The cohort of young Danish farmers – A longitudinal study of the health effects of farming exposure

Abstract

Working in agriculture poses a serious risk for development of respiratory diseases, especially when working in animal housing. Animal workers are exposed to a mixture of organic and inorganic dust together with fumes and gases, including allergens and microbial-associated molecular patterns with a potentially major impact on respiratory health and the immune system. Exposure to microbial agents in animal housing is associated with an increased prevalence of respiratory symptoms, including bronchial hyperresponsiveness, accelerated lung function decline, and neutrophil-mediated inflammation. These clinical findings are often seen without IgE-mediated sensitization. In fact it has been found in recent studies that the prevalence of atopic sensitization and atopic asthma is low among farmers compared with other populations. The SUS study was designed to identify the type and occurrence of respiratory symptoms and disease, and to investigate risk factors for respiratory disorders and changes in lung function among young farming students. The cohort of young Danish farmers was established in 1992/1994 and followed up in 2007/2008 with a participation rate of 51.7%. The cohort consists of 1734 male farming students, 230 female farming students, and 407 army recruits as controls.

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The cohort of young Danish farmers – A
longitudinal study of the health effects of farming
exposure
Grethe Elholm1,2
Øyvind Omland1,2
Vivi Schlünssen1
Charlotte Hjort3
Ioannis Basinas1
Torben Sigsgaard1
1Department of Environmental and
Occupational Medicine, Institute of
Public Health, Aarhus University;
2Department of Occupational Health,
Aalborg Hospital, Aarhus University
Hos pital; 3Regional Hospital Viborg,
Skive, Kjellerup
Correspondence: Grethe Elholm
Institute of Public Health, Department
of Environmental and Occupational Health,
Aarhus University, Bartholins Alle 2,
Building 1260, 8000 Aarhus C, Denmark
Tel +45 22112044
Fax +45 89426199
Email gelh@mil.au.dk
Abstract: Working in agriculture poses a serious risk for development of respiratory diseases,
especially when working in animal housing. Animal workers are exposed to a mixture of organic
and inorganic dust together with fumes and gases, including allergens and microbial-associated
molecular patterns with a potentially major impact on respiratory health and the immune system.
Exposure to microbial agents in animal housing is associated with an increased prevalence of
respiratory symptoms, including bronchial hyperresponsiveness, accelerated lung function
decline, and neutrophil-mediated inflammation. These clinical findings are often seen without
IgE-mediated sensitization. In fact it has been found in recent studies that the prevalence of atopic
sensitization and atopic asthma is low among farmers compared with other populations. The SUS
study was designed to identify the type and occurrence of respiratory symptoms and disease,
and to investigate risk factors for respiratory disorders and changes in lung function among
young farming students. The cohort of young Danish farmers was established in 1992/1994 and
followed up in 2007/2008 with a participation rate of 51.7%. The cohort consists of 1734 male
farming students, 230 female farming students, and 407 army recruits as controls.
Keywords: respiratory health, atopy, asthma, rhinitis, lung function, farming environment,
occupational exposure, cohort study
Introduction
The farming industry is an important export industry in Denmark, as well as in many
other Western countries. Investigation of the occupational health hazards of farming
is therefore of considerable interest to both the farming industry and the Danish
community. Despite major changes in farming during recent decades, and an increased
awareness of the potential hazards from agricultural exposure, the risk of lung diseases
and loss of lung function in farm workers is still considerable.1
Working in agriculture poses a serious risk for development of respiratory diseases,
especially when working in animal housing. Animal housing workers are exposed
to a mixture of organic and inorganic dust together with fumes and gases, including
allergens and microbial-associated molecular patterns (MAMP) with a potentially
major impact on respiratory health and the immune system.2,3
Respiratory health effects in farming, especially in swine-confinement work-
ers are well described. Exposure to microbial agents in a swine-confinement
environment is associated with an increased prevalence of respiratory symptoms,
including bronchial hyperresponsiveness (BHR), accelerated lung function decline,
and neutrophil-mediated inflammation,2,4 without IgE-mediated sensitization
against swine and food allergens. In fact, it has been found in recent studies that
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the prevalence of atopic sensitization and atopic asthma
is low in farmers compared with other populations. A low
prevalence of allergy and allergic asthma has been found
in studies of children5 and young adults6 born and raised
on a farm,6 as well as in adult farmers exposed to the same
environment.7,8 The general respiratory health of any farmer
is also dependent on individual genetic makeup. It has been
found that toll-like receptor (TLR) gene polymorphisms
are important determinants of susceptibility to asthma and
allergy.9 TLRs are an evolutionarily conserved group of
molecules which are a part of the innate immune system.
