predisposition and the relation to different health effects focused on in the thesis (bold)
There is also accumulating evidence showing that ASD is related to genetic factors
with complex inheritance factors coming into play (Monaco et al. 2001, Levy et al.
2009). It has been suggested that a family with a child with ASD have 20-50%
higher risk of having a second child with ASD is 20-50% compared with the
population base rate (O'Roak et al. 2008). However, there is still little known about
the biological basis of the disorder and the specific genes that are associated with
ASD (Monaco et al. 2001, Daniels 2006).
During this short time period which the prevalence of asthma has increased, as
well as the pronounced disparities of asthma prevalence in populations with the
same ethnic background but diverging environmental exposures, indicate that
24
genetic factors alone can not explain such an increase (Pearce et al. 2006, Wong et
al. 2008). This is probably true for ASD, as well. As recent research has not
identified a specific set of genes for autism and as rates for ASD seem to have
increased, the increases in this diagnosis might be associated with changes in the
environment (Daniels 2006), with genes interacting with environmental exposure
(Daniels 2006, Kinney et al. 2008, Martinez 2008).
Environmental exposures
There has been a concern about outdoor pollutants and this field has been
extensively studied and debated. Outdoor air is a main source of exposure to
airborne allergens such as pollen from plants and molds. It has also been suggested
that different types of compounds, such as particulate matter, vehicle pollutants
and ozone, increases the risk of asthma and allergies or act as triggers in already
asthmatic persons (Asher et al. 1998, Brauer et al. 2007).
Another environment of importance for asthma in the population is occupational
settings, both industries and non-industrial workplaces such as offices, hospitals,
school, day care centers etc. Studies have shown that industrial workplace
exposures are important causes of both new-onset asthma and exacerbations of
pre-existing disease. Occupational exposures from industrial environments have
been proposed to cause 10-15% of new-onset asthma in adults (Stenton 2010). In
occupational environments different allergens such as flour and grain dusts, wood
dusts and latex allergens are present, along with chemical agents (Lombardo et al.
2000).
Even though the occupational environment is an important setting in terms of risk
factors associated with adult-onset asthma, the environment in which most people
spend 90% of their time are non-industrial indoor environments (Figure 5). Such
environments include the home environment besides offices, hospitals etc.
Children spend even more time indoors, especially in the home, but also in indoor
settings at schools and in day care centers (Leech et al. 2002, Brasche et al. 2005).
Children are suspected to be more vulnerable to environmental exposures than
adults (Landrigan et al. 2003, Grandjean et al. 2006).
25
All age groups
Indoor, at home
Outdoors
Schools, public buildings
Indoors, other
Off ices, factories
In vehicles
Children < 11 y
Figure 5. Time spent in different locations (%) for 9,386 persons in U.S. for all age groups and for a subgroup of 1,126 children < 11 years of age, data from Leech et al. (2002)
Over the past decades the indoor environment has changed for most children
living in affluent countries. Before 1950 most houses were built with natural
materials such as wood and bricks; and the technical installations for heating and
ventilation were relatively uncomplicated. During the 1960’s building technology
changed to emphasize the use of new composite building materials and new
construction designs. A decade later the energy crises appeared and energy saving
became a priority. Energy savings in buildings called for more insulation and
reduced ventilation rate which in turn impacted indoor air quality. These standards
also resulted in higher relative indoor humidity which increased the risk for
moisture related problems. Along with the trend toward such constructions, a
tremendous number of consumer products and articles made from synthetic
materials and/or chemical compounds have been introduced to our daily life.
Many products such as plastics, toys, cleaning products, cosmetics, packages,
textiles, electronic equipments etc. includes chemicals of health concern that may
leak into the surrounding environment. Since many of these products are used
indoors such environments are important when assessing exposure and subsequent
disease (Hwang et al. 2008, Weschler et al. 2008).
Humans are in general constantly exposed to microbiological organisms and
chemical components and sometimes to radiation. Microbiological exposures
consist of e.g. allergens, bacteria, mold, virus, dust mites etc. Exposure to indoor
allergens has been found to cause asthma symptoms (Gina 2006). However, the
26
importance of allergen exposure for sensitization and the risk with such exposure
for development of allergy-related diseases is complex in the sense that not all
exposures result in sensitization (Johansson et al. 2004, Henderson 2008). It has
also been proposed that certain exposures early in life may protect from
developing asthma and allergy, the so-called the hygiene hypothesis (Strachan
1989). This hypothesis has been driven by the results of several epidemiological
studies showing that unhygienic conditions including pet exposure, farming life,
overcrowding, more siblings, and day care attendance among other factors are
associated with a lower prevalence of rhinitis and eczema in children, although the
evidence for such factors resulting in lower prevalence rates for asthma is less
consistent (Strachan 1989, Strachan 2000, von Mutius 2007).
Different chemical exposures may affect asthma and ASD. Studies show that
asthma, wheezing and ASD in the child are strongly associated with pre- and
postnatal parental smoking (Henderson et al. 2001, Hultman et al. 2002, Linnet et
al. 2003, Lannero et al. 2006, Pattenden et al. 2006). Exposure to environmental
tobacco smoking consistently exacerbates asthma symptoms and is a risk for severe
asthma (James et al. 2005). Other factors that are associated with asthma or allergy
include various building materials, pesticides, cleaning agents, and personal care
products. Industrial chemicals that serve as additives in flooring materials (e.g.
phthalates) and formaldehyde have been suggested to increase the risk for asthma
(Mendell 2007, Wang et al. 2007). Different chemical exposures to pesticides, have
been associated with ASD, along with prenatal exposure to maternal use of alcohol
and thalidomide (Mendola et al. 2002, Rodier 2004).
Psychological and social factors
To this date, relatively little has been done to identify the psychological and social
factors related to asthma, allergy and ASD. A Swedish study found that
psychological and social factors such as occupation as a manual worker (which was
used as a proxy for low socioeconomic status) increased the risk for asthma and
respiratory symptoms in adults and their children (Almqvist et al. 2005, Ekerljung
et al. 2010). Other studies have demonstrated that stress symptoms and depression
during pregnancy and the presence of psychiatric illness in the mother were
associated with increased rates of asthma diagnoses in children (Kozyrskyj et al.
2008, Barreto do Carmo et al. 2009, Cookson et al. 2009). Stress during pregnancy
27
has also been associated with increased risk for the development of cognitive and
emotional disorders, including autism, in offspring (Wadhwa 2005, Previc 2007).
Indoor environmental risk factors
The causes behind the increase in asthma and allergies are largely unknown. The
reasons for growth in rates for ASD are still unclear as well and very little is known
regarding indoor environmental risk factors for these diseases. The following
section of this document will discuss the knowledge regarding the relationship
between indoor moisture problems and respiratory diseases. The section will also
discuss indoor exposure for certain chemicals and resultant diagnoses for both
asthma and autism spectrum disorders.
Moisture related problems and asthma
Moisture related problems in buildings - also called dampness - have been
associated with respiratory problems in a large number of epidemiological studies.
The Nordic interdisciplinary review, NORDDAMP, conducted a multidisciplinary
meta-analysis of 61 studies and found that living or working in buildings with
dampness problems increased the risk for respiratory symptoms for people
(Bornehag et al. 2001). This result was further confirmed in the EUROEXPO
review (Bornehag et al. 2004a). Furthermore, in 2004 the Institute of Medicine
(IOM) concluded in their review that “excessive indoor dampness is a public
health problem” and that dampness problems in buildings are common (IOM
2004). Recently, the World Health Organization (WHO) published a report
showing that dampness and moisture related problems in buildings are associated
with respiratory symptoms such as cough, wheeze and asthma (WHO 2009).
These reviews, involving large numbers of participants, show that dampness in
buildings appears to increase the risk of respiratory problems with odds ratios in
the range from 1.4 to 2.2. These adverse effects are similar for infants, children and
adults and are similar in different types of buildings and in different parts of the
world. However, there is a lack of studies explaining the biological mechanisms for
such a relationship and there is no consistent scientific evidence that exposure to
mold is the causal factor. Both microbiological and chemicals exposures are
suggested as possible causal factors for respiratory diseases (Bornehag et al. 2001,
Bornehag et al. 2004a, IOM 2004, WHO 2009).
28
Bacteria, fungi, and mycotoxins all flourish in indoor environments. The main
sources of bacteria in indoor environments are people, outdoor air and indoor
bacterial growth. To this date, little is known about how specific bacteria indoor
affect health (WHO 2009). Fungi producing allergens such as Cladosporium,
Alternaria, Penicillium and Aspergillus are known to develop in the presence of
moisture (Bloom et al. 2009). Mycotoxins, which are toxic fungi, have been
hypothesized to cause adverse health effects, but evidence showing such
relationship is weak (WHO 2009). Mold appears to have limited predictive value
for the development of allergic symptoms, and studies have failed to show
associations between mold or fungi and asthma and allergy in children at least in
Scandinavia and regions with about the same climate (Bornehag et al. 2001,
Bornehag et al. 2004a, IOM 2004, WHO 2009). Due to variations in study design,
methodology, the lack of standardized procedures for environmental assessments
of mold and the sheer number of mold found in indoor environment, health
problems are complicated to evaluate (WHO 2009). Furthermore, the specific
mechanisms by which these health outcomes are created (microbiological or
chemical exposure or both), is still not known.
However, there is a general problem to make risk assessment of mold exposure on
a global basis. In general, the exposure indoor is low in e.g. Scandinavian countries
when compared with regions with a more hot and humid climate. This implies that
mold exposure differ in risk between different regions globally.
Recent reviews conclude that moisture related problems in buildings are associated
with respiratory problems in children. However, such studies are often designed
around questionnaires, using a cross-sectional design which limits the possibility of
establishing temporality between exposure and health outcome and increasing the
risk for reporting bias. Due to these methodological concerns, one of the questions
at issue in this thesis is to investigate the health risk with moisture related problems
indoor using a longitudinal study design where problems with reporting bias can be
reduced.
29
Chemical exposure and asthma
During the last decades in Europe more than 100 000 new chemicals have been
introduced to the entire environments (Commission of the European
Communities: White paper 2001). However, a majority of these chemicals are most
probably not harmful to humans under normal circumstances. Sources for
chemical contamination in indoor environments include building materials
(Bornehag et al. 2005a), water based paints and cleaning agents (Choi et al. 2010),
personal care products (Sathyanarayana et al. 2008) etc. Some of these chemicals
may persist from several months to years in the indoor environment (Weschler et
al. 2008).
Some chemicals have been shown to be toxic in animal studies and an increasing
body of evidence suggests that they are also impacting human health. There are
suggestions that the increase in exposure for suspected endocrine disrupting
chemicals (EDCs) might explain the increase in several chronic diseases/disorders
including asthma and allergies (Bornehag et al. 2010). EDCs have in animal tests
shown to be able to mimic or block the endocrine activity (Rudel et al. 2009).
EDCs during developing stages may affect the endocrine system with potential
impact on the immune system (Chalubinski et al. 2006).
One group of chemicals that has been suggested to have endocrine disrupting
properties are phthalates, used in soft poly vinyl chloride (PVC) material and in a
huge number of consumer products such as toys, cleaning products, cosmetics,
and hygiene products. Phthalates are not chemically bound to the polymers or the
products where they are used, which means they can migrate to the surrounding
environment (Wormuth et al. 2006). Phthalates are also routinely found in indoor
dust and air which is to be expected since very many potential sources are used
indoor (Oie et al. 1997, Becker et al. 2004, Bornehag et al. 2004c) and identified
sources are e.g. flooring materials of PVC (Bornehag et al. 2005a). Metabolites of
phthalates are furthermore routinely found in human fluids such as urine, blood,
breast milk and amniotic fluids meaning that the general population is exposed
including pregnant women, foetus and infants (Stahlhut et al. 2007). This trail of
markers means that we can follow phthalates from their sources to human uptake.
This means that studies should be possible to examine if such exposure is
associated with asthma and other conditions (diseases) in children.
30
A dose response relationship between asthma, rhinitis and eczema and different
phthalates in indoor dust have been reported (Bornehag et al. 2004c). A Bulgarian
study, using the same methodology as Bornehag’s study, found that phthalates in
indoor dust were associated with airway symptoms in children (Kolarik et al.
2008b). In the Bulgarian study, PVC was not identified as a source for phthalates in
indoor dust - rather, furniture polish was strongly associated as a source of
phthalates in indoor dust (Kolarik et al. 2008a). Other epidemiological research
indicates that phthalates and/or sources for phthalates are related to respiratory
diseases in children. A Norwegian case-control study showed that the risk of
bronchial obstruction was related to the presence of PVC-flooring (Jaakkola et al.
1999, Oie et al. 1999). Furthermore, three cross-sectional studies from Finland,
Russia and Sweden showed associations between plastic wall materials and/or
PVC-flooring and airway symptoms in children (Jaakkola et al. 2000, Jaakkola et al.
2004, Bornehag et al. 2005c).
There are suggestions that phthalates may act as potential modulators of the
immune system in humans, with allergic responses as a possible result.
Experimental studies present support for an adjuvant effect on basic mechanisms
in allergic sensitization by high doses of phthalates. Thus, phthalate exposure
could possibly affect fundamental mechanisms in the pathophysiology, responsible
for asthma and allergy. However, there is still limited knowledge about this
relationship and there is a need to look at real life exposure of phthalates and to
identify molecular targets that can explain this interaction (Bornehag et al. 2010).
Another recent study show that bedroom air concentrations of propylene glycol
and glycol ethers (PGEs) was significantly associated with multiple allergic
symptoms as well as sensitization (IgE) in pre-school children (Choi et al. 2010).
PGEs are volatile organic compounds that can be found in e.g. water based paint
and water based cleaning products. This finding indicates again that common
household products may be of health relevance.
In conclusion, while the relationship between PVC or phthalate exposure and
airway diseases is becoming better known, there are still methodological
shortcomings that limit our knowledge on this subject. The available data is
primarily from cross-sectional studies, which means that we can not determine the
31
exposure involved in the development of these diseases. Longitudinal studies are
needed in order to investigate the relationship between exposure and development
of disease. This is one of the questions at issue in the current thesis; to investigate
if PVC-flooring is related to the incidence of asthma.
Chemical exposure and autism spectrum disorders
Theories regarding the vulnerability of the human central nervous system to
environmental chemicals have been developed. There is clear evidence that the
developing nervous systems in foetuses and children are more vulnerable to many
chemical agents than adult nervous systems (Tilson 1998). Exposure to chemicals
such as pesticides, PCBs, along with exposure to alcohol during gestation, have
been associated with adverse neurodevelopmental outcomes in children
(Grandjean et al. 2006). Some of these chemicals are also considered to be
potential endocrine disruptors and such exposure can result in a spectrum of
adverse health outcomes depending on the timing and doses of these chemical
agents (Mendola et al. 2002). Other environmental factors that are associated with
autistic behaviours are prenatal exposures to thalidomide (Stromland et al. 1993,
Rodier 2004) or valproic acid (Christianson et al. 1994). Although lead is a known
neurotoxin and studies have found adverse effects of prenatal exposure on growth
and development, surprisingly little research regarding chemical exposure has been
done with respect to autism (Banks et al. 1997, Mendola et al. 2002).
Exposure to modern chemicals, commonly occurring in indoor environments has
been suggested as a possible causal factor for neurodevelopmental disorders
including ASD (Grandjean et al. 2006). There are suspicions that EDCs can
interfere with brain development and might cause a wide range of developmental
disabilities in children (Weiss et al. 2000). However, the contribution of such
exposures to ASD remains uncertain and scientific evidence to support this theory
is lacking (Grandjean et al. 2006). Due to this uncertainty, one of the questions at
issue in the current thesis is to investigate if ASD is related to certain indoor
environmental factors, such as PVC-flooring, a known source for indoor phthalate
exposure.
