Inflammation Clinical Trial
Official title:
Exposure to Aerosols and Airway Inflammation Among Workers in the Silicon Carbide Processing Industry
Exposure to noxious gases and particles is associated with an increased prevalence of
respiratory and cardiovascular diseases. Thus, investigation of possible airway inflammation
and/or systemic inflammation in workers exposed to high levels of dust is important. Silicon
Carbide (SiC) Processing Inc. provides cutting fluid (slurry) for the production of solar
cells and is at present the largest provider of slurry to the solar industry worldwide. In
the production process, the recyclable materials (SiC), polyethylene glycol (PEG)) of the
used slurry are recovered. The airborne exposure consists mainly of SiC (dust particles) and
evaporation from the recycling of PEG. High levels of dust have been measured and, seventeen
per cent of the measurements in the processing hall were equal to or higher than the
Norwegian occupational exposure limit. Thus, assessment of possible systemic and airway
effects of this exposure is of interest. A prospective design will be applied and the
effects studied by means of registration of respiratory symptoms, spirometry, nitric oxide
(NO) in exhaled air, induced sputum and blood sampling over a 3 year period. Exposed
subjects will also be compare with non- or low exposed subjects (administrative/office
workers). Efforts will be made to include all eligible subjects and to avoid drop-outs. If
early signs of airway or systemic inflammation in workers or in cells are demonstrated in
the study, it will be necessary to implement measures to reduce the exposure levels.
The primary aim of the present study of workers exposed to Silicon Carbide dust in the
workplace is to determine whether this exposure is associated with inflammatory changes in
the lungs.
The secondary aims are: - to examine possible changes in systemic inflammatory markers and -
to examine changes in lung function among Silicon Carbide processing workers during a period
of 3 years. Possible changes in lung function will be monitored by spirometry and gas
diffusion measurements (study A). Airway inflammatory responses and changes in circulating
inflammatory markers will be assessed by examination of the induced sputum samples and blood
samples every 6th month in a subgroup of workers (study B).
Does exposure to aerosols induce airway inflammation and/or a systemic inflammatory response
in workers in the silicon carbide (SiC) processing industry?
As yet, no human studies describing the health effects from exposure during recycling of
slurry containing SiC and/or PEG have been reported. However, there are several studies that
may be relevant which assess the health effects of other particles. It has been demonstrated
that small particles penetrate further into the lungs than larger particles and thereby have
stronger irritating properties [2]. Results from 2 experimental studies where the effect
variables were lung function, organ weights and characteristics of broncho-alveolar lavage
(BAL) [3, 4] indicate that SiC dust and PEG itself are probably relatively inert. However,
in a third study it was demonstrated that SiC particles have the potential to stimulate test
cells (murine macrophage cell line and human osteoblast-like cell line) to produce
inflammatory signal substances (tumour necrosis factor (TNF)-alfa), indicating possible
inflammatory responses in the lungs [5]. Furthermore, it is thought that the total amount of
inhaled dust is important ("overload") even if the substance itself is relatively inert [6].
Repeated high exposures (peaks) may act as a reinforcing factor.
Because there are few previous studies, and the available data are conflicting, there is a
need for more knowledge about the association between health effects and exposure to
particles in general and to exposure in the SiC processing industry in particular.
Our hypothesis is that airway inflammation may be induced by exposure to SiC particles and
would probably be detectable as increased levels of inflammatory cells and soluble
inflammatory markers in the sputum and blood samples from non-smoking, asymptomatic workers.
The primary aim of the present study of workers exposed to SiC dust in the work-place is to
determine whether this exposure is associated with inflammatory changes in the lungs.
The secondary aims are:
- to examine possible changes in systemic inflammatory markers, and
- to examine changes in lung function among SiC-processing workers over a period of 3
years.
Possible changes in lung function will be monitored by spirometry measurements (study A).
Airway inflammatory responses and changes in circulating inflammatory markers will be
assessed by examination of the induced sputum samples and blood samples in a subgroup of
workers (study B).
General value An important goal of the study is to provide knowledge that can be important
for workers who are exposed to particles and aerosols in the SiC-processing industry or
other industries processing SiC and/or PEG. The study may also be relevant to workers in
other industries with dusty environments given the possible "overload" mechanisms. The study
could possibly also have the potential to provide additional knowledge about effects of
exposure to similar particles e.g from air pollution. Because few former studies have used
induced sputum in a prospective design, such studies are of particular interest.
If early signs of lung inflammation or a decrease in lung function are demonstrated in the
present study, it will be necessary to implement additional measures to reduce the dust
levels in this industry; e.g., through enclosure of processes. The investigators believe
that the results from this study together with the existing knowledge of inflammatory
effects associated with occupational exposure to particles may be relevant for the
prevention of chronic respiratory disease.
III - Study design and methods Study population In the present study, the effects of
exposure to aerosols on airway inflammation and systemic inflammation will be investigated
by means of spirometry, FeNO, induced sputum and blood sampling over a three-year period.
Study A: The whole group of workers will complete a questionnaire on respiratory symptoms
and undergo spirometry at baseline, and again after 3 years. All former workers will be
contacted and asked to complete a questionnaire to assess the proportion of workers
resigning because of (or partly because of) health effects. These workers will also be
invited to undergo an examination of lung function (spirometry). This is to ensure that all
workers ever employed are included in the study population.