TLRs are expressed in antigen-presenting cells and epithe-
lial cells, and have microbial molecules as ligands.10
The SUS study was designed to identify the type and
occurrence of respiratory symptoms, measure lung function,
and investigate risk factors for respiratory disorders and
annual rates of change in lung function among young farm-
ing students. Data were analyzed both as a cross-sectional
study at baseline and as part of a case-control follow-up
study over five years.
Most of the research in this area has been in the form of
cross-sectional studies. Few cohort studies have been reported
thus far and, to our knowledge, no studies have addressed the
respiratory health of people entering the farming industry at a
young age. Although sensitization to storage mites and other
airborne allergens has been described, reports on sensitization
to hog antigens have been inconclusive concerning the extent
to which allergies contribute to the increased prevalence of
respiratory symptoms in farm workers.
In an attempt to clarify the contribution of farming expo-
sure to respiratory disease and loss of lung function over time,
the SUS study was followed up with the SUS12 study. During
the SUS12 study, the initial SUS cohort was re-examined.
The SUS12 follow-up study in combination with the origi-
nal data from the SUS study now allows for longitudinal
investigation of risk factors and occupational influence on
the development of respiratory disease. Furthermore, it is
possible to investigate potential gene-environment interac-
tions related to farming exposure. The SUS project group is
collaborating with the European research group GABRIEL,
which is focusing on genes important for asthma and gene-
environment interactions among children and working adult
populations, using a whole genome analysis and candidate
gene approach (http://www.gabriel-fp6.org/).
Despite the wealth of research on sensitisation, lung dis-
ease, and lung function done in farm workers in the last three
decades, important questions remain unanswered. There is
no unequivocal documentation of which dust components in
the exposure have adverse health effects. Incidence studies
of health outcomes which include reliable, representative,
and valid exposure assessments have yet to be published.
Incidence studies with asthma and COPD as outcomes still
need to be performed. The question of phenotypes and geno-
types of asthma and the association with exposure is yet to
be fully answered. There is currently no knowledge of any
time window for the “protective effect” of being raised on a
farm regarding sensitisation, inflammation, and lung disease.
Does childhood exposure to rural allergens confer an overall
protection, or does the individual experience an increase in
sensitization with time in a dose-dependent manner? Does the
protective effect of farming exposure on allergic sensitization
continue over time? Additionally, how can a supposed high
allergen exposure convey loss of sensitization? What is the
association between changes in sensitization and the risk
of respiratory disorders? What influence does occupational
activation of MAMPs have on the diseases encountered in
farming?
Trial design
This research included both a cohort study which was a cross-
sectional comparison of type and occurrence of respiratory
symptoms in farming students and nonfarming rural controls
and a longitudinal study which investigated new cases of respi-
ratory disease over time in relation to farming exposure.
Study population
The cross-sectional study consisted of 2478 farming students
identified during their second stay at the farming schools in
Denmark during the period February 1992 to February 1994.
of 2004 students (81%) who indicated that they wished to
participate, 40 (2%) did not attend for their baseline clini-
cal assessment. The final group consisted of 1734 male and
230 female farming students. Army recruits were invited to
participate as controls, provided that they came from rural
areas but were not planning on becoming farmers. There
were 967 eligible army recruits of whom 592 (61%) agreed
to participate. A random sample of 407 of these recruits
were chosen and used in the study. The demographics of the
cohort are presented in Table 1 and their lung function and
respiratory symptoms are summarized in Table 2.
Follow-up
The subjects were investigated at baseline and then followed
up with annual questionnaires and phone interviews for
five years. All new respiratory symptoms were recorded.