32
Methodological problems in epidemiology
The incidence of asthma in Swedish children estimated with questionnaire studies
varies widely, from 0.9 to 1.6%. This variation may be due to true differences in
incidence rates; but might also be due to methodological problems. Estimating the
incidence of allergic diseases from questionnaire studies can be done by the use of
data from birth cohort studies as well as from cohorts established later on in life
(Figure 6).
Baseline Follow up
”healthy”
”Asthma”excluded
Incidenceasthma
Birth
”healthy”
Incidenceasthma
Birth cohort study
Established cohort study
Baseline Follow up
”healthy”
”Asthma”excluded
Incidenceasthma
Birth
”healthy”
Incidenceasthma
Birth cohort study
Established cohort study
Figure 6. Different principles for estimating the incidence rate of asthma in a cohort study
When not using birth cohort data, as in the current study, the estimated incidence
rates depends on how the baseline population is defined from a health point of
view and how the studied health outcome is defined in the follow-up. For example,
should subjects reporting wheezing or other airway symptoms (but not asthma) at
baseline be excluded? Some studies using established cohort designs excluded both
doctor diagnosed asthma and asthma ever from the baseline population (Larsson
1995, Smedje et al. 2001, Rönmark 2002) while other only excluded doctor
diagnosed asthma (Dik et al. 2004, Jaakkola et al. 2005). It is also important to
consider that studies have investigated different health outcomes at follow-up, e.g.
doctor diagnosed asthma (Larsson 1995, Rönmark 2002, Dik et al. 2004), parental
reported asthma or wheezing ever (Anderson et al. 1992), or parental reported
asthma ever (Larsson 1995, Rönmark 2002, Jaakkola et al. 2005). As a result it is
difficult to compare results between investigations.
33
Studies that employ a cross-sectional design may also limit the possibility for
establishing temporality between exposure and health outcome due to the risk for
reporting bias. Reporting bias occurs when those affected by the outcome are
more likely to report the exposure than the unaffected. This makes it difficult to
interpret associations between exposure and outcome in cross-sectional studies.
This particular source of reporting bias occur to a lesser degree in longitudinal
studies where exposure is reported separately from the disease that is studied
(Bonita et al. 2006).
These two issues, one regarding how to estimate the incidence rate of asthma,
rhinitis and eczema and one regarding reporting bias, are elaborated in the current
thesis.
34
AIMS AND OBJECTIVES
The aim of this work has been to investigate certain environmental factors in the
dwelling and their impact on children’s health, in terms of asthma, rhinitis, eczema
as well as autism spectrum disorders and to identify certain methodological
difficulties in epidemiological studies.
The thesis includes four major objectives:
I To estimate the incidence rates for asthma, rhinitis and eczema symptoms during a
5-year period among Swedish pre-school children. A further objective was to
investigate the importance of the baseline health status and the definition of the
health outcome for the incidence rates and identification of different influential
factors for the incidence of asthma, rhinitis and eczema
II To investigate if the association between reported moisture related problems
indoor and asthma in children found in cross-sectional data can be confirmed in
longitudinal analyses
III To examine the association between exposure to PVC-flooring in the home during
early childhood and the incidence of asthma, rhinitis and eczema in children
IV To investigate associations between certain indoor environmental factors and
autism spectrum disorders in children
35
MATERIALS AND METHODS
The DBH-study
The Dampness in Buildings and Health (DBH) study started in the year 2000 in
the county of Värmland, Sweden with an overall aim to investigate the importance
of indoor exposures for asthma and allergy in children. The study was divided into
four phases (Figure 7). The first phase was a questionnaire study in 2000 to the
parents of 14,077 children aged 1-5 years (Bornehag et al. 2004b). One and a half
years later, the second phase of the study was conducted including an analysis of
subpopulation, using a nested case-control design (Bornehag et al. 2004c). In the
third phase, a five year follow-up questionnaire study was carried out in 2005 and a
ten year follow-up questionnaire was conducted during spring 2010 in the fourth
phase. This thesis is based upon questionnaire data from the first and the third
phase of the DBH-study.
DBH phase ICross-Sectional study
BaselineMarch 2000
Questionnaire
n=14 077 children, 1-5y (rr=79%)
DBH phase IICase-Control Study
October 2001-April 2002
Professional inspectionsExposure measurements
Clinical examinationsN=200+200 children/dwellings
DBH phase III1st Follow-up Study
March 2005
Questionnaire
n=7 509 children, 6-8y (rr=73%)(incidence of chronic diseases)
DBH-phase IV2nd Follow-up Study
March 2010
Questionnaire
n=15 043 children, 11-15y (rr=53%)(incidence of chronic diseases)
DBH phase ICross-Sectional study
BaselineMarch 2000
Questionnaire
n=14 077 children, 1-5y (rr=79%)
DBH phase IICase-Control Study
October 2001-April 2002
Professional inspectionsExposure measurements
Clinical examinationsN=200+200 children/dwellings
DBH phase III1st Follow-up Study
March 2005
Questionnaire
n=7 509 children, 6-8y (rr=73%)(incidence of chronic diseases)
DBH-phase IV2nd Follow-up Study
March 2010
Questionnaire
n=15 043 children, 11-15y (rr=53%)(incidence of chronic diseases)
Figure 7. Overview of the four conducted phases of the Dampness in Building and Health study
DBH Phase I
The first step was carried out in March 2000 as a cross-sectional questionnaire
study. This baseline questionnaire was distributed to the parents of all children
aged 1–5 years (n=14,077) in the Swedish county of Värmland, with about 273,000
inhabitants. The county is divided into 16 municipalities where the county capital is
Karlstad with almost 84,000 inhabitants.
The questionnaire was distributed by post, with three postal reminders sent to
potential participants. Of the study population, parents of 100 randomly selected
children participated in a pilot study for development of the questionnaire. Of the
potential respondents, 200 children could not be found by post. In total, the
36
parents of 10,851 children responded to the questionnaire, corresponding to a
response rate of 79 % (Figure 9). These children lived in 8,918 homes as siblings
were included in the study.
DBH phase II
The second phase of the study was based on 400 children (198 cases and 202
healthy controls) living in 390 homes, since there were ten pairs of siblings. The
cases and the healthy controls were selected from the baseline questionnaire,
described further elsewhere (Bornehag et al. 2004c). From October 2001 to April
2002 medical examinations of the 400 children and technical investigations of the
homes were performed. The medical examinations were focused on asthma,
rhinitis and eczema and included collection of biological samples (blood, nasal
secretions, condensed breath). The aim of the technical inspection and
measurements in the dwellings was to perform visual inspections (by professional
inspectors) and indoor air quality (IAQ) assessments, including collection of dust
and air, and measurements of ventilation rate, temperature and relative humidity.
These samples were further analyzed for the content of microbiological and
chemical agents. Data from this phase in not included in this thesis, but discussed
in some sections.
DBH phase III
In the third phase of the study, a follow-up questionnaire was conducted five years
after the baseline questionnaire. This phase included the children of the first three
year cohorts, who were 1-3 years at baseline and consequently 6-8 years in 2005
(n=7,509). The parents of 5,483 children responded, corresponding to a response
rate of 73%.
DBH phase IV
During spring 2010, a ten year follow-up investigation with focus on chronical
diseases was conducted including all children in Värmland, who were part of the
original study population, or also those who had moved to Värmland during the
period, now between the ages of 11-15 years (n=15,043). The response rate was
53%.
37
In order to examine selection problems in the baseline material (DBH-phase I),
200 families were randomly selected from those who did not answer the
questionnaire. Of these, 116 were reached by telephone and asked to respond to
five questions related to their children’s health (Figure 8). There were no
significant differences in prevalence of symptoms in the child between responding
and non-responding families, i.e. “wheezing ever” (24.3 vs. 23.1 for responders
and non-responders, respectively) and “doctor diagnosed asthma” (5.4 vs. 4.3%).
Participating families reported 23.5% “eczema ever” while non-responding
families reported 12.1%. However, the difference was not significant. Neither was
there any significant difference between responders and non-responders regarding
type of building “single family house vs. multifamily house” (82.0 vs. 81.0%), and
“suspected mold problem in the dwelling” (7.8 vs. 9.5%). A relatively high
response rate (79%) in combination with minor differences between participating
and non-participating families means that the risk for selection bias in this the first
phase investigation is limited.
It was not possible to do an analysis of the 2,026 families that did not respond to
the follow-up questionnaire (Figure 8). However, we can compare the health status
of the children who were participants on both questionnaires (n=4,779) with the
children who did not respond to the DBH-I questionnaire (n=704). Analyses
showed that there were no significant differences in prevalence of symptoms
between these two groups (4,779 vs. 704), i.e. “wheezing ever” (24.1 vs. 22.0%),
“doctor diagnosed asthma” (8.7 vs. 8.3%), “doctor diagnosed rhinitis” (6.3 vs.
7.5%) and “eczema ever” (23.2 vs. 23.3%). Reports of “visible dampness” were
almost the same in the two groups (1.0 vs. 1.1%) as was housing status, living in a
single family house (88.2 vs. 83.4%).
The study population
The population investigated in this thesis is 4,779 children who participated in both
the baseline and the follow-up questionnaire (Table 1). The children were between
1-3 years of age in the baseline study 2000 and 6-8 years in the follow-up 2005. The
population was equally distributed between boys and girls and more than half of
the children had at least one family member (mother, father, siblings) who had
asthma, rhinitis or eczema symptoms at baseline. Baseline data in 2000 showed that
most of the families lived in single family houses and almost 22% of the children
38
had at least one smoking parent at baseline, with a slight decrease during the 5 year
follow-up period. A more detailed description of the studied population is given in
the different papers included in the thesis.
No address foundn=200
Pilot study n=100
Participantsn=10,851, rr=79%
Included in non-reponders analysis
n=116, rr=58%
Did not respondn=17
Could not be reached n=67
DBH phase IBaseline study 2000
Study populationn=14,077 children (1-5y)
(subgroup 1-3 y, n=7,509)
Invitedn=13,777
Did not respondn=2,926
Invited to a non-reposnders
analysisn=200
Non-respondersAnalysis I
Participantsin DBH III
n=5,483, rr=73%
Did not respondn=2,026
DBH phase IIIFollow-up Study 2005
Invitedn=7,509 children (6-8y in 2005)
DBH I-IIILongitudinal study
2000-2005
Children participatingin both questionnaires
n=4,77964% (4,779/7,509)
Did not respond to DBH I questionnaire
n=704
Non-respondersAnalysis II
No address foundn=200
Pilot study n=100
Participantsn=10,851, rr=79%
Included in non-reponders analysis
n=116, rr=58%
Did not respondn=17
Could not be reached n=67
DBH phase IBaseline study 2000
Study populationn=14,077 children (1-5y)
(subgroup 1-3 y, n=7,509)
Invitedn=13,777
Did not respondn=2,926
Invited to a non-reposnders
analysisn=200
Non-respondersAnalysis I
Participantsin DBH III
n=5,483, rr=73%
Did not respondn=2,026
DBH phase IIIFollow-up Study 2005
Invitedn=7,509 children (6-8y in 2005)
DBH I-IIILongitudinal study
2000-2005
Children participatingin both questionnaires
n=4,77964% (4,779/7,509)
Did not respond to DBH I questionnaire
n=704
Non-respondersAnalysis II
Figure 8. Description of participating and non-participating families in the baseline (phase I) and the follow-up (phase III) of the DBH-study
39
Table 1. Description of the study population participated in the baseline and follow-up study
Factor Frequency n (%)
Year Baseline questionnaire 2000 (n=4,779)
Follow-up questionnaire 2005 (n=4,779)
Sex Girls 2388 2388 Boys 2391 2391
Age of the child (y) 6 - 1557 (32.6) 7 - 1568 (32.8) 8 - 1654 (34.6)
Type of building1) SH 3871 (81) 4090 (85.6) MH 793 (16.6) 546 (11.4)
Size of the home (m2) <75 326 (6.8) 135 (2.8) 75-150 3389 (70.9) 3240 (67.8)
>150 1013 (21.2) 1332 (27.9) Divorce Yes 324 (6.8) 960 (20.1)
Economical problems No - 4174 (87.3) Yes - 537 (11.2)
No reply - 68 (1.4) Allergy in family No 2167 (45.3) -
Yes 2563 (53.6) - Smoking in family Any smoker 1044 (21.8) 909 (19.0)
Smoking mother 673 (14.1) 605 (12.7) Smoking father 497 (10.4) 398 (8.3)
1) SH=single family house, MH=multi family house
Descriptions of the used questionnaires
The questionnaire from phase I is described in Appendix A and the phase III
questionnaire is described in Appendix B. Information on allergic symptoms
among children and their parents was collected with the same validated questions
as used in the ISAAC-studies (Table 2)(Pearce et al. 2007).
Data on background factors such as age, sex, birth weight, gestation length, and
length of breastfeeding period as well as the number of family members, and
smoking habits in the home were collected. Moreover, information regarding day
care attendance, sick building syndrome (SBS) symptoms of one parent, pet-
keeping, cleaning frequency, and food habits was collected. There were further
questions about the dwelling e.g. type of house, type of surroundings and type of
construction, surface material on walls and floors.
40
Table 2. Description of used questions in the questionnaire regarding symptoms and diseases Health definitions
Wheezing ever Yes vs. No “Has your child ever had wheezing or whistling in the chest at any time in the past?”
Wheezing during last 12 month
Yes vs. No “Has your child had wheezing or whistling in the chest in the last 12 months?”
Cough Yes vs. No “In the last 12 months, has your child had a dry cough at night for more than two weeks, apart from a cough associated with a cold or chest infection?”
Doctor diagnosed asthma
Yes vs. No “Has your child been diagnosed with asthma by a doctor?”
Rhinitis ever Yes vs. No “Has your child ever had a problem with sneezing, or a runny, or a blocked nose when he/she did not have a cold or a flu?”
Rhinitis during last 12 months
Yes vs. No “In the past 12 months, has your child had a problem with sneezing, or a runny, or a blocked nose when he/she did not have a cold or the flu?”
Rhinitis on pets Yes vs. No “In the past 12 months, has your child had a problem with sneezing, a runny or a blocked nose, or itchy-watery eyes after been in contact with furred animals?”
Rhinitis on pollen Yes vs. No “In the past 12 months, has your child had a problem with sneezing, a runny or a blocked nose, or itchy-watery eyes after been in contact with pollen?”
Doctor diagnosed rhinitis
Yes vs. No “Has your child been diagnosed with hay fever or allergic rhinitis by a doctor?”
Eczema ever Yes vs. No “Has your child ever had an itchy rash (eczema), which was coming and going for the last 6 months?”
Eczema during last 12 months
Yes vs. No “Has your child had this itchy rash at any time in the last 12 months?”
Data on moisture related problems were collected both regarding the current
dwelling as well as the home where the child was born (Table 3). In the baseline
questionnaire thirteen questions on moisture problems in different rooms in the
home were used. Answers to these single questions were “Yes”, “No” or “Don’t
know”. With the single questions as a ground, different dampness indices were
calculated where “Yes” and “No” were used and the answer “Don’t know” was
excluded. In the baseline questionnaire, there were further retrospective questions
about moisture related problems in the child’s birth residence. However, these
questions were not specified to what room the moisture problem existed and the
parents could only answer “Yes, at least one problem” or “No such problems”. In
the follow-up questionnaire (2005) only three indices were asked for.
41
Table 3. Description of different moisture related indices in the questionnaire
Moisture related indices in the home collected in the baseline questionnaire
Water leakageBL
No such indices vs. Yes at least one indices during the past 12 month, Yes at least one earlier
“Have you had flooding or other types of water damages in the child’s and/or parent’s bedroom and/or in kitchen and/or bathroom?”
