Occupational Respiratory Carcinogens

Although smoking is the major cause of lung cancer, other respiratory
tract carcinogens have been identified, or are suspect, and may
enhance the carcinogenic effects of tobacco smoke. Notable
among these independent determinants of lung cancer are
chemical and physical agents that have been identified in the
workplace. An example of an occupational lung cancer was described
in central Europe in the latter part of the 19th century
in underground metal miners. The likely cause of what was described
historically as “mountain disease” has been attributed to
the miners’ inhalation of radon and -emitting radon daughters.
At that time, lung cancer was a rare disease, and the prevalence
of cigarette smoking was low. Other occupational agents classified
as group 1 carcinogens by the IARC include inorganic arsenic,
asbestos, bis(chloromethyl)ether, chromium (hexavalent),
nickel and nickel compounds, polycyclic aromatic compounds
(PAHs), radon, and vinyl chloride (Table 1.5). Group 2A probable
carcinogens included acrylonitrile, beryllium, cadmium,
formaldehyde, acetaldehyde, synthetic fibers, silica, and welding
fumes. Currently, occupational exposures have been estimated
to account for 5% to 15% of lung cancers occurring among
men and women of different cultures and nations. 90
Asbestos The association between asbestos exposure and
lung cancer has been established by epidemiological and animal
experimental studies. It has been estimated that since the beginning
of World War II, up to 8 million persons in the United
States have been exposed to asbestos in the workplace. In the
United States, more than 90% of the production and consumption
of asbestos is represented by the serpentine or curly form
of fiber known as chrysotile (“white asbestos”). The bronchopulmonary
neoplasms of various cell types induced by asbestos
tend to originate peripherally and in the lower lobes, accompanied
frequently by the fibrosis of asbestosis. 91–93
Asbestos is a general term used to describe a variety of
naturally occurring hydrated silicates that produce mineral fibers
upon mechanical processing. In addition to the serpentine
group, there are the amphiboles, a larger family of straight,
needlelike fibers that includes anthophyllite, tremolite, and
amosite (“brown asbestos”), and crocidolite (“blue asbestos”).
Most mesotheliomas are associated with exposure to crocidolite
asbestos. Because of unique physical and chemical properties,
such as noncombustibility, withstanding temperatures of over
5000°C, resistance to acids, high tensile strength, and use in
thermal and acoustic insulation, asbestos has had wide applications
in commercial