All subjects reporting new asthma symptoms and a matched

Clinical Epidemiology 2010:2 47
The cohort of young danish farmers
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control group without symptoms were offered a clinical
assessment to establish a diagnosis. In 2007 a comprehensive
follow-up of the cohort was done using the Danish Civil
Registration System to track new addresses, deaths, and
emigration in the cohort. Of the 2371 participants, 2262 were
identified to have a new Danish address, while 26 had died,
and 51 had emigrated or did not have a permanent address.
Thirty-two subjects could not be identified, most often
because of incorrect registration of their unique personal
identity number during the baseline study.
Measurements
Health outcome
At baseline the original SUS questionnaire was used, and
in SUS12 this was extended to include further questions
from the European Community Respiratory Health Survey
(http://www.ecrhs.org). Lung function was measured
with a dry bellow spirometer and with a spirometer
(MicroMedical®; Lyngby Denmark). For the SUS12 study the
software was transferred for use on portable computers using
the Windows 2000 platform. BHR was recorded according to
the Yan method11 with a calibrated DeVilbiss No 40 nebulizer
(Devilbiss Healthcare, LLC, Johnstown, PA, USA) con-
nected to an “artificial hand” which uses compressed air to
produce a pressure pulse similar to that created by a hand.12
For skin prick tests (SPT), a panel of nine common inhalant
allergens (grass, mugwort, horse, dog, cat, house dust mites,
moulds [Alternaria alternata and Claudosporium herbarum],
extended with three storage mites [Tyrophagus putres-
centiae, Lepidoglyphus destructor, and Acarus siro], and
swine and cow dander were used (Soluprick®, ALK-Abello,
Copenhagen, Denmark).
Exposure data
At baseline and annually for five consecutive years, ques-
tionnaire information about the number and type of housed
animals and amount of work done in these settings was
recorded for all subjects in the cohort. In the case-control
Table 1 Demographic and exposure characteristics of the cohort (n = 2,371)
Female students
(n = 232)
Male students
(n = 1734)
Male controls
(n = 405)
Demographics
Age (yrs)§19.1 (17–47) 18.5 (17–49) 19.0 (18–23)
Height (cm)§169 (149–192) 183 (161–198) 181 (166–197)
Smokers* 73 (32) 554 (32) 136 (34)
Exposures
Hours farm work/week§37 (0–72) 40 (0–100) 0 (0–65)
Work with swine* 67 (29) 433 (25) 10 (3)
Work with cattle* 66 (28) 575 (34) 18 (4)
Work with swine and cattle* 22 (10) 231 (13) 13 (3)
Field work* 89 (39) 1125 (66) 64 (16)
Notes: §Median (min – max), *n (%).
Table 2 Lung function and respiratory symptoms in the cohort
Female students Male students Male rural controls
Smokers
(n = 73)
Non-smokers
(n = 159)
Smokers
(n = 554)
Non-smokers
(n = 1180)
Smokers
(n = 136)
Nonsmokers
(n = 269)
Lung function mean (SD)
FEV13.49 (±0.47) 3.61 (±0.55) 4.57 (±0.58) 4.64 (±0.61) 4.75 (±0.59) 4.70 (±0.65)
FVC 4.04 (±0.55) 4.14 (±0.67) 5.48 (±0.68) 5.42 (±0.72) 5.57 (±0.69) 5.50 (±0.78)
Respiratory symtoms N (%)
Asthma 5 (6.8) 10 (6.3) 35 (6.3) 46 (3.9) 4 (2.9) 11 (4.1)
BHR 6 (8.5) 15 (9.8) 66 (12.2) 94 (8.2) 9 (7.2) 22 (8.5)
Hayfever 14 (19.2) 20 (12.6) 48 (8.7) 109 (9.3) 18 (13.2) 42 (15.6)
§Median (min – max), *(n) may vary due to missing values (%).
Abbreviation: BHR, bronchial hyperresponsiveness.

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study, detailed hygienic information was recorded on,
eg, type of feeding systems, type of litter, use of respirators,
and cleaning procedures.