Floor moistureBL
No such indices vs. Yes at least one
“Is there loosening, bubbling or discoloured flooring material in the child’s and/or parent’s bedroom and/or in the bathroom?” and/or “Is there miscoloured plastic cork or parquet in the dwelling?”
Visible dampnessBL
No such indices vs. Yes at least one
“Is there visible mold on the floor, wall or roof in the parent’s and/or child’s bedroom?” and/or “Is there visible damp stains on the floor, wall or roof in the parent’s and/or child’s bedroom?”
Condensation on windowBL
No condensation vs. Yes, less than 5 cm, Yes, more than 5 cm
“Is there condensation on the inside of the windows during winter time in the parent’s and/or child’s bedroom?”
Moldy odorBL
No odor vs. Yes, sometimes; Yes, often
“Have you perceived mold odor in your dwelling during the last three months?” and/or “Have you perceived earthy odor in your dwelling during the last three months?”
Moisture related indices in birth residence collected retrospectively in the baseline questionnaire Water leakageBR
No such problems vs. Yes, at least one problem
“Was there flooding or other types of water damages in the child’s birth residence?”
Floor moistureBR
No such problems vs. Yes, at least one problem
“Was there loosening, bubbling or miscoloured floor carpets in the child’s birth residence?” and/or “Was there miscoloured plastic cork or parquet in the child’s birth residence?”
Visible dampnessBR
No such problems vs. Yes, at least one problem
“Was there visible mold or damp stains on the floor, wall or roof in the child’s birth residence?”
Condensation on windowBR
No such problems vs. Yes, at least one problem
“Was there condensation on the inside of the window during winter time in the child’s birth residence?”
Moldy odorBR
No such problems vs. Yes, at least one problem
“Did you perceive mold odor in the dwelling in the child’s birth residence?” and/or “Did you perceive earthy odor in your dwelling in the child’s birth residence?”
Moisture related indices in the home collected in the follow-up questionnaire
Visible dampnessFU
No such problems vs. Yes at least one
“Is there visible mold on the floor, wall or roof in the parent’s and/or child’s bedroom?” and/or “Is there visible damp stains on the floor, wall or roof in the parent’s and/or child’s bedroom?”
Condensation on windowFU
No condensation; Yes, less than 5 cm vs. Yes, more than 5 cm
“Is there condensation on the inside of the windows during winter time in the parent’s and/or child’s bedroom?”
Floor moistureFU
No such problems vs. Yes, floor moisture
“Is there loosening, bubbling or discoloured flooring material in the child’s and/or parent’s bedroom and/or in the bathroom?”
42
In both the baseline and the follow-up questionnaire there were questions on
different flooring materials (PVC, plastic cork, wood, linoleum, stone, wall-to-wall
carpet). The flooring material “plastic cork” has been grouped together with PVC-
material in the analyses. The reason for this was that an earlier validation study
showed that 40 out of 55 parental reports of “plastic cork” was PVC when
evaluated by the professional inspectors (Engman et al. 2007). Furthermore,
“plastic cork” material has traditionally not been used in bedrooms.
The follow-up questionnaire also had an additional question on different chronic
disorders. The question used in this thesis was if the child had “autism, Asperger
or Tourette’s syndrome”, also described as the composite definition of ASD
(Gillberg et al. 2006).
Estimation of incidence rates for asthma, rhinitis and eczema
The impact of different health status of the baseline population as well as different
health outcomes at follow-up on the incidence of asthma, rhinitis and eczema was
investigated in paper I. The different baseline and follow-up definitions are also
described in Table 4.
Table 4. Description of different baseline and follow-up definitions to be used for estimation of incidence rates of asthma, rhinitis and eczema in children
Definition of the baseline group Follow-up
Asthma
No doctor diagnosed asthma Doctor diagnosed asthma
No doctor diagnosed asthma
and No wheezing ever Doctor diagnosed asthma
Wheezing, but No doctor
diagnosed asthma Doctor diagnosed asthma
No doctor diagnosed asthma
and No wheezing ever
Doctor diagnosed asthma
and/or wheezing ever
Rhinitis
No doctor diagnosed rhinitis Doctor diagnosed rhinitis
None of the following symptoms;
doctor diagnosed rhinitis, rhinitis
ever, rhinitis during last 12 month,
rhinitis to pollen and rhinitis to pets
Doctor diagnosed rhinitis, rhinitis
ever, rhinitis during last 12 month,
rhinitis to pollen and rhinitis to pets
Eczema
No eczema ever Eczema ever
43
The incidence of doctor diagnosed asthma was estimated for four different groups
of children. In the first baseline definition children with doctor diagnosed asthma
were excluded. In the second baseline definition also wheezing ever were excluded.
In the third group the incidence was estimated in those children that had wheezing
at baseline, but not doctor diagnosed asthma. When estimating the incident of
doctor diagnosed asthma and/or wheezing ever, such symptoms were excluded
from the baseline population.
When estimating the incidence of doctor diagnosed rhinitis, children with such
symptoms were excluded from the baseline population. The incidence of any of
the symptoms-; diagnosed rhinitis, rhinitis ever, rhinitis during last 12 month,
rhinitis to pollen and rhinitis to pets- was estimated by excluding such symptoms
from the baseline population.
Finally, the incidence of eczema ever was only calculated in one way, where
children with eczema ever were excluded from the baseline population.
Statistical methods
Since we collected questionnaire data for a 5-year period, we had no information of
the yearly incidence during the intervening years. The yearly incidence was
therefore estimated by dividing the 5-year incidence by the number of years in the
period (5), meaning a mean incidence rate per year during the period.
Differences in frequencies, prevalence and incidence have been tested with Chi-
square test (χ2) and trends in data have been tested with linear by linear
associations.
Associations between different environmental and lifestyle factors and symptoms
have been estimated by crude and adjusted odds ratios (ORs and aORs), and are
expressed as estimated odds ratios and 95% confidence intervals. Adjusted odds
ratios were computed using logistic regression models. In Paper I a stepwise
method was used (forward: conditional) where only factors remaining statistically
significant in the final model are reported. The specific adjustment variables used
in each analysis are further described in each paper, but commonly used potential
confounders were age (6, 7 or 8 years of age) and sex of the child as well as allergy
44
in family (history of symptoms of asthma, rhinitis and/or eczema in other family
members; yes vs. no). Also type of dwelling (multi family house vs. single family
house) and smoking in the family (any smoker in the dwelling vs. no smoker) was
used. In order to even further avoid confounders, stratifications where done.
The associations were considered to be statistically significant when the p-value
was below 0.05. Statistical analyses were carried out using SPSS for Windows
(version 14.0, 15.0 and 18.0).
Ethics
The DBH phase I study was approved by the regional ethical committee in
Örebro, Sweden. Phase III was approved by the regional ethical review board at
Uppsala University, Uppsala, Sweden.
45
RESULTS AND DISCUSSION
Prevalence and incidence rates of asthma, rhinitis and eczema
The cumulative prevalence of doctor diagnosed asthma increased from 5.2% for
children aged 1-3 years to 8.7% for children aged 6-8 years (Figure 9). The
cumulative prevalence of wheezing ever was surprisingly lower in the follow-up
questionnaire compared to baseline (24.9% in baseline vs. 24.1% in the follow-up),
which could be due to recall bias. Furthermore, the cumulative prevalence for
doctor diagnosed rhinitis increased from 1.4% to 6.3%. Rates for rhinitis ever
(12.0% to 20.4%) and eczema ever were found to increase from 21.9% to 23.2%.
The cumulative prevalence rates have been compared with two other Swedish
studies. Björksten et al. (1998) investigated asthma and allergies in 3,029 children
aged 6-7 years in Stockholm, and Bjerg et al. (2010) studied 2,585 children 7-8
years old in northern Sweden. Both these studies has have shown that the
cumulative prevalence of doctor diagnosed asthma, wheezing ever, and rhinitis are
in line with our results from the follow-up study, with children who were between
6 and 8 years old. The prevalence of eczema ever was higher (35.7%) in the study
in Stockholm (Björksten et al. 1998) compared with our rate (23.2%).
0
5
10
15
20
25
30
35
40
Doctor diagnosedasthma
Wheezing ever Doctor diagnosedrhinitis
Rhinitis ever Eczema ever
Pre
vale
nce
(%
)
Baseline
Follow up
Björksten et al. (1998)
Bjerg et al. (2010)
Figure 9. Cumulative prevalence of doctor diagnosed asthma, rhinitis and eczema ever at baseline (n=10,851) and at follow-up (n=5,483) in the current DBH study and data from two other Swedish studies on children in the age of 6-8 years (Björksten et al. 1998, Bjerg et al. 2010) *Prevalence’s that was not estimated in these studies
* * *
46
The prevalence of wheezing during the previous 12 months declined significantly
from 22.2% at baseline to 10.0% at follow-up in our study. Prevalence rates for
rhinitis during the previous 12 months increased slightly from 11.4% to 14.8%,
while the prevalence of eczema during the previous 12 months was about the same
at baseline and follow-up (18.7% and 18.3%) as seen in Figure 10.
Prevalence rates for wheezing during the previous 12 months and rhinitis during
the previous 12 months are similar to results from the two other Swedish studies
while the prevalence rates for eczema during the previous 12 months in our study
was lower than these other two studies.
0
5
10
15
20
25
30
Wheezing last 12 months Rhinitis last 12 months Eczema last 12 months
Pre
vale
nce
(%
)
Baseline
Follow up
Björksten et al. (1998)Bjerg et al. (2010)
Figure 10. Prevalence of wheezing, rhinitis and eczema during the last 12 months at baseline (n=10,851) and at follow-up (n=5,483) in the current DBH study as well as in two other Swedish studies on children aged 6-8 years (Björksten et al. 1998, Bjerg et al. 2010) *Prevalence that was not estimated in this study
Health status at baseline and follow-up and incidence rates
In cohort studies that are established after participants are born, children in the
baseline population may already have developed allergic symptoms and/or disease.
Therefore, when estimating the incidence of asthma, rhinitis and eczema a study
population of healthy subjects must be defined, from which incidence can be
*
47
calculated. In paper I there is a discussion how incidence rates of asthma, rhinitis
and eczema change, when calculating the incidence with different formulae.
Incidence of asthma
We found that the mean incidence rate per year for doctor diagnosed asthma
ranged between 0.6 and 2.4% depending on different definitions of the baseline
group and health outcome at follow-up (Table 5).
Table 5. The yearly incidence rate of different symptoms based on different baseline and follow-up definitions of the studied disease
Definition of the baseline group Follow-up Mean yearly
incidence
Asthma
No doctor diagnosed asthma Doctor diagnosed asthma 1.0%
No doctor diagnosed asthma
and No wheezing ever Doctor diagnosed asthma 0.6%
Wheezing, but No doctor
diagnosed asthma Doctor diagnosed asthma 2.4%
No doctor diagnosed asthma
and No wheezing ever
Doctor diagnosed asthma
and/or wheezing ever 2.4%
Rhinitis
No doctor diagnosed rhinitis Doctor diagnosed rhinitis 1.1%
None of the following symptoms;
doctor diagnosed rhinitis, rhinitis
ever, rhinitis during last 12 month,
rhinitis to pollen and rhinitis to pets
Doctor diagnosed rhinitis, rhinitis
ever, rhinitis during last 12 month,
rhinitis to pollen and rhinitis to pets
3.7%
Eczema
No eczema ever Eczema ever 2.7%
When children with doctor diagnosed asthma at baseline were excluded from
baseline, the five year incidence of doctor diagnosed asthma became 4.9%, and the
mean incidence per year was 1.0 child/100 children/year (1.0%). This incidence
rate is similar with other studies in Sweden. Larsson (1995) found an incidence of
1.1% in young adults aged 16-19 years, while Smedje et al. (2001) found similar
rates in children aged 7-13 years. However, the most comparable study, due to
study definitions and the studied age group, conducted by Rönmark et al. (2002)
who reported an incidence rate of doctor diagnosed asthma of 0.9% in children
aged 7-9 years. Our study had the same outcome definition for new cases (doctor
diagnosed asthma) as the other studies when estimating the incidence of asthma
48
but we had different baseline definitions. Our study excluded solitary doctor
diagnosed asthma from the baseline population while the other three studies
excluded both doctor diagnosed asthma and ever asthma from baseline. In our
study, we did not have a specific question on “ever asthma”, so an exact
comparison could not be done.
When excluding both doctor diagnosed asthma and wheezing ever from the
baseline population, the incidence of doctor diagnosed asthma decreased to 0.6%.
This finding indicates that children with wheezing are at risk for developing
asthma. Furthermore, children who are reported to have wheezing or other
asthma-associated symptoms (but not doctor diagnosed asthma) at baseline may
have an increased risk to develop asthma. In fact, they may already have asthma,
but have not yet been diagnosed.
The incidence rate for asthma in our study was also related to how the health
outcomes at follow-up were defined (Table 5). When we excluded children with
doctor diagnosed asthma and wheezing from the baseline population, we found a
large variation for the incidence of doctor diagnosed asthma (0.6%) or the
incidence of any of the two outcomes; doctor diagnosed asthma and/or wheezing
ever (2.4%). Our study showed that the vast majority of children having doctor
diagnosed asthma were also reported to have wheezing (95%). Yet, out of children
with wheezing only about 20-35% had doctor diagnosed asthma. A possible
explanation for this discrepancy has been proposed by Rönmark et al. (2000) who
found different incidence rates when using two different definitions of asthma.
The incidence of doctor diagnosed asthma in that study was found to be 0.9%
while the incidence of ever asthma was 1.6%. This shows that different definitions
of asthma, both at baseline and as outcome, have a considerable impact of the
reported incidence rates in different studies.
Incidence of rhinitis and eczema
In contrast to many studies on the prevalence of rhinitis and eczema in children,
only a few have investigated the incidence rates using questionnaire studies. We
found the mean annual incidence of doctor diagnosed rhinitis to be 1.1%, while
the incidence of any rhinitis symptom was 3.7% (Table 5). We found only one
other Swedish study studying the incidence of rhinoconjunctivitis in teenagers aged
49
13-16 years (Norrman et al. 1998). That study reported an incidence rate of 1.1%
which was comparable to the incidence rate of doctor diagnosed rhinitis in our
study. Even though the rates are similar, the age of the children in Norrman et al.’s
study differs from the age of children in our study and both baseline and outcome
definitions at follow-up were different from our study.
The incidence of eczema was estimated in only one way with an yearly incidence of
2.7%, which is slightly lower than another Swedish study in children aged 5.5 years
showing an incidence rate of 3.8%/year (Broberg et al. 2000).
Our study used the definitions below for the baseline group and health outcomes.
These definitions were used in paper II and III in the thesis:
• The incidence of parental reported doctor diagnosed asthma during the five
year period (2000-2005) was estimated by excluding children reported to
have “doctor diagnosed asthma” and/or “wheezing ever” at baseline and
calculating the incidence of “doctor diagnosed asthma” in the follow-up
questionnaire.
• The incidence of rhinitis was estimated by excluding “doctor diagnosed
rhinitis” at baseline and calculating the incidence based on those that were
reported to have “doctor diagnosed rhinitis” in the follow-up questionnaire.
• Finally, the incidence of eczema was calculated by excluding children with
“eczema ever” at baseline and calculating the incidence based on those that
reported “eczema ever” in the follow-up questionnaire.
Factors associated with incidence of asthma, rhinitis and eczema
The following section provides a summary of study results of factors that are
significantly associated with the incidence of asthma, rhinitis and eczema.