Study B: A subgroup comprising non-smokers will in addition be followed with blood samples,
induced sputum tests and exposure measurements every 6 months over the same time period.
Controls: Exposed subjects will be compared with non- or low-exposed subjects
(administrative/office workers). In addition to the prospective study, the investigators
will compare the baseline findings from the sputum and blood samples with those from already
established external control groups from previous studies on healthy non-exposed workers and
from cement production workers from the same geographic area [7].
Exposure-response analyses: Workers will be divided into groups with different exposure
levels in order to study exposure-response trends of the measured agents in the exposed
population (this design is less vulnerable to selection effects).
Baseline examinations will be repeated for all subjects and for the sputum subgroup.
Detailed, validated questionnaires will record the medical history, relevant illnesses, use
of medications, occupational history as well as present exposures.
Spirometry will allow registration of lung function and FeNO measurements the monitoring of
possible airway inflammation.
A group-based strategy will be applied for the collection of exposure measurements at
baseline and at follow-up (3 years) for the subjects not included in the sputum part of the
study.
Induced sputum collection will be applied to detect possible changes in inflammatory cells
and soluble markers from the airways.
Blood analysis will be collected to examine possible changes in circulating inflammatory
markers and their association to exposure.
All participants in the sputum subgroup will carry individual exposure measurement.
The employees who leave the cohort will contribute with data while they are employed
(defined as time-at-risk) and a drop-out test will be performed to determine whether they
experienced work-related respiratory symptoms or diseases. New employees will be included
during the study period and assigned a time-at-risk equal to their time of exposure.
Exposure measurement and assessment The dust/aerosol samples will be collected with the use
of thoracic and inhaled respirable cyclones to estimate the doses for the deposition in the
bronchi and in the alveoli.
Validity Factors that may affect lung function and inflammatory markers in sputum Age,
height, BMI and sex will be recorded for the study. Height in meters will be entered into
the computer program for calculating spirometry values. Weight (body mass index) affects
lung function and will be measured before the examination. The investigators will also
record possible acute respiratory infections during the preceding 12 months. An upper
respiratory infection during the preceding three weeks may affect the level of inflammatory
cells and markers in sputum.
There is a possibility that very early inflammatory effects among these workers could be
succeeded by adaptation and thereby reduction of effects. In this case, the inflammatory
response at some time after employment could be smaller than observed initially. This may
lead to underestimation of effects. The investigators consider that a dynamic cohort design
including only subjects exposed for the first time in this industry is not feasible.
However, a follow-up of three years is considered sufficient to detect clinically relevant
changes. The cohort in this study will also have a relatively short prior employment in the
industry because the plants were opened in 2006 and 2009. Spirometry screening of all
workers, performed during the first days of employment at the local health services, is
available. These will be compared with the baseline recordings to evaluate possible effects
prior to inclusion in the present study.
Statistical analysis and study power
The associations to be studied are individual changes in the effect variables:
- the trend over the study period (study A: baseline and 36 months for the whole group of
workers; study B for the sputum subgroup: baseline, 6, 12, 24 and 36 months), and
- between exposed and controls (exposed and unexposed/administrative staff/office
workers) at baseline and differences in trend during the study period.
T tests will be used to compare cases and controls at baseline for normally distributed
variables, and a Mann-Whitney test for non-normally distributed variables. Where multiple
tests are to be conducted, ANOVA and Kruskal-Wallis tests will be applied prior to the
pairwise comparisons to determine the overall significance level.
Multiple regression models with adjustment for age, sex, smoking habits and other relevant
factors for each analysis will be applied when adjusting for other factors at baseline.
To analyse the repeated measures, general linear models (GLM) and mixed models will be used.
The power calculations are based on clinically interesting differences in percentage of
neutrophils and spirometry values. The study is designed to include at least 20 participants
in each group based on a power estimate of 90%, which assumes a 95% significance level, to
detect a true difference in the percentage neutrophils between two tests of at least 16%.
Power calculation for FEV1 and FVC% of predicted: if the goal is to detect a difference of
1.5% in FEV1 and FVC% predicted, then given a standard deviation of 5% the sample must
consist of 117 persons in each group. This will ensure 90% power to detect a difference at
the 5% significance level.
It is expected that the response rate among non-smokers will allow approximately 40
employees and 20 unexposed workers to be included in the sputum part of the study (study B).
Based on the power calculations, prior experience and published studies, this will be enough
to detect a difference in development between the two groups of the expected magnitude. In
total, 150 workers are employed at SiC I and II (to be included in study A). It is planned
to include the employees at Glomfjord (Nordland) SiC processing if the sample size from
Porsgrunn is not sufficient. To ensure sufficient unexposed workers, the neighbouring
Renewable Energy Corporation (REC) plant will be used to recruit controls if needed. The REC
plant started production at about the same time and has a similar work-force to the study
group.
VI - Ethical aspects It is considered that the purpose of the study and the methods being
used do not violate generally accepted ethical values. Participation in the project is
voluntary. Collection of biological material and information will take place with the
participants' consent. All participants will sign consent forms after receiving written
information about the survey. Participants will at any time have the opportunity to withdraw
from the study without giving a reason.
According to an agreement with the SIC- processing, the research fellow and project group
can freely publish the results of the survey. The project is not financially dependent on
grants from the industry, and the industry (SIC) financing of the project is limited to the
exposure monitoring.
;
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