The question of whether occupational asbestos exposure is an under-
recognized cause of idiopathic pulmonary fibrosis arises because it is
clinically and epidemiologically plausible, and consistent with fibre studies,
case-control, and toxicological data. This thesis examines the question by
means of a literature review and a novel hospital based case-control study,
the idiopathic pulmonary fibrosis job exposures study (IPFJES).

In a literature review and meta-analysis of studies reporting on occupational
exposures in idiopathic pulmonary fibrosis (IPF) I found significant associ-
ations with metal, wood, and stone dust, but not asbestos. However, there
was considerable heterogeneity and confidence in the meta-analysis result
is tempered by a high risk of bias arising from selection, lack of blinding,
exposure misclassification, incomplete exposure data, and selective report-
ing of exposures. In a mortality analysis I found that the UK incidence of
IPF continues to rise and appears to be correlated with mesothelioma mor-
tality. I did not find clear evidence of an association between IPF, pleural
mesothelioma, and asbestosis at a regional level.

In a critical review of methods for assessing occupational asbestos exposure
I found support for the use of a job exposure matrix based on proportional
mortality rates for mesothelioma and validated by quantification of asbestos
fibre lung burden. I also found support for using a structured interview tool
to provide a quantitative estimate of previous exposure which was validated
using historic and simulated exposure data.

In a review of MUC5b and IPF I found evidence supporting a common
MUC5b driven pulmonary fibrosis endotype and a candidate mechanism for
3occupational asbestos exposure contributing to this; alveolar macrophage
NLRP3 inflammasome activation resulting in increased IL-1 β driven airway
MUC5b expression.

Occupational asbestos exposure alone was not associated with IPF in IPF-
JES. It was associated with dyspnoea independent of smoking and case
status. It was associated with IPF in participants who also had smoking
exposure and the strength of this association was greatest for participants
with the minor allele of the MUC5b promoter variant rs3505950 and when
a stricter case definition (definite UIP rather than definite UIP or possible
UIP) was used.

These studies suggest that occupational asbestos exposure in smokers, cou-
pled with genetic susceptibility factors, may be an important cause of IPF.