We found that allergic problems in the family were strongly associated with an
incidence of asthma, rhinitis and eczema, a finding which also has been shown in
many other studies (Norrman et al. 1998, Rönmark 2002, Jaakkola et al. 2005,
Willemsen et al. 2008). Our data show that allergic symptoms in the mother were
more strongly associated with the incidence of asthma and eczema in the child
(adjusted odds ratio (aOR) for asthma 2.16; 95% CI 1.27-3.66 and aOR for eczema
50
1.92; 1.48-2.49) than such symptoms in the father (aOR for asthma 1.33; 0.72-2.45
and aOR for eczema 1.28; 0.96-1.71). Overall, the highest incidence rates were
found in children where both parents were reported to have allergic symptoms.
Another factor related to the incidence of asthma in children in our data was male
sex, (aOR 1.99; 1.29-3.06), a finding which also has been reported in several other
studies (Roel et al. 1999, Rönmark 2002, Dik et al. 2004). Our results also showed
that male sex was associated with the development of rhinitis, another finding
which also has been stated before (Peroni et al. 2003). Girls were more inclined to
develop eczema in our study population. This is a finding which was also shown to
be the case in both a study including data from Germany, Denmark and Sweden
(Schultz Larsen et al. 1996) and another Swedish study (Broberg et al. 2000).
Other studies have shown that asthma and wheezing in children up to 3 years of
age are strongly associated with parental smoking (Lannero et al. 2006,
Moshammer et al. 2006, Pattenden et al. 2006). In our study, however, we could
not find any significant relationship between smoking in the family and the
incidence of asthma, rhinitis or eczema in the child. About 22% of the children in
the baseline population live with at least one smoking parent, which is a low rate
compared with many other countries (Warren et al. 2008). The low rate of parental
smoking may be due to successful prevention actions regarding smoking during
recent decades. Moreover, our data show that even if parents are reporting that
they smoke, most of them report that they don’t smoke indoor. An outdoors
smoking habit is probably due to the fact that Swedish parents are well informed
about the risks of exposing their children to tobacco smoke.
Our study shows that breastfeeding during the first three months after birth
reduced the risk of developing asthma in the child. This finding has also been
shown in other studies (Oddy et al. 1999, Rönmark 2002, van Odijk et al. 2003,
Kull et al. 2005). It is possible that parents’ reports on the extent of breastfeeding
is underestimated since there is a broad public opinion in Sweden that
breastfeeding protects small children from developing asthma and allergy. A
mother in a family with allergic symptoms may tend to breastfeed the child for a
longer period compared to a mother in a family with no allergic problem, due to
the belief that breastfeeding protects against development of allergy in the child.
51
The study show that 97% of the mothers had breastfed their children but there
were no difference in breastfeeding patterns between families with allergic
symptoms and families without such problems. Moreover, both groups reported
that they continued breastfeeding at the same length of time.
We found that proxies for lower SES were associated with the development of
asthma, rhinitis and eczema. Children living with one parent were more often
reported to develop asthma and eczema than children living with both parents.
Furthermore, living in a multifamily house was associated with the incidence of
rhinitis and eczema, when compared with living in a single family house. Other
Swedish studies have also shown that childhood asthma and rhinitis are more
common in families with low SES (Lindbaek et al. 2003, Almqvist et al. 2005,
Bråbäck et al. 2005). It has further been discussed that these differences might be
related to differences in lifestyle and environmental exposures between different
SES groups (Almqvist et al. 2005). However, one limitation with the DBH phase I
and III study is that we don’t have specific data on socioeconomic status of the
family.
Moisture related problems indoor and asthma
Results in paper II show that different moisture related problems are rather
frequently reported in the homes in this study (Figure 11).
Water leakage was reported in 6.9% of the birth residences. The reports of water
leakage were more than doubled in houses where respondents lived at the study’s
baseline (17.8%). One explanation for such a discrepancy could be that at baseline
the parents could report if they ever had water leakage, a category that included
both the current dwelling and the birth residence while reports in the birth
residence was limited to the birth residence (Table 3). Questions about water
leakage were not included in the follow-up questionnaire. Our study findings can
be compared to a Swedish 8-year follow-up study of 348 persons aged 20-65 years
(Sahlberg et al. 2009) who found a water leakage prevalence rate of about 11%, a
value that lies between our findings.
52
0
5
10
15
20
25
30
35
Water leakage Moldy Odor Floor moisture Visible dampness Condensation onwindow
Freq
uenc
e (%
)
Birth residence
Baseline
Follow-up
Figure 11. Frequencies of self reported moisture related problems in the birth residence (n=8,918), the home at baseline (n=8,918) and in the home at follow-up (n=5,483) *There were no questions for water leakage and moldy odor in the follow-up study
The reported frequencies of parents’ perception of moldy odor in the birth
residence are somewhat higher than reports of moldy odor from the baseline home
(6.3 and 4.3% respectively). Both reports were somewhat higher than found in
Sahlberg’s study, which showed a report rate of moldy odor of 2%. A comparison
between the data in our study show that the reporting criteria for the time periods
for moldy odor were defined slightly differently regarding the birth and the
baseline dwelling. Moldy odor at baseline was reported only over the previous
three months while the reporting period for moldy odor in the birth residence
could take in a longer period of time, depending on how long the family had lived
in the child’s birth residence. Questions about moldy odor were not included in the
follow-up questionnaire of our study.
Floor moisture was reported to be present in 6.5% of birth residences and 8.3% of
residences at the baseline study period. Sahlberg et al. (2009) described a
respondent-reported rate for floor moisture of 6%. The respondents’ reports of
floor moisture index at our study’s follow-up was somewhat lower (4.7%) than
* *
53
reports at birth and baseline, which might be due to different inclusion criteria in
the index definitions (see Table 3 in the method section).
Parent reports of visible dampness in the birth residence was much higher (7.2%)
compared with both baseline (1.5%) and follow-up (1.0%) reports. One possible
explanation for this might be that visible dampness in the birth residence included
dampness signs in the whole dwelling including cellar, bathrooms, etc., while
reporting criteria for visible dampness at baseline and at follow-up only included
the child’s or parent’s bedroom. In comparison, Sahlberg’s study (2009) found a
frequency of visible mold of 3%.
Reports of condensation on windows in the birth residence are more than doubled
(32.3%) compared to reports from baseline (14.3%) and follow-up (10.6%). One
possible explanation for this variation is that reports on condensation on windows
in the birth residence included reports from anywhere in the home, while data
from the baseline only included reports for the parent’s or the child’s room.
In conclusion, our data show that parental reports of moisture problems varied
when comparing reports from birth residence, the baseline and the follow-up
home. Some of the variation is due to discrepancy in definitions, but it may also
involve recall bias. What can be speculated from our study’s findings is that
retrospective reports regarding moisture problems might be more biased than
reports involving present-day conditions in one’s current home. This bias might
occur when families report more problems retrospectively, i.e. in the home where
they don’t live, which would result in over reporting of moisture problems in the
birth residence.
Moisture related problems and incidence of asthma
In paper II, the focus was to investigate the importance of moisture related
problems in the home on the development of asthma in children. The overall aim
was to investigate if the associations between parental reported moisture related
problems in the home and asthma in children found in our cross-sectional data
could be confirmed in longitudinal analyses. Analyses between moisture related
problems in the birth residence and in the baseline home and asthma was
54
estimated in both cross-sectional data (n=10,851) and longitudinal data five years
later (n=4,779).
Adjusted associations between moisture related problems in the birth residence
and asthma in both cross-sectional and longitudinal data are showed in Figure 12.
Adjustments were made for possible confounders (age, sex, allergic symptoms in
family and smoking in family). In the cross-sectional analyses, significant
associations were found between all moisture indices in the birth residence and
asthma at baseline with aOR in the range of 1.4-2.1. However, we also analyzed
longitudinal data, meaning that we examined the relationship between moisture
indices in the birth residence and the incidence of asthma during the five years
after the baseline study. Our longitudinal data showed that all associations that
were significant in cross-sectional analyses disappeared.
Figure 12. Associations between moisture related problems in the birth residence and asthma in cross-sectional (n=10,851) and longitudinal analyses (n=4,779)
When analyzing moisture related problems in the home at baseline, cross-sectional
data showed that visible dampness and floor moisture were associated with asthma
but after longitudinal analyses these associations decreased and was found to be
non-significant (Figure 13). Reports of condensation on windows and water
leakage were associated with asthma in cross-sectional analyses but after analysis of
longitudinal data these associations disappeared. However, the association between
0
1
2
3
4
DAMPbr
Floor br
COND br
Waterleaka
ge br
MOLD O
DOR br
AO
R 9
5% C
I
VisibledampnessBR
FloormoistureBR
Condensationon windowBR
Water leakageBR
Moldy odorBR
Cross sectional dataLongitudinal data
0
1
2
3
4
DAMPbr
Floor br
COND br
Waterleaka
ge br
MOLD O
DOR br
AO
R 9
5% C
I
VisibledampnessBR
FloormoistureBR
Condensationon windowBR
Water leakageBR
Moldy odorBR
Cross sectional dataLongitudinal data
55
moldy odor and asthma found from cross-sectional data were also found in
longitudinal analyses - in fact the risk was increased.
Figure 13. Associations between moisture related problems at baseline and asthma in cross-sectional (n=10,851) and longitudinal analyses (n=4,779)
Can cross-sectional associations be due to reporting bias?
In Sweden there is a common opinion that moisture related problems in homes
are related to respiratory health effects. This might influence results in cross-
sectional studies which can lead to reporting bias. This means that families with
symptomatic children might be more prone to remember and report moisture
damages in their dwelling compared to families without such health problems. It
could also be that families living in homes with signs of moisture problems might
be more inclined to systematically remember and report symptoms in the children.
Such reporting bias does not occur to the same extent in longitudinal studies,
where exposure and disease are not reported at the same point in time and where
the diseased children at baseline are excluded.
Based on our findings, we believe that reporting bias may explain at least part of
the associations found in cross-sectional data in the baseline material. However,
the findings pose another question: why did we find an association between moldy
0
1
2
3
4
DAMP
Floor
COND
Water
leaka
ge
MOLD
ODOR
AO
R 9
5% C
I
VisibledampnessBL
FloormoistureBL
Condensationon windowBL
Water leakageBL
Moldy odorBL
Cross sectional dataLongitudinal data
0
1
2
3
4
DAMP
Floor
COND
Water
leaka
ge
MOLD
ODOR
AO
R 9
5% C
I
VisibledampnessBL
FloormoistureBL
Condensationon windowBL
Water leakageBL
Moldy odorBL
Cross sectional dataLongitudinal data
56
odor in the baseline residence and incidence of asthma when such an association
couldn’t be found regarding moldy odor in the birth residence?
We showed earlier that there were slightly more reports of moldy odor in the birth
residence compared with the baseline dwelling (Figure 11), which could indicate
that retrospective reports may lead to over-estimation. Retrospective reports from
cross-sectional data showed stronger association between the prevalence of asthma
and moisture problems in the birth residence compared to reports regarding the
residence at baseline. This could mean that parents who had a child with asthma at
baseline were perhaps trying to attribute health problems to moisture problems in
an earlier residence, compared to their current home.
Other studies have investigated the association between moisture problems,
including moldy odor, and the incidence of asthma. A population-based
questionnaire study of Finnish children aged 1-6 years also showed a discrepancy
between results from cross-sectional and longitudinal data. They found in cross-
sectional analyses that visible mold, moisture, water damage and moldy odor
anywhere in the dwelling were all significantly associated with wheezing in separate
analyses (Jaakkola et al. 1993). However, the longitudinal analyses six years later
showed that the association between visible mold, moisture or water damage at
baseline and asthma incidence had disappeared, but moldy odor remained as a
significant risk factor in the longitudinal analyses (Jaakkola et al. 2005), which is in
line with our data. Another Finnish study also found associations between moldy
odor and incidence of asthma (Karvonen et al. 2009). These results raise the
question if moldy odor could be of importance for the development of asthma in
the child.
In the second phase of the DBH-study, which is not reported in detail in this
thesis, a nested case-control study was conducted. Trained inspectors visited 390
dwellings looking for moisture related problems. The analyses did not indicate that
case children were over-represented in homes where the inspectors perceived a
general moldy odor. However, it was found that case children were over
represented in the group of homes where the inspector perceived moldy odors
along the skirting board when compared with homes without such odor. It was
suggested that moldy odor along the skirting board could be seen as an indicator of
57
moisture related problems inside the building structure, which might be of
importance for the development of asthma in the child (Hagerhed-Engman et al.
2009).
A problem observed in the study’s second phase was the low concordance between
parent’s report of moldy odor in the home and inspectors’ observations of moldy
odor (Engman et al. 2007). These diverse findings between parent’s and inspectors
reports show the complexity in measuring and interpreting perceptions of odor in
different kind of studies.
Our data indicates that moldy odor in homes might be seen as a risk factor for
developing asthma in children, but the results are not conclusive since there are
such differences in reports between odor in the birth residence and odor in the
baseline dwelling. Furthermore, even if moldy odor in the home is related to the
development of asthma in children, such exposures can explain very little of the
onset of asthma in the current study population since moldy odor were reported
from less than 4% of the homes and the attributable fraction can be estimated to
about 6%. This means that elimination of the exposure (moldy odor in the
baseline home) will reduce the number of children developing asthma during the
five year period from 100 to about 94 children.
In conclusion, significant associations between parental reported moisture
problems in the dwelling and parental reported asthma in children were found in
cross-sectional data but these associations disappeared or decreased in longitudinal
analyses. A significant association between moldy odor reports in the home at
baseline and the incidence of asthma was found in the longitudinal analyses but
odor reports from birth residence were not associated with development of
asthma. Our results therefore suggest that cross-sectional associations between
moisture related problems in homes and asthma in children at least in part can be
explained by reporting bias, and this problem might be even stronger when
reporting exposure problems retrospectively. This means that cross-sectional data
have to be interpreted with caution.
58
PVC-flooring and development of asthma
There are accumulating scientific data supporting the hypothesis that exposure to
PVC-materials indoor may be linked to asthma and allergies, as presented in two
recent reviews (Jaakkola et al. 2008, Bornehag et al. 2010). It has been suggested
that such a relationship could be due to phthalate exposure as it is known that
PVC-materials include phthalates and that PVC-materials emit phthalates to the
surrounding environment. However, the biological mechanism for such a
relationship is not at all obvious. Furthermore, most of the studies on the
relationship between PVC-flooring and asthma are cross-sectional (Bornehag et al.
2010). There is need for longitudinal data investigating if exposure to PVC is
associated with the incidence of asthma in children. With these factors serving as
motivation, paper III examined the associations between PVC-flooring in the
bedrooms at baseline and the incidence of asthma during the following 5 years.
The results in paper III show that children living in homes with PVC-flooring in
the bedroom of residences where they lived when they were 1-3 years old were
more likely to develop asthma during the following 5-year period when compared
with children living without PVC-flooring (the child’s bedroom aOR 1.52; 0.99-
2.35 and parent’s bedroom aOR 1.46; 0.96-2.23). There were also findings of a
positive relationship between the number of rooms in a home with PVC-flooring
and the incidence of asthma (p=0.01); the more rooms with PVC-flooring, the
higher risk of developing asthma (Figure 14).
Other epidemiological studies have reported an association between PVC-material
and airway symptoms. The Norwegian Oslo birth cohort study employed a case-
control design and found that the presence of PVC-flooring significantly increased
the risk for bronchial obstruction in children (Jaakkola et al. 1999, Oie et al. 1999).