In SUS12, a more comprehensive exposure assessment
including personal measurements and exposure modeling has
been applied. One hundred farms were randomly selected
and stratified by type and size in a defined geographical
area among the remaining active farming population of the
initial SUS cohort. Approximately 250 farmers employed in
the selected farms have been monitored during the summer
and winter of 2008–2009. Full-shift personal inhalable dust
samples (one in each season) are being collected on 37 mm
glass fiber filters using GSP sampling heads at a flow rate of
3.5 L/min from every farmer. Concurrently, farmers are asked
to fill in a detailed diary regarding their working activities
for one week in each period (14 days in total). Walk-through
surveys and personal interviews are performed to collect
information on technical parameters and farm characteristics
with known or suspected influence on the levels of expo-
sure. Models on associations between technical parameters,
farm characteristics, working tasks and exposure (dust and
MAMPs) including within- and between-worker variabil-
ity will be developed using regression analysis based on
linear mixed-effect models. The derived equations will be
used along with questionnaire data on historical exposure
and exposure information from two previous studies13,14 to
estimate current and retrospective exposure in the follow-up
study.
Completeness of follow-up
The cohort consists of 2371 participants; for the SUS12 study,
only 2262 of these could be identified with an address in
Denmark, because some of the participants had immigrated,
died, or were simply lost to follow-up. Of the identifiable par-
ticipants, only 1170 were available to be re-examined, represent-
ing an overall attrition rate of 51.7%, which was attributable to
several reasons, including subjects choosing not to participate in
the follow-up study, failure to attend for their follow-up appoint-
ment, and/or not responding to letters or phone calls.
Ongoing release of data
The SUS study has so far lead to the publication of 13 peer-
reviewed articles,6,15–26 one thesis,27 and several presentations
at international conferences. An overview of the 13 articles
and the main findings is summarised in Table 3.
The study showed that sensitisation to mites, animal
dander, and pollen was higher in controls than in farming
school students.16 Analyses published in 2002 demon-
strated a lower prevalence of allergic symptoms, BHR, and
sensitisation measured with skin prick test, and specific
Table 3 Published articles originating from the SUS study
References Main ndings
15 The resistance of the mini-Wright ow meter causes less variation in recordings but reduce peak expiratory ow.
16 Skin prick tests to house dust and storage mites were more prevalent among controls compared with male and female
farming students; size of house dust mite weal and number of positive skin prick reactions were associated with BHR.
17 No relation between asthma and farming exposure was seen, but lung function was slightly reduced in the male
farming students compared with male controls. Prevalence of asthma was related to smoking, female sex, and family
history of asthma and allergy.
18 The shape of the maximum expiratory ow-volume curve reects exposure in farming.
19 S and Z α1-antitrypsin alleles are risk factors for BHR in young farmers indicating a gene/environment interaction.
20 LDS using FEV1 is the best spirometric index to measure short time repeatability of histamine bronchial testing.
6 Farming students born and raised on a farm had lower prevalence of allergic symptoms, BHR, positive SPT, and
specic IgE than students raised on a farm.
21 Selenium measured both in serum and urine is associated with mild asthma and atopy.
22 For asthmatics the time domain index α175 was found to discriminate better among the ow indices applied
whereas for BHR the LDS using FEV1 was superior to other measures of BHR.
23 CD3 levels in young farmers correlate with respirable dust exposure levels during work in swine-connement housing.
24 Exposure to work-related levels of swine dust upregulates CD106 in human alveolar macrophages.
25 A single exposure to organic dust in non-naïve nonexposed volunteers induces long lasting symptoms of endotoxin
tolerance.
26 CD14/-260 and CD14/-651 promoter polymorphisms associated with atopy prevalence in young adults with farm
exposure.
Abbreviations: BHR, bronchial hyperresponsiveness; LDS, log dose slope; SPT, skin prick test.