Within five years after this study, three other cross-sectional studies reported that
plastic wall materials and/or PVC-flooring increased the risk of airway symptoms
in children (Jaakkola et al. 2000, Jaakkola et al. 2004, Bornehag et al. 2005c). Up to
now there has only been cross-sectional data on the relationship between
respiratory symptoms and PVC-material. To our knowledge, our results were the
first showing an association using longitudinal data. Although the available number
of studies of the risk with PVC-material for airway diseases are few, all studies
59
0
1
2
3
4
No PVC PVC in one bedroom PVC in two bedrooms
Inci
den
ce o
f as
thm
a (%
)
0
1
2
3
4
AO
R (
95%
CI)
point in the same direction; PVC-materials seems to increase the risk of airway
symptoms and diseases.
We found a stronger association between PVC-flooring and development of
asthma among families living in multi-family houses (e.g. PVC in the child’s
bedroom: OR 4.19; 0.96-18.28) compared with those living in single family houses
(PVC in the child’s room: OR 1.32; 0.83-2.11). One possible explanation for these
findings could be due to the fact that most multi-family houses in Sweden are built
with a concrete floor structure while the single family houses most often have a
wooden structure. PVC-flooring in multifamily houses is often glued directly on
the concrete floor. If PVC-flooring material is glued on a concrete structure with
high moisture and high alkalinity content, there is a risk for chemical degradation
of the PVC-material and adhesives followed by increased emissions of degradation
products, e.g. phthalates (Wengholt Johnsson 1995, Gustafsson et al. 1997, Sjoberg
et al. 2007).
Figure 14. Number of bedrooms in the home with PVC-flooring at baseline and the risk for doctor diagnosed asthma at follow-up five years later among 4,779 children aged 6-8 years. The bars express the five year incidence rate of asthma (left y-axis) and the adjusted ORs including a 95% confidence interval on the right y-axis
Furthermore, asthma has been shown to be more common in lower
socioeconomic groups (Lindbaek et al. 2003, Almqvist et al. 2005, Bråbäck et al.
2005). As shown in the current study, PVC-flooring was associated with incidence
60
of asthma, but PVC-flooring was also correlated with proxies for lower SES such
as living in multi-family houses, divorce in the family (Lindbaek et al. 2003) and
parental smoking. It is therefore possible that the reported associations between
PVC-flooring and asthma in the current study are confounded by socioeconomic
factors. However, we made adjustments and stratifications for SES factors and
could not find any substantial reduction in the estimated risks between PVC-
flooring and incidence of asthma in the affected children.
Our study indicated an association between PVC-flooring in the bedroom and
development of asthma in children, but data has to be interpreted with caution due
to methodological limitations. The data are based on questionnaire reports on
environmental factors and health which may be a source for confounding
problems. There is a risk for misclassification of flooring materials. We have earlier
showed that parental reports of flooring materials are frequently in error (Engman
et al. 2007), i.e. people are in general quite bad in judging the source of some
flooring material (this is true for PVC and linoleum, while people in general are
good judging wooden flooring). Consequently, families often misclassify types of
flooring. However, we have no reason to believe that such misclassification errors
differ between groups of parents who had children with and without asthma,
especially because the type of flooring was assessed before the onset of asthma.
In conclusion, most studies of the relationship between PVC and/or phthalates
and asthma are of a cross-sectional design. Our data show an association between
PVC-flooring in the bedrooms and incidence of asthma as well as a relationship
between the number of rooms with PVC-flooring and the incidence of asthma.
Limitations with the study are the use of questionnaire reports on environmental
factors and health outcomes and the risk for misclassification of flooring materials.
Further, we only found borderline significance for associations. This means that
our data should be interpreted with caution and warrants confirmation in a
prospective cohort design including early life exposure during pregnancy and
infancy period. Further investigation will require measurements of the phthalate
exposure in the environment as well as human uptake of such compounds.
61
Autism spectrum disorders and indoor environmental factors
Many studies in the past few decades have shown that the developing brain may be
vulnerable to a variety of environmental chemicals, such as metals, pesticides,
phthalates, solvents etc. (Weiss et al. 2000, Hertz-Picciotto et al. 2009). Hypotheses
have been proposed that fetal and early childhood exposures to industrial
chemicals in the environment could lead to neurodevelopmental disorders such as
ASD (Grandjean et al. 2006). However, while many investigators believe that an
environmental component is involved in the etiology of ASD, there is still a
tremendous lack of evidence for such a relationship. With this background, paper
IV examined if different indoor environmental factors, such as PVC-flooring, was
associated with ASD.
Our study showed that the presence of PVC-flooring material in the bedroom of a
home when the child was 1-3 years was associated with an ASD diagnoses five
years later (Figure 15). It was found that PVC-flooring in the parent’s bedroom
showed a slightly stronger association with ASD compared to PVC-flooring in the
child’s bedroom. One explanation for such a difference in association could be that
children with ASD more often sleep in a parent’s bedroom when they are in the
age 1-3 years compared with children without ASD. This was in fact true for our
study population, as 47.9% of the children with ASD did sleep in the parents’
bedroom compared with 43.2% of the children without an ASD diagnosis.
However, this finding was not significant. Another speculation could be that
maternal exposure to PVC during the pregnancy is more critical than later on,
when the child him- or herself is exposed. Our data had limitations that did not
allow for further exploration.
In the follow-up questionnaire in phase III of the DBH-study we found that 72
children out of 4,779 had parents who reported that the child had ASD,
corresponding to a prevalence of 1.5%. Our prevalence figure for ASD is slightly
higher than those reported in several other studies where rates range between 0.3-
1.2% (Bertrand et al. 2001, Fombonne 2005, Rutter 2005, Baird et al. 2006,
Gillberg et al. 2006). These studies have defined ASD according to the
classification system DSM-IV or ICD-10, which refer ASD as a composite
diagnosis including infantile autism/autistic disorder, Asperger syndrome,
disintegrative disorder, other autistic-like conditions and severe autistic features.
62
Our ASD index included reports of diagnoses of at least one of the following:
autism, Asperger syndrome and Tourette’s syndrome.
Our slightly higher prevalence could therefore be ascribed to our inclusion of
Tourette’s syndrome in the definition of ASD, unlike the definitions of most other
studies, which did not include Tourette’s syndrome. This indicates that our
prevalence rate is in accordance with other studies investigating ASD. Our study is
also in accordance with other studies in that we found that ASD was five times
more common among boys compared with girls (Fombonne 1999, Honda et al.
2005, Gillberg et al. 2006, Hertz-Picciotto et al. 2006, Landa 2008).
Figure 15. Type of flooring in the child’s and parent’s bedroom at baseline and the risk for ASD at follow-up five years later among 4,779 children aged 6-8 years. The bars express the prevalence of ASD (left y-axis) and the adjusted ORs including a 95% confidence interval on the right y-axis Another environmental factor that was shown by our data to be associated with
ASD was condensation on the window. Condensation may serve as a proxy for
low air exchange rate in the home. A low ventilation rate in the building might
increase many indoor-generated exposures and different pollutants and act as an
effect modifier (Seppanen et al. 2004, Bornehag et al. 2005b, Hägerhed-Engman et
63
al. 2009). However, earlier results in the DBH-study did not lead to a conclusion
that low ventilation rate was associated with higher concentration of phthalates in
dust (Bornehag et al. 2005a). There are very few papers published discussing how
ventilation rates influence indoor contaminant levels. However, there are
suggestions that phthalates have long indoor persistency and that if ventilation is
the only removal mechanism, these compounds may persist for years in areas with
low ventilation (Weschler et al. 2008).
Smoking around children is a well-documented risk factor for child behavior
problems, including ASD (Fergusson et al. 1998, Williams et al. 1998, Hultman et
al. 2002, Wakschlag et al. 2002, Indredavik et al. 2007). Our data show that
maternal smoking (during pregnancy, during the child’s first year and/or current
smoking) was associated with ASD. When calculating smoking and its association
with ASD, this factor is difficult to sort from other SES-related factors.
Furthermore, families with an ASD child reported more socioeconomic problems
and displayed more proxy indicators for lower SES, such as living in a multi-family
house, having a smaller living area of the home, and comprising family units where
parents were divorced, compared with families without an ASD child. Since these
SES proxies showed a stronger association to ASD in the cross-sectional data from
2005 compared to data from 2000, there are indications that economic problems
are more likely a result of ASD rather than a risk factor.
Our results showed that children with ASD reported twice as many airway
symptoms (i.e. doctor diagnosed asthma and wheezing) compared with children
without ASD. Our study showed that allergic symptoms in the mother were weakly
associated with ASD in the child. Similar results have been reported from a study
in U.S. where the risk for ASD doubled in the offspring of mothers with allergic
diseases during pregnancy (Croen et al. 2005). These findings that asthma and
allergy could be associated with ASD are not at all obvious. An hypothesis has
been expounded that postulates that early infections activate the immune system
and may affect brain structure or function contributing to the development of
ASD (Becker 2007, Fatemi et al. 2008).
A limitation of this study is also that we only have diagnosed ASD via parental
reports. We interviewed ten randomly selected families who had reported children
64
with ASD from the study population and found that the parental reports of ASD
were matched by clinical diagnoses of ASD by medical professionals. Our
experience tells us that there is no reason to believe that the parents would report
autism, Asperger or Tourette’s syndrome without a clinical diagnosis or other
relevant information as a basis for their reports but it is possible that such
reporting errors can occur.
In conclusion, we have found an association between ASD and PVC-flooring in
the home during early childhood, which we presume to reflect exposure to
phthalates in air and dust. Even though this study was not designed specifically to
address ASD, and confirmation would require further efforts, this suggests that
chemical contaminants with suspected endocrine disruptor properties might yield
useful insights into the genesis of ASDs.
Similarities in risk pattern for asthma and autism spectrum disorders
Our data related to asthma and ASD seem to covariate, meaning that children with
ASD were reported to have more asthma and airway symptoms. We also find
similarities in the pattern of risk factors, both environmental exposures and
background factors, in both conditions.
Our results show that boys who were enrolled in our study were twice as likely to
have doctor diagnosed asthma compared with girls (6.8% vs. 3.6% <0.001), a
finding that has been replicated elsewhere (Anderson et al. 1992, Almqvist et al.
2008, Bjerg et al. 2010). Our study found a similar pattern for ASD (boys 2.5% vs.
girls 0.5% <0.001), a finding that is also replicated in other studies (Honda et al.
2005, Gillberg et al. 2006, Landa 2008).
Environmental exposures that were associated with ASD in our study included
maternal smoking during pregnancy, which is a well-documented risk factor for
child behavior problems, such as ASD (Wakschlag et al. 2002, Linnet et al. 2003,
Indredavik et al. 2007). Other studies have found associations between maternal
smoking and asthma (Lannero et al. 2006, Moshammer et al. 2006, Pattenden et al.
2006), even though this was not found in the study we conducted.
65
The data from our research showed that different indoor environmental factors
were associated with both asthma and ASD. PVC-flooring in the bedroom of
participants when they were between 1 and 3 years old was shown to be related to
both ASD and asthma five years later. Earlier findings in the DBH-study show
that PVC-flooring was a source for phthalate emission (Bornehag et al. 2005a)
which was related to asthma in the child (Bornehag et al. 2004c).
Our work and other research have described other similarities related to risk
factors between the two diseases/disorders. There is data indicating that both
asthma (Pearce et al. 2006) and ASD (Rutter 2005) have increased during the last
few decades. Both diseases are often diagnosed in early childhood; 3-6 years for
children with asthma (Morgan et al. 2005) and 2-4 years for autism (Mandell et al.
2005), which indicates that the early life period is important and similar for both
diseases.
The striking similarities in risk factors are worth focusing on in coming studies.
The findings presented here raise the issue that there could be common etiological
factors behind both these diseases. There have been suggestions that there might
be a tight connection between development of the immune system and the central
nervous system, and that the disruption of critical events in immune development
may play a role in neurodevelopmental disorders. Of specific concern is that
exposure to different environmental agents such as chemicals might be highly
detrimental during critical developmental stages such as the prenatal and early
post-natal period and may lead to long-term health effects (Hertz-Picciotto et al.
2008).
Limitations in the current study
To conduct epidemiological studies and to establish relationships between
environmental exposures and health effects is an adventure in that it involves
many assumptions and has inherent uncertainties which most often limit the
possibilities for conclusive results.
Epidemiological studies may generate hypotheses about a causal relationship
between an exposure and a health effect, nothing more. To decide whether our
results are causal or not is impossible, as a completely reliable criterion for causality
66
does not exist. The findings from epidemiological research are, at best, only
tentative formulations of a description of nature (Rothman et al. 2005). If one risk
factor has been identified in several studies one may suppose that a causal
relationship is more likely. But the same type of bias can be present in all studies
without investigators being able to identify it. One can see hints of this problem
within review studies, where manuscripts with positive findings are more likely to
get published than those with negative findings, a so-called publication bias.
To establish understanding of the subject matter, a fair interpretation of the results
should be obtained. It is of greatest importance that epidemiologic results are
looked upon critically and that study strengths and weaknesses as well as
limitations are highlighted.
One of the weaknesses of our study is how we defined the study problem and
population when estimating the incidence. Children who had already developed
asthma during their infancies and early childhood (the first year of life for the
youngest children and the first three years for the oldest children) were excluded
from the baseline population in order to estimate the incidence (that is, new cases)
of asthma. This means that we have not investigated the importance of different
exposures for the development of asthma during infancy.
Our data suggest that the association between moisture related problems and
asthma in cross-sectional analysis might be biased, as we used self-reports for some
of the data. The results may be skewed due to common opinion in the general
population that such exposure is a risk for airway problems. Another reporting bias
from parents, which has already been documented in this study, was reporting bias
due to misclassification of types of flooring (Engman et al. 2007).
Another problem affecting our study is the loss of statistical power in the
longitudinal analyses. When estimating the association between the incidence of
asthma and certain moisture indices, the number of cases became small. When the
study measured visible dampness or moldy odor at baseline, only 2 and 10
children, respectively, were found to have developed asthma in the exposed group.
Even if these exposures is related to the development of asthma in children, such
67
exposures can explain very little of the onset of asthma in the current study
population since these exposures where reported from less than 4% of the homes.
A further problem in the current study is that we can not distinguish between the
three disorders; autism, Asperger and Tourette’s syndrome because they where
included in the same category in the questionnaire that was used in the current
study.
There are also other factors that may contribute to an appearance of a cause-effect
relationship that in reality does not exist. Confounding in epidemiological studies
can occur when another factor exists and is associated both with the disease and
exposure that are being studied. The collection of detailed information about
confounding risk factors, such as SES, is a way to limit this confounding. In our
study adjustments and stratifications were conducted for SES factors such as single
parenthood, smoking in the family and type of dwelling. However, as the most
efficient proxies of SES, such as parental occupation, occupation status, income,
and education level, or a combination of these (Liberatos et al. 1988, Lindbaek et
al. 2003, Eagan et al. 2004) were not measured in this study, there is still the
possibility of residual confounding.
Further studies
The two first phases of the Swedish DBH-study are being replicated in seven other
countries from different global regions (Figure 16). These studies have been
conducted with similar questionnaires and protocols in order to establish
comparable data sets. The first country to carry out a DBH-study after Sweden was
Bulgaria, followed by Singapore, Taiwan, Denmark, USA, China and South Korea.
The overall aim with such global mapping is to establish comparable data on the
prevalence of asthma and allergy in children as well as collecting information on
the characteristics of homes and indoor environmental exposures. A further aim is
to identify general risk and protection factors for asthma and allergy but also
region specific factors due to climate, culture, traditions etc.
68
Sweden, Bulgaria, Singapore, Taiwan, Denmark,Sweden, Bulgaria, Singapore, Taiwan, Denmark, USA, China, South KoreaUSA, China, South Korea
Dampness inDampness inDampness inDampness in BuildingsBuildingsBuildingsBuildings andandandand Health worldwideHealth worldwideHealth worldwideHealth worldwide
Sweden, Bulgaria, Singapore, Taiwan, Denmark,Sweden, Bulgaria, Singapore, Taiwan, Denmark, USA, China, South KoreaUSA, China, South Korea
Dampness inDampness inDampness inDampness in BuildingsBuildingsBuildingsBuildings andandandand Health worldwideHealth worldwideHealth worldwideHealth worldwide
Figure 16. Studies with a DBH design are currently conducted in 8 different countries
Furthermore, findings from the DBH-study will be tested in an ongoing
longitudinal birth cohort study; the Swedish Environmental Longitudinal, Mother
and child, Asthma and allergy study (SELMA) presented in Figure 17. The overall
aim with the SELMA-study is to investigate the importance of early life exposure
to environmental agents, such as suspected EDCs, as risk factors for different
chronic diseases/disorders in children later on in life. In that study both
questionnaires are used and medical examinations including bio-sampling will be
conducted, as well as environmental exposure measurements.
One way to establish knowledge about a causal relationship between exposures and
health effects is to combine epidemiological investigations with controlled
experimental in-vitro and in-vivo studies. Findings from the DBH-study and the
SELMA-study will be tested in experimental in vitro investigations at Biomedical
Science at Karlstad University.
69
DBH phase ICross-Sectional study
BaselineMarch 2000
Questionnaire
n=14 077 children, 1-5y (rr=79%)
Birth Cohort Study incl. 2 500 mother-child pairs
September 2007- March 2010
Experimental studiesBiomedical studies
Karlstad University
xxx(x)Clinical examinations
xxxQuestionnaires
Sleeping roomSleeping roomDust and Air samples
ChildChildCord bloodPregnant womenBlood/Urine samples
ChildhoodInfancyBirthPregnancyData collection
xxx(x)Clinical examinations
xxxQuestionnaires
Sleeping roomSleeping roomDust and Air samples
ChildChildCord bloodPregnant womenBlood/Urine samples
ChildhoodInfancyBirthPregnancyData collection
DBH phase IICase-Control Study
October 2001-April 2002
Professional inspectionsExposure measurements
Clinical examinationsN=200+200 children/dwellings
DBH phase III1st Follow-up Study
March 2005
Questionnaire
n=7 509 children, 6-8y (rr=73%)(incidence of chronic diseases)
DBH-phase IV2nd Follow-up Study
March 2010
Questionnaire
n=15 043 children, 11-15y (rr=53%) (incidence of chronic diseases)
Figure 17. Study description of the different phases of the DBH-study, the SELMA-study and experimental studies
70
MAIN CONCLUSIONS AND RECOMMENDATIONS
The incidence of allergic symptoms from questionnaire studies can be estimated by
the use of data from birth cohort studies as well as from cohorts established later
on in life. When not using birth cohort data the estimated incidence rates are
strongly dependent of how the baseline population is defined from a health point
of view and how the studied health outcome at follow-up is defined. We found
that, for our study’s participants, the mean incidence rate per year for doctor
diagnosed asthma was in the range of 0.6 to 2.4% and incidence of doctor
diagnosed rhinitis in the range of 1.1 to 3.7% depending on different definitions of
baseline and health outcome at follow-up. The incidence rate of eczema ever was
2.7%.
Recommendations: Our results show that wheezing could be an indicator of
that the child already has asthma, not yet diagnosed, and therefore suggests that
children with asthma and wheezing should be excluded from the baseline
population when estimating the incidence of asthma.
The associations between parental reported moisture problems in the home and
asthma in children that was found in cross-sectional analyses decreased or
disappeared when longitudinal data were used. No association between moldy
odor in the birth residence and incidence of asthma was found but moldy odor in
the home at baseline was associated to the incidence of asthma.
Recommendations: Our results indicate that associations between parental
reported moisture problems and asthma from cross-sectional questionnaire
studies should be interpreted with caution due to the risk for reporting bias.
This might be due to the fact that there is a general opinion that moisture
problems at home are a risk factor for airway problems in many regions in the
world.
71
Children living in homes with PVC-flooring in the bedroom when they were 1-3
years of age were more likely to develop asthma during the following 5-year period
when compared with children living in homes without such flooring material.
Recommendations: Our findings regarding associations in a longitudinal design
warrant confirmation in a prospective birth cohort study including early life
exposure during pregnancy and infancy period as well as measurements of the
phthalate exposure in the environment and human uptake of such exposures.
Children living in homes with PVC-flooring in the bedroom when they were 1-3
years of age were more likely to have a diagnose of autism spectrum disorders five
years later compared with children living in homes without such flooring material.
Recommendations: Our study is one of only a few linking ASD with indoor
environmental factors such as building materials including suspected endocrine
disrupting chemicals such as phthalates. There is a need for more extensive
studies focusing on this problem.
72
ACKNOWLEDGEMENTS
My PhD scholarship was financially supported by Karlstad University and
FORMAS (the Swedish Research Council for Environment, Agricultural Sciences
and Spatial Planning).
I would like to thank all of you that have supported me and my work during these
years of my doctoral studies. First of all I want to sincerely thank my supervisor
Carl-Gustaf Bornehag for your never ending patience, continuous support and
enthusiasm but also for introducing me to the exciting field of indoor environment
and health. I believe you are “Mr Never Good Enough”, which is an excellent
quality in science ☺.
Thanks to Staffan Janson, my second supervisor, for your important help and
guidance in the field of medicine and child health and to Jan Sundell, my informal
supervisor, for your driving force, advices and encouragement.
I want to send special thanks to my colleague, co-author and friend, Linda
Hägerhed-Engman for your great understanding, collaboration and discussions but
also for the wonderful and fun trips to conferences all over the world. I can’t
express enough gratitude for your endless support in my ups and downs in writing
my thesis and in life. Thank you so much for always being there for me!
Many thanks to additional co-authors in my papers, Torben Sigsgaard, Fredrik
Lundin, Barbara Kolarik, Bernard Weiss, Peter James and Syed Moniruzzaman, for
help with the process of planning, analyses, discussions and writing. Together we
have done a great job with finalizing four papers within four years. I would never
have made it without your effort and knowledge.
My thanks go to my colleagues at Public Health Sciences at Karlstad University
and LiV (County Council of Värmland), but a special one to my co-workers and
close friends Birgitta, Carolina, Pernilla, Linda, Lisa and Cecilia for your support,
for better and for worse. Without our laughter I would never have survived these
years!
73
Many thanks to Mikke for our discussions and your help of bringing me down to
earth and to Diana who has given me valuable advice in the last stage of writing
my thesis but who also has improved my written English.
In Swedish…
… vill jag tacka min underbara familj som alltid uppmuntrar mig, ger mig energi
och tror på mig. Ni finns där i vått och torrt med både matlådor, skjutsande och
massa glädje. Pappa, jag hade visst rätt, man behöver inte ha 7-årig folkskola – det
kan gå bra ändå ☺. Mamma, tack för allt ”paketerande” i Selmastudien och för att
du ville måla den otroligt fina framsidan på min avhandling. Det är underbart att
ha föräldrar som ni, som stöttat mig genom hela min utbildning, även om det
ibland har varit svårt att förstå vad jag har gjort ☺. Ett annat stort tack vill jag ge
min syster med familj för alla glädjestunder, en speciell kram till Mathilda - du är
min lillskita.
Sist men inte minst vill jag tacka Ola, för att du alltid stödjer och uppmuntrar mig
men också för din förståelse för mina sena nätter och helger med jobb. Utan ditt
stöd och din kärlek hade resan inte varit lika lätt. Tack för att du hjälpte mig i mål!
Jag vill även tacka Maria och Tony Cronstam som lät mig använda deras underbara
karaktärer, Elvis and Hedvig i min avhandling.
Malin Larsson
10/12/2010 Karlstad University
74
REFERENCES Almqvist, C., Pershagen, G. and Wickman, M. (2005) "Low socioeconomic status as a risk factor for
asthma, rhinitis and sensitization at 4 years in a birth cohort", Clin Exp Allergy, 35, 612-618. Almqvist, C., Worm, M. and Leynaert, B. (2008) "Impact of gender on asthma in childhood and
adolescence: a GA2LEN review", Allergy, 63, 47-57. Anderson, H.R., Pottier, A.C. and Strachan, D.P. (1992) "Asthma from Birth to Age 23 - Incidence and
Relation to Prior and Concurrent Atopic Disease", Thorax, 47, 537-542. Anderson, H.R., Ruggles, R., Strachan, D.P., Austin, J.B., Burr, M., Jeffs, D., Standring, P., Steriu, A.
and Goulding, R. (2004) "Trends in prevalence of symptoms of asthma, hay fever, and eczema in 12-14 year olds in the British Isles, 1995-2002: questionnaire survey", Br Med J, 328, 1052-1053.
Asher, M.I., Keil, U., Anderson, H.R., Beasley, R., Crane, J., Martinez, F., Mitchell, E.A., Pearce, N., Sibbald, B., Stewart, A.W. and Et Al. (1995) "International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods", Eur Respir J, 8, 483-491.
Asher, M.I., Anderson, H.R. and Stewart, A. (1998) "Worldwide variations in the prevalence of asthma symptoms: the International Study of Asthma and Allergies in Childhood (ISAAC)", Eur Respir J, 12, 315-335.
Asher, M.I., Montefort, S., Björksten, B., Lai, C.K., Strachan, D.P., Weiland, S.K. and Williams, H. (2006) "Worldwide time trends in the prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and eczema in childhood: ISAAC Phases One and Three repeat multicountry cross-sectional surveys", Lancet, 368, 733-743.
Atladottir, H.O., Parner, E.T., Schendel, D., Dalsgaard, S., Thomsen, P.H. and Thorsen, P. (2007) "Time trends in reported diagnoses of childhood neuropsychiatric disorders: a Danish cohort study", Arch Pediatr Adolesc Med, 161, 193-198.
Bach, J.F. (2002) "The effect of infections on susceptibility to autoimmune and allergic diseases", N Engl J Med, 347, 911-920.
Bahadori, K., Doyle-Waters, M.M., Marra, C., Lynd, L., Alasaly, K., Swiston, J. and Fitzgerald, J.M. (2009) "Economic burden of asthma: a systematic review", BMC Pulm Med, 9, 24.
Baird, G., Simonoff, E., Pickles, A., Chandler, S., Loucas, T., Meldrum, D. and Charman, T. (2006) "Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP)", Lancet, 368, 210-215.
Banks, E.C., Ferretti, L.E. and Shucard, D.W. (1997) "Effects of low level lead exposure on cognitive function in children: a review of behavioral, neuropsychological and biological evidence", Neurotoxicology, 18, 237-281.
Barreto Do Carmo, M.B., Neves Santos, D., Alves Ferreira Amorim, L.D., Fiaccone, R.L., Souza Da Cunha, S., Cunha Rodrigues, L. and Barreto, M.L. (2009) "Minor psychiatric disorders in mothers and asthma in children", Soc Psychiatry Psychiatr Epidemiol, 44, 416-420.
Beasley, R., Crane, J., Lai, C.K. and Pearce, N. (2000) "Prevalence and etiology of asthma", J Allergy Clin Immunol, 105, S466-472.
Beasley, R. (2002) "The burden of asthma with specific reference to the United States", J Allergy Clin Immunol, 109, S482-489.
Becker, K., Seiwert, M., Angerer, J., Heger, W., Koch, H.M., Nagorka, R., Rosskamp, E., Schluter, C., Seifert, B. and Ullrich, D. (2004) "DEHP metabolites in urine of children and DEHP in house dust", Int J Hyg Environ Health, 207, 409-417.
Becker, K.G. (2007) "Autism, asthma, inflammation, and the hygiene hypothesis", Med Hypotheses, 69, 731-740.
Becker, K.G. and Schultz, S.T. (2010) "Similarities in features of autism and asthma and a possible link to acetaminophen use", Med Hypotheses, 74, 7-11.
Beggs, P.J. and Bambrick, H.J. (2005) "Is the global rise of asthma an early impact of anthropogenic climate change?" Environ Health Perspect, 113, 915-919.
Bertrand, J., Mars, A., Boyle, C., Bove, F., Yeargin-Allsopp, M. and Decoufle, P. (2001) "Prevalence of autism in a United States population: the Brick Township, New Jersey, investigation", Pediatrics, 108, 1155-1161.
75
Bjerg, A., Sandstrom, T., Lundback, B. and Ronmark, E. (2010) "Time trends in asthma and wheeze in Swedish children 1996-2006: prevalence and risk factors by sex", Allergy, 65, 48-55.
Björksten, B., Dumitrascu, D., Foucard, T., Khetsuriani, N., Khaitov, R., Leja, M., Lis, G., Pekkanen, J., Priftanji, A. and Riikjarv, M.A. (1998) "Prevalence of childhood asthma, rhinitis and eczema in Scandinavia and Eastern Europe", Eur Respir J, 12, 432-437.
Bloom, E., Nyman, E., Must, A., Pehrson, C. and Larsson, L. (2009) "Molds and mycotoxins in indoor environments--a survey in water-damaged buildings", J Occup Environ Hyg, 6, 671-678.
Bonita, R., Beaglehole, R. and Kjellström, T. (2006) Basic Epidemiology, Geneva, WHO. Bornehag, C.G., Blomquist, G., Gyntelberg, F., Järvholm, B., Malmberg, P., Nordvall, L., Nielsen, A.,
Pershagen, G. and Sundell, J. (2001) "Dampness in buildings and health. Nordic interdisciplinary review of the scientific evidence on associations between exposure to "dampness" in buildings and health effects (NORDDAMP)", Indoor Air, 11, 72-86.
Bornehag, C.G., Sundell, J., Bonini, S., Custovic, A., Malmberg, P., Skerfving, S., Sigsgaard, T. and Verhoeff, A. (2004a) "Dampness in buildings as a risk factor for health effects, EUROEXPO: a multidisciplinary review of the literature (1998-2000) on dampness and mite exposure in buildings and health effects", Indoor Air, 14, 243-257.
Bornehag, C.G., Sundell, J. and Sigsgaard, T. (2004b) "Dampness in buildings and health (DBH): Report from an ongoing epidemiological investigation on the association between indoor environmental factors and health effects among children in Sweden", Indoor Air, 14 Suppl 7, 59-66.
Bornehag, C.G., Sundell, J., Weschler, C.J., Sigsgaard, T., Lundgren, B., Hasselgren, M. and Hägerhed-Engman, L. (2004c) "The association between asthma and allergic symptoms in children and phthalates in house dust: a nested case-control study", Environ Health Perspect, 112, 1393-1397.
Bornehag, C.G., Lundgren, B., Weschler, C.J., Sigsgaard, T., Hägerhed-Engman, L. and Sundell, J. (2005a) "Phthalates in indoor dust and their association with building characteristics", Environ Health Perspect, 113, 1399-1404.
Bornehag, C.G., Sundell, J., Hagerhed-Engman, L. and Sigsgaard, T. (2005b) "Association between ventilation rates in 390 Swedish homes and allergic symptoms in children", Indoor Air, 15, 275-280.
Bornehag, C.G., Sundell, J., Hägerhed-Engman, L., Sigsggard, T., Janson, S. and Aberg, N. (2005c) "'Dampness' at home and its association with airway, nose, and skin symptoms among 10,851 preschool children in Sweden: a cross-sectional study", Indoor Air, 15 Suppl 10, 48-55.
Bornehag, C.G. and Nanberg, E. (2010) "Phthalate exposure and asthma in children", Int J Androl, 33, 333-345.
Brasche, S. and Bischof, W. (2005) "Daily time spent indoors in German homes--baseline data for the assessment of indoor exposure of German occupants", Int J Hyg Environ Health, 208, 247-253.
Brauer, M., Hoek, G., Smit, H.A., De Jongste, J.C., Gerritsen, J., Postma, D.S., Kerkhof, M. and Brunekreef, B. (2007) "Air pollution and development of asthma, allergy and infections in a birth cohort", Eur Respir J, 29, 879-888.
Broberg, A., Svensson, A., Borres, M.P. and Berg, R. (2000) "Atopic dermatitis in 5-6-year-old Swedish children: cumulative incidence, point prevalence, and severity scoring", Allergy, 55, 1025-1029.
Bråbäck, L., Hjern, A. and Rasmussen, F. (2005) "Social class in asthma and allergic rhinitis: a national cohort study over three decades", Eur Respir J, 26, 1064-1068.
Burke, W., Fesinmeyer, M., Reed, K., Hampson, L. and Carlsten, C. (2003) "Family history as a predictor of asthma risk", Am J Prev Med, 24, 160-169.
Burr, M.L., Butland, B.K., King, S. and Vaughan-Williams, E. (1989) "Changes in asthma prevalence: two surveys 15 years apart", Arch Dis Child, 64, 1452-1456.
Burr, M.L., Wat, D., Evans, C., Dunstan, F.D. and Doull, I.J. (2006) "Asthma prevalence in 1973, 1988 and 2003", Thorax, 61, 296-299.
Chalubinski, M. and Kowalski, M.L. (2006) "Endocrine disrupters--potential modulators of the immune system and allergic response", Allergy, 61, 1326-1335.
76
Choi, H., Schmidbauer, N., Sundell, J., Hasselgren, M., Spengler, J. and Bornehag, C.G. (2010) "Common household chemicals and the allergy risks in pre-school age children", PLoS One, 5, e13423.
Christianson, A.L., Chesler, N. and Kromberg, J.G. (1994) "Fetal valproate syndrome: clinical and neuro-developmental features in two sibling pairs", Dev Med Child Neurol, 36, 361-369.
Commission of the European Communities: White Paper (2001) Strategy for a Future Chemical Policy (COM2001 88 final, 2001). http://www.societechimiquedefrance.fr/IMG/pdf/LivreBlancEU-REACH-01-2.pdf, Brussels.
Cookson, H., Granell, R., Joinson, C., Ben-Shlomo, Y. and Henderson, A.J. (2009) "Mothers' anxiety during pregnancy is associated with asthma in their children", J Allergy Clin Immunol, 123, 847-853 e811.
Croen, L.A., Grether, J.K., Yoshida, C.K., Odouli, R. and Van De Water, J. (2005) "Maternal autoimmune diseases, asthma and allergies, and childhood autism spectrum disorders: a case-control study", Arch Pediatr Adolesc Med, 159, 151-157.
Daniels, J.L. (2006) "Autism and the environment", Environ Health Perspect, 114, A396. Dik, N., Tate, R.B., Manfreda, J. and Anthonisen, N.R. (2004) "Risk of physician-diagnosed asthma in
the first 6 years of life", Chest, 126, 1147-1153. Eagan, T.M., Gulsvik, A., Eide, G.E. and Bakke, P.S. (2004) "The effect of educational level on the
incidence of asthma and respiratory symptoms", Respir Med, 98, 730-736. Ekerljung, L., Sundblad, B.M., Ronmark, E., Larsson, K. and Lundback, B. (2010) "Incidence and
prevalence of adult asthma is associated with low socio-economic status", Clin Respir J, 4, 147-156.
Ellwood, P., Asher, M.I., Beasley, R., Clayton, T.O. and Stewart, A.W. (2005) "The international study of asthma and allergies in childhood (ISAAC): phase three rationale and methods", Int J Tuberc Lung Dis, 9, 10-16.
Engman, L.H., Bornehag, C.G. and Sundell, J. (2007) "How valid are parents' questionnaire responses regarding building characteristics, mouldy odour, and signs of moisture problems in Swedish homes?" Scand J Public Health, 35, 125-132.
Fatemi, S.H., Reutiman, T.J., Folsom, T.D., Huang, H., Oishi, K., Mori, S., Smee, D.F., Pearce, D.A., Winter, C., Sohr, R. and Juckel, G. (2008) "Maternal infection leads to abnormal gene regulation and brain atrophy in mouse offspring: implications for genesis of neurodevelopmental disorders", Schizophr Res, 99, 56-70.
Fergusson, D.M., Woodward, L.J. and Horwood, L.J. (1998) "Maternal smoking during pregnancy and psychiatric adjustment in late adolescence", Arch Gen Psychiatry, 55, 721-727.
Fombonne, E. (1999) "The epidemiology of autism: a review", Psychol Med, 29, 769-786. Fombonne, E. (2003) "The prevalence of autism", Jama, 289, 87-89. Fombonne, E. (2005) "Epidemiology of autistic disorder and other pervasive developmental disorders",
J Clin Psychiatry, 66 Suppl 10, 3-8. Gillberg, C., Cederlund, M., Lamberg, K. and Zeijlon, L. (2006) "Brief report: "the autism epidemic".
The registered prevalence of autism in a Swedish urban area", J Autism Dev Disord, 36, 429-435.
Gina (2006) The Global Initiativ For Asthma Report:Global Strategy for Asthma Management and Prevention, Available from http://ginaasthma.org.
Grandjean, P. and Landrigan, P.J. (2006) "Developmental neurotoxicity of industrial chemicals", Lancet, 368, 2167-2178.
Groholt, E.K., Stigum, H., Nordhagen, R. and Kohler, L. (2003) "Health service utilization in the Nordic countries in 1996: Influence of socio-economic factors among children with and without chronic health conditions", Eur J Public Health, 13, 30-37.
Gustafsson, H. and Lundgren, N. (1997) Off-gassing from bilding materials; a survey of case studies, In: Brune, D., Gerhardsson, G., Crockford, G. W. and D'auria, D. (eds) The Workplace, Vol. 1, Geneva: International Labour Office, Fundamentals of Health, Safety and Welfare, 533-555.
Hagerhed-Engman, L., Bornehag, C.G. and Sundell, J. (2009) "Building characteristics associated with moisture related problems in 8,918 Swedish dwellings", Int J Environ Health Res, 19, 251-265.
Han, J.C., Lawlor, D.A. and Kimm, S.Y. (2010) "Childhood obesity", Lancet, 375, 1737-1748.
77
Henderson, A.J., Sherriff, A., Northstone, K., Kukla, L. and Hruba, D. (2001) "Pre- and postnatal parental smoking and wheeze in infancy: cross cultural differences", Eur Respir J, 18, 323-329.
Henderson, A.J. (2008) "What have we learned from prospective cohort studies of asthma in children?" Chron Respir Dis, 5, 225-231.
Hertz-Picciotto, I., Croen, L.A., Hansen, R., Jones, C.R., Van De Water, J. and Pessah, I.N. (2006) "The CHARGE study: an epidemiologic investigation of genetic and environmental factors contributing to autism", Environ Health Perspect, 114, 1119-1125.
Hertz-Picciotto, I., Park, H.Y., Dostal, M., Kocan, A., Trnovec, T. and Sram, R. (2008) "Prenatal exposures to persistent and non-persistent organic compounds and effects on immune system development", Basic Clin Pharmacol Toxicol, 102, 146-154.
Hertz-Picciotto, I. and Delwiche, L. (2009) "The rise in autism and the role of age at diagnosis", Epidemiology, 20, 84-90.
Honda, H., Shimizu, Y., Imai, M. and Nitto, Y. (2005) "Cumulative incidence of childhood autism: a total population study of better accuracy and precision", Dev Med Child Neurol, 47, 10-18.
Hultman, C.M., Sparen, P. and Cnattingius, S. (2002) "Perinatal risk factors for infantile autism", Epidemiology, 13, 417-423.
Hwang, H.M., Park, E.K., Young, T.M. and Hammock, B.D. (2008) "Occurrence of endocrine-disrupting chemicals in indoor dust", Sci Total Environ, 404, 26-35.
Hägerhed-Engman, L., Sigsgaard, T., Samuelson, I., Sundell, J., Janson, S. and Bornehag, C.G. (2009) "Low home ventilation rate in combination with moldy odor from the building structure increase the risk for allergic symptoms in children", Indoor Air, 19, 184-192.
Indredavik, M.S., Brubakk, A.M., Romundstad, P. and Vik, T. (2007) "Prenatal smoking exposure and psychiatric symptoms in adolescence", Acta Paediatr, 96, 377-382.
Iom (2004) Damp Indoor Spaces and Health, Washington DC., The National Academy Press. Jaakkola, J.J., Jaakkola, N. and Ruotsalainen, R. (1993) "Home dampness and molds as determinants of
respiratory symptoms and asthma in pre-school children", J Expo Anal Environ Epidemiol, 3 Suppl 1, 129-142.
Jaakkola, J.J., Oie, L., Nafstad, P., Botten, G., Samuelsen, S.O. and Magnus, P. (1999) "Interior surface materials in the home and the development of bronchial obstruction in young children in Oslo, Norway", Am J Public Health, 89, 188-192.
Jaakkola, J.J., Verkasalo, P.K. and Jaakkola, N. (2000) "Plastic wall materials in the home and respiratory health in young children", Am J Public Health, 90, 797-799.
Jaakkola, J.J., Parise, H., Kislitsin, V., Lebedeva, N.I. and Spengler, J.D. (2004) "Asthma, wheezing, and allergies in Russian schoolchildren in relation to new surface materials in the home", Am J Public Health, 94, 560-562.
Jaakkola, J.J., Hwang, B.F. and Jaakkola, N. (2005) "Home dampness and molds, parental atopy, and asthma in childhood: a six-year population-based cohort study", Environ Health Perspect, 113, 357-361.
Jaakkola, J.J. and Knight, T.L. (2008) "The role of exposure to phthalates from polyvinyl chloride products in the development of asthma and allergies: a systematic review and meta-analysis", Environ Health Perspect, 116, 845-853.
James, A.L., Palmer, L.J., Kicic, E., Maxwell, P.S., Lagan, S.E., Ryan, G.F. and Musk, A.W. (2005) "Decline in lung function in the Busselton Health Study: the effects of asthma and cigarette smoking", Am J Respir Crit Care Med, 171, 109-114.
Jarbrink, K. (2007) "The economic consequences of autistic spectrum disorder among children in a Swedish municipality", Autism, 11, 453-463.
Johansson, S.G.O., Bieber, T., Dahl, R., Friedmann, P.S., Lanier, B.Q., Lockey, R.F., Motala, C., Ortega Martell, J.A., Platts-Mills, T.A., Ring, J., Thien, F., Van Cauwenberge, P. and Williams, H.C. (2004) "Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003", J Allergy Clin Immunol, 113, 832-836.
Kadesjo, B. and Gillberg, C. (2000) "Tourette's disorder: epidemiology and comorbidity in primary school children", J Am Acad Child Adolesc Psychiatry, 39, 548-555.
78
Karvonen, A.M., Hyvarinen, A., Roponen, M., Hoffmann, M., Korppi, M., Remes, S., Von Mutius, E., Nevalainen, A. and Pekkanen, J. (2009) "Confirmed moisture damage at home, respiratory symptoms and atopy in early life: a birth-cohort study", Pediatrics, 124, 329-338.
Kielinen, M., Linna, S.L. and Moilanen, I. (2000) "Autism in Northern Finland", Eur Child Adolesc Psychiatry, 9, 162-167.
Kinney, D.K., Munir, K.M., Crowley, D.J. and Miller, A.M. (2008) "Prenatal stress and risk for autism", Neurosci Biobehav Rev, 32, 1519-1532.
Kolarik, B., Bornehag, C.G., Naydenov, K., Sundell, J., Stavova, P. and Faurskov Nielsen, O. (2008a) "The concentration of phthalates in settled dust in Bulgarian homes in relation to building characteristic and cleaning habits in the family", Atmos Environ, 42, 8553-8559.
Kolarik, B., Naydenov, K., Larsson, M., Bornehag, C.G. and Sundell, J. (2008b) "The association between phthalates in dust and allergic diseases among Bulgarian children", Environ Health Perspect, 116, 98-103.
Kozyrskyj, A.L., Mai, X.M., Mcgrath, P., Hayglass, K.T., Becker, A.B. and Macneil, B. (2008) "Continued exposure to maternal distress in early life is associated with an increased risk of childhood asthma", Am J Respir Crit Care Med, 177, 142-147.
Kull, I., Bohme, M., Wahlgren, C.F., Nordvall, L., Pershagen, G. and Wickman, M. (2005) "Breast-feeding reduces the risk for childhood eczema", J Allergy Clin Immunol, 116, 657-661.
Lai, C.K., Beasley, R., Crane, J., Foliaki, S., Shah, J. and Weiland, S. (2009) "Global variation in the prevalence and severity of asthma symptoms: phase three of the International Study of Asthma and Allergies in Childhood (ISAAC)", Thorax, 64, 476-483.
Landa, R.J. (2008) "Diagnosis of autism spectrum disorders in the first 3 years of life", Nat Clin Pract Neurol, 4, 138-147.
Landrigan, P., Garg, A. and Droller, D.B. (2003) "Assessing the effects of endocrine disruptors in the National Children's Study", Environ Health Perspect, 111, 1678-1682.
Lannero, E., Wickman, M., Pershagen, G. and Nordvall, L. (2006) "Maternal smoking during pregnancy increases the risk of recurrent wheezing during the first years of life (BAMSE)", Respir Res, 7, 3.
Larsen, S.T., Hansen, J.S., Hansen, E.W., Clausen, P.A. and Nielsen, G.D. (2007) "Airway inflammation and adjuvant effect after repeated airborne exposures to di-(2-ethylhexyl)phthalate and ovalbumin in BALB/c mice", Toxicology, 235, 119-129.
Larsson, L. (1995) "Incidence of Asthma in Swedish Teenagers - Relation to Sex and Smoking-Habits", Thorax, 50, 260-264.
Leech, J.A., Nelson, W.C., Burnett, R.T., Aaron, S. and Raizenne, M.E. (2002) "It's about time: A comparison of Canadian and American time-activity patterns", J Expo Anal Environ Epidemiol, 12, 427-432.
Levy, S.E., Mandell, D.S. and Schultz, R.T. (2009) "Autism", Lancet, 374, 1627-1638. Liberatos, P., Link, B.G. and Kelsey, J.L. (1988) "The measurement of social class in epidemiology",
Epidemiol Rev, 10, 87-121. Lindbaek, M., Wefring, K.W., Grangard, E.H. and Ovsthus, K. (2003) "Socioeconomical conditions as
risk factors for bronchial asthma in children aged 4-5 yrs", Eur Respir J, 21, 105-108. Lindbaek, M., Wefring, K.W. and Bjerkedal, T. (2005) "[Chronic diseases among and social benefits to
four-to-five-year-old children]", Tidsskr Nor Laegeforen, 125, 2362-2365. Linnet, K.M., Dalsgaard, S., Obel, C., Wisborg, K., Henriksen, T.B., Rodriguez, A., Kotimaa, A.,
Moilanen, I., Thomsen, P.H., Olsen, J. and Jarvelin, M.R. (2003) "Maternal lifestyle factors in pregnancy risk of attention deficit hyperactivity disorder and associated behaviors: review of the current evidence", Am J Psychiatry, 160, 1028-1040.
Litonjua, A.A., Carey, V.J., Burge, H.A., Weiss, S.T. and Gold, D.R. (1998) "Parental history and the risk for childhood asthma. Does mother confer more risk than father?" Am J Respir Crit Care Med, 158, 176-181.
Lombardo, L.J. and Balmes, J.R. (2000) "Occupational asthma: a review", Environ Health Perspect, 108 Suppl 4, 697-704.
Lorente, F., Isidoro, M., Davila, I., Laffond, E. and Moreno, E. (2007) "Prevention of allergic diseases", Allergol Immunopathol (Madr), 35, 151-156.
79
Main, K.M., Skakkebaek, N.E., Virtanen, H.E. and Toppari, J. (2010) "Genital anomalies in boys and the environment", Best Pract Res Clin Endocrinol Metab, 24, 279-289.
Mandell, D.S., Novak, M.M. and Zubritsky, C.D. (2005) "Factors associated with age of diagnosis among children with autism spectrum disorders", Pediatrics, 116, 1480-1486.
Martinez, F.D. (2008) "Gene-environment interaction in complex diseases: asthma as an illustrative case", Novartis Found Symp, 293, 184-192; discussion 192-187.
Mendell, M.J. (2007) "Indoor residential chemical emissions as risk factors for respiratory and allergic effects in children: a review", Indoor Air, 17, 259-277.
Mendola, P., Selevan, S.G., Gutter, S. and Rice, D. (2002) "Environmental factors associated with a spectrum of neurodevelopmental deficits", Ment Retard Dev Disabil Res Rev, 8, 188-197.
Milgrom, H. (2006) "Childhood asthma: breakthroughs and challenges", Adv Pediatr, 53, 55-100. Monaco, A.P. and Bailey, A.J. (2001) "Autism. The search for susceptibility genes", Lancet, 358 Suppl,
S3. Morgan, W.J., Stern, D.A., Sherrill, D.L., Guerra, S., Holberg, C.J., Guilbert, T.W., Taussig, L.M.,
Wright, A.L. and Martinez, F.D. (2005) "Outcome of asthma and wheezing in the first 6 years of life: follow-up through adolescence", Am J Respir Crit Care Med, 172, 1253-1258.
Moshammer, H., Hoek, G., Luttmann-Gibson, H., Neuberger, M.A., Antova, T., Gehring, U., Hruba, F., Pattenden, S., Rudnai, P., Slachtova, H., Zlotkowska, R. and Fletcher, T. (2006) "Parental smoking and lung function in children: an international study", Am J Respir Crit Care Med, 173, 1255-1263.
Newschaffer, C.J. and Curran, L.K. (2003) "Autism: an emerging public health problem", Public Health Rep, 118, 393-399.
Norrman, E., Nystrom, L., Jonsson, E. and Stjernberg, N. (1998) "Prevalence and incidence of asthma and rhinoconjunctivitis in Swedish teenagers", Allergy, 53, 28-35.
O'roak, B.J. and State, M.W. (2008) "Autism genetics: strategies, challenges, and opportunities", Autism Res, 1, 4-17.
Oddy, W.H., Holt, P.G., Sly, P.D., Read, A.W., Landau, L.I., Stanley, F.J., Kendall, G.E. and Burton, P.R. (1999) "Association between breast feeding and asthma in 6 year old children: findings of a prospective birth cohort study", Bmj, 319, 815-819.
Odhiambo, J.A., Williams, H.C., Clayton, T.O., Robertson, C.F. and Asher, M.I. (2009) "Global variations in prevalence of eczema symptoms in children from ISAAC Phase Three", J Allergy Clin Immunol, 124, 1251-1258 e1223.
Oie, L., Hersoug, L.G. and Madsen, J.O. (1997) "Residential exposure to plasticizers and its possible role in the pathogenesis of asthma", Environ Health Perspect, 105, 972-978.
Oie, L., Nafstad, P., Botten, G., Magnus, P. and Jaakkola, J.K. (1999) "Ventilation in homes and bronchial obstruction in young children", Epidemiology, 10, 294-299.
Pattenden, S., Antova, T., Neuberger, M., Nikiforov, B., De Sario, M., Grize, L., Heinrich, J., Hruba, F., Janssen, N., Luttmann-Gibson, H., Privalova, L., Rudnai, P., Splichalova, A., Zlotkowska, R. and Fletcher, T. (2006) "Parental smoking and children's respiratory health: independent effects of prenatal and postnatal exposure", Tob Control, 15, 294-301.
Pearce, N., Douwes, J. and Beasley, R. (2000) "The rise and rise of asthma: a new paradigm for the new millennium?" J Epidemiol Biostat, 5, 5-16.
Pearce, N. and Douwes, J. (2006) "The global epidemiology of asthma in children", Int J Tuberc Lung Dis, 10, 125-132.
Pearce, N., Ait-Khaled, N., Beasley, R., Mallol, J., Keil, U., Mitchell, E. and Robertson, C. (2007) "Worldwide trends in the prevalence of asthma symptoms: phase III of the International Study of Asthma and Allergies in Childhood (ISAAC)", Thorax, 62, 758-766.
Peroni, D.G., Piacentini, G.L., Alfonsi, L., Zerman, L., Di Blasi, P., Visona, G., Nottegar, F. and Boner, A.L. (2003) "Rhinitis in pre-school children: prevalence, association with allergic diseases and risk factors", Clin Exp Allergy, 33, 1349-1354.
Posserud, M.B., Lundervold, A.J. and Gillberg, C. (2006) "Autistic features in a total population of 7-9-year-old children assessed by the ASSQ (Autism Spectrum Screening Questionnaire)", J Child Psychol Psychiatry, 47, 167-175.
80
Previc, F.H. (2007) "Prenatal influences on brain dopamine and their relevance to the rising incidence of autism", Med Hypotheses, 68, 46-60.
Robertson, C.F., Roberts, M.F. and Kappers, J.H. (2004) "Asthma prevalence in Melbourne schoolchildren: have we reached the peak?" Med J Aust, 180, 273-276.
Rodier, P.M. (2004) "Environmental causes of central nervous system maldevelopment", Pediatrics, 113, 1076-1083.
Roel, E., Olsen Faresjö, Å., Kjellman, N.-I.M. and Faresjö, T. (1999) "Cumulative incidence of asthma diagnosis at the age of seven in a birth cohort", Eur J Gen Pract, 5, 71-74.
Rothman, K.J. and Greenland, S. (2005) "Causation and causal inference in epidemiology", Am J Public Health, 95 Suppl 1, S144-150.
Rudel, R.A. and Perovich, L.J. (2009) "Endocrine disrupting chemicals in indoor and outdoor air", Atmos Environ, 43, 170-181.
Rutter, M. (2005) "Incidence of autism spectrum disorders: changes over time and their meaning", Acta Paediatr, 94, 2-15.
Rönmark, E. (2002) "Incidence rates and risk factors for asthma among school children: A 2-year follow-up. Report from the Obstructive Lung Disease in Northern Sweden (OLIN) studies", Respir Med, 96, 1006-1013.
Sahlberg, B., Mi, Y.H. and Norback, D. (2009) "Indoor environment in dwellings, asthma, allergies, and sick building syndrome in the Swedish population: a longitudinal cohort study from 1989 to 1997", Int Arch Occup Environ Health, 82, 1211-1218.
Sathyanarayana, S., Karr, C.J., Lozano, P., Brown, E., Calafat, A.M., Liu, F. and Swan, S.H. (2008) "Baby care products: possible sources of infant phthalate exposure", Pediatrics, 121, e260-268.
Schultz Larsen, F., Diepgen, T. and Svensson, A. (1996) "The occurrence of atopic dermatitis in north Europe: an international questionnaire study", J Am Acad Dermatol, 34, 760-764.
Seppanen, O.A. and Fisk, W.J. (2004) "Summary of human responses to ventilation", Indoor Air, 14 Suppl 7, 102-118.
Shaaban, R., Zureik, M., Soussan, D., Neukirch, C., Heinrich, J., Sunyer, J., Wjst, M., Cerveri, I., Pin, I., Bousquet, J., Jarvis, D., Burney, P.G., Neukirch, F. and Leynaert, B. (2008) "Rhinitis and onset of asthma: a longitudinal population-based study", Lancet, 372, 1049-1057.
Sjoberg, A. and Ramnas, O. (2007) "An experimental parametric study of VOC from flooring systems exposed to alkaline solutions", Indoor Air, 17, 450-457.
Smedje, G. and Norback, D. (2001) "Incidence of asthma diagnosis and self-reported allergy in relation to the school environment - a four-year follow-up study in schoolchildren", Int J Turberc Lung Dis, 5, 1059-1066.
Spector, S. (2001) "The linkage between rhinitis, sinusitis and asthma", Clinical and Applied Immunology Reviews, 1, (229-234).
Spergel, J.M. (2010) "From atopic dermatitis to asthma: the atopic march", Ann Allergy Asthma Immunol, 105, 99-106; quiz 107-109, 117.
Stahlhut, R.W., Van Wijngaarden, E., Dye, T.D., Cook, S. and Swan, S.H. (2007) "Concentrations of urinary phthalate metabolites are associated with increased waist circumference and insulin resistance in adult U.S. males", Environ Health Perspect, 115, 876-882.
Stenton, S.C. (2010) "Occupational and environmental lung disease: occupational asthma", Chron Respir Dis, 7, 35-46.
Stoloff, S.W. (2008) "Asthma management and prevention: current perspectives", Clin Cornerstone, 8, 26-43.
Strachan, D.P. (1989) "Hay fever, hygiene, and household size", Br Med J, 299, 1259-1260. Strachan, D.P. (2000) "Family size, infection and atopy: the first decade of the "hygiene hypothesis"",
Thorax, 55 Suppl 1, S2-10. Stromland, K. and Miller, M.T. (1993) "Thalidomide embryopathy: revisited 27 years later", Acta
Ophthalmol (Copenh), 71, 238-245. Tilson, H.A. (1998) "Developmental neurotoxicology of endocrine disruptors and pesticides:
identification of information gaps and research needs", Environ Health Perspect, 106 Suppl 3, 807-811.
81
Wadhwa, P.D. (2005) "Psychoneuroendocrine processes in human pregnancy influence fetal development and health", Psychoneuroendocrinology, 30, 724-743.
Wakschlag, L.S., Pickett, K.E., Cook, E., Jr., Benowitz, N.L. and Leventhal, B.L. (2002) "Maternal smoking during pregnancy and severe antisocial behavior in offspring: a review", Am J Public Health, 92, 966-974.
Van Odijk, J., Kull, I., Borres, M.P., Brandtzaeg, P., Edberg, U., Hanson, L.A., Host, A., Kuitunen, M., Olsen, S.F., Skerfving, S., Sundell, J. and Wille, S. (2003) "Breastfeeding and allergic disease: a multidisciplinary review of the literature (1966-2001) on the mode of early feeding in infancy and its impact on later atopic manifestations", Allergy, 58, 833-843.
Wang, S., Ang, H.M. and Tade, M.O. (2007) "Volatile organic compounds in indoor environment and photocatalytic oxidation: state of the art", Environ Int, 33, 694-705.
Warren, C.W., Jones, N.R., Peruga, A., Chauvin, J., Baptiste, J.P., Costa De Silva, V., El Awa, F., Tsouros, A., Rahman, K., Fishburn, B., Bettcher, D.W. and Asma, S. (2008) "Global youth tobacco surveillance, 2000-2007", MMWR Surveill Summ, 57, 1-28.
Weiland, S.K., Bjorksten, B., Brunekreef, B., Cookson, W.O., Von Mutius, E. and Strachan, D.P. (2004) "Phase II of the International Study of Asthma and Allergies in Childhood (ISAAC II): rationale and methods", Eur Respir J, 24, 406-412.
Weiss, B. and Landrigan, P.J. (2000) "The developing brain and the environment: an introduction", Environ Health Perspect, 108 Suppl 3, 373-374.
Wengholt Johnsson, H. (1995) Kemisk emission från golvsystem -effekt av olika betongkvalitet och fuktbelastning (in Swedish). Tekn Dr, Chalmers University of Technology, Institutionen för byggnadsmaterial. P-95:4.
Weschler, C.J., Wells, J.R., Poppendieck, D., Hubbard, H. and Pearce, T.A. (2006) "Workgroup report: Indoor chemistry and health", Environ Health Perspect, 114, 442-446.
Weschler, C.J. and Nazaroff, W.W. (2008) "Semivolatile organic compounds in indoor environments", Atmospheric Environment, 42, 9018-9040.
Who (2009) Dampness and mould; WHO guidelines for indoor air quality, World Health Organization. Wickman, M. (2009) Definitioner och epidemiologi (in Swedish), In: Hedlin, G. and Larsson, K. (eds)
Allergi och astma, Lund, Studentlitteratur. Willemsen, G., Van Beijsterveldt, T.C., Van Baal, C.G., Postma, D. and Boomsma, D.I. (2008)
"Heritability of self-reported asthma and allergy: a study in adult Dutch twins, siblings and parents", Twin Res Hum Genet, 11, 132-142.
Williams, G.M., O'callaghan, M., Najman, J.M., Bor, W., Andersen, M.J., Richards, D. and U, C. (1998) "Maternal cigarette smoking and child psychiatric morbidity: a longitudinal study", Pediatrics, 102, e11.
Von Mutius, E. (2007) "Allergies, infections and the hygiene hypothesis--the epidemiological evidence", Immunobiology, 212, 433-439.
Wong, G.W. and Chow, C.M. (2008) "Childhood asthma epidemiology: insights from comparative studies of rural and urban populations", Pediatr Pulmonol, 43, 107-116.
Wormuth, M., Scheringer, M., Vollenweider, M. and Hungerbuhler, K. (2006) "What are the sources of exposure to eight frequently used phthalic acid esters in Europeans?" Risk Anal, 26, 803-824.
Yeargin-Allsopp, M., Rice, C., Karapurkar, T., Doernberg, N., Boyle, C. and Murphy, C. (2003) "Prevalence of autism in a US metropolitan area", Jama, 289, 49-55.
Yuksel, H., Dinc, G., Sakar, A., Yilmaz, O., Yorgancioglu, A., Celik, P. and Ozcan, C. (2008) "Prevalence and comorbidity of allergic eczema, rhinitis, and asthma in a city in western Turkey", J Investig Allergol Clin Immunol, 18, 31-35.
Yunginger, J.W., Reed, C.E., O'connell, E.J., Melton, L.J., 3rd, O'fallon, W.M. and Silverstein, M.D. (1992) "A community-based study of the epidemiology of asthma. Incidence rates, 1964-1983", Am Rev Respir Dis, 146, 888-894.
Åberg, N. (1993) "Familial occurrence of atopic disease: genetic versus environmental factors", Clin Exp Allergy, 23, 829-834.
Karlstad University StudiesISSN 1403-8099
ISBN 978-91-7063-324-9
Indoor Environmental Factors
and Chronic Diseases in
Swedish Pre-School Children
The aim of this thesis has been to investigate environmental factors in ho-mes and their impact on asthma, rhinitis, eczema as well as autism spectrum disorders in children, and to identify certain methodological difficulties in epidemiological investigations.
We found that the mean incidence rate per year for doctor diagnosed asthma was in the range of 0.6-2.4% and for doctor diagnosed rhinitis in the range of 1.1-3.7%. The incidence rate of eczema ever was 2.7%. The results show that when establishing a cohort after birth the estimated incidence rates are dependent of how the baseline population’s health and how the studied health outcome at follow-up is defined.
Our results show that the associations between parental reported moisture problems in the home and asthma in children, which were revealed in cross-sectional analyses, decreased or disappeared when longitudinal data were used. Our results therefore indicate that associations between parental reported moisture problems and asthma from cross-sectional questionnaire studies should be interpreted with caution due to the risk for reporting bias.
Finally, the results indicate that PVC-flooring in the bedrooms was associated to development of asthma as well as autism spectrum disorders. These results indicate that environmental factors such as building materials including suspec-ted endocrine disrupting chemicals such as phthalates might be of importance for the development of these chronic diseases. Further studies are needed to explore early life exposure and the mechanisms and contribution of phthalates in the development of diseases.