Clinical Epidemiology 2010:2 49
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and total IgE in subjects raised on a farm, compared with
upbringing elsewhere.6 As opposed to a possible protective
effect of being raised on a farm, low concentrations of alpha-
1 antitrypsin and rare genotypes (ZZ, ZS, SS) were found
to increase the risk of BHR, but only among the farming
students, indicating a gene-environment interaction for the
inflammatory asthma phenotype.19 Preliminary analyses
using available exposure data from other sources have found
a dose-response relationship between estimated exposure to
total dust and new onset of asthma.28 Furthermore, the preva-
lence of chronic bronchitis, self-reported asthma with BHR,
and BHR was low. The prevalence of self-reported asthma
without BHR was high. Lung function was slightly lower in
male farming students compared with controls. There was
a weak or no association between smoking and respiratory
symptoms as well as lung function. It was found that FEV1
was the best index to measure basal lung function in response
to bronchial provocation.
The SUS study has contributed significantly to our
understanding of the inflammatory mechanisms involved
in the immune response to organic dust exposure. This was
investigated by exposing the participants for three hours
to a swine-confinement environment containing dust and
endotoxin levels at the lower end of the exposure range for
Danish and European farms. It was found that dust exposure
activated the complement system. Particularly for the farm-
ing students, C3d plasma levels correlated with respirable
dust. Acute exposure was also seen to lead to other weak
systemic inflammatory responses.23 Further dust exposure
studies suggest that there is a specific requirement for CD106
during inflammatory recruitment of monocytes in the human
lung,24 and this has previously been shown to be the case in
the murine lung. Endotoxin tolerance has previously been
described in vitro and in animal studies as a mechanism that
modifies the threshold at which immune response occurs. It
has also been found that long-lasting endotoxin tolerance
and immune suppression may be induced by brief exposure
to dust concentrations in the medium-low range of occupa-
tional levels.25
The SUS study has furthermore been used to investigate
the correlation between selenium levels and asthma and
atopy. It was found that selenium in serum and urine is
associated with mild asthma and atopy.21
The longitudinal study provides data for investigating the
incidence of respiratory disease in a farming environment.
These data will also enable investigation of the interactions
between genes and the environment and elucidation of the
risk factors involved in the development of new asthma
cases. It will also be possible to investigate the effects
of respiratory diseases on lung function, and identify the
parameters that describe this change best. Finally it would
be helpful to be able to estimate the effect of respiratory
symptoms and disease on change of work environment for
the individual.
Strengths and weaknesses
The SUS cohort affords a unique opportunity for a longitu-
dinal investigation of the effect of farming exposure on lung
function and respiratory symptoms. To our knowledge, this
cohort is unique. As already mentioned, lung function and
respiratory symptoms have been assessed in all study partici-
pants in both at the SUS and the SUS12. It will also be pos-
sible using these data to assess respiratory health in relation
to specific farming exposure for each subject. Additionally,
important information on potential gene-environment interac-
tion is emerging from this research through the GABRIEL
collaboration. However, a potential weakness of this research
is the relatively high attrition rate of approximately 50%,
which might affect the significance of data generated by
future statistical analyses.
Access to data
A website has been created (http://www.folkesundhed.au.dk/
mil/forskning/sus12), where the status of the SUS12 project
is regularly updated. Specific questions regarding the cohort
or the SUS12 project can be addressed to either Professor
Torben Sigsgaard (ts@mil.au.dk), Associate Professor Vivi
Schlünssen (vs@mil.au.dk), Associate Professor Øyvind
Omland (oo@rn.dk), or Senior Consultant Charlotte Hjort
(c.hjort@dadlnet.dk).
Acknowledgments
The cohort study was set up by Charlotte Hjort, Torben Sigs-
gaard and Øyvind Omland from The Institute of Public Health
at University of Aarhus, Denmark. Funding for the SUS
study was from The Danish Agency for Science Technology
and Innovation, The Danish Medical Research Council, The
Danish Agricultural Research Council, Helsefonden, and the
PC Petersen Foundation. In SUS12 Vivi Schlünssen joined
the core group. The main contributors for the SUS12 study
were The Danish Working Environment Research Fund,
The Danish Research Council Aarhus University, and The
Danish Lung Association. The authors wish to thank the
farming students and the control subjects for their patience
and enthusiasm, and the staff of the farming schools for their
ongoing support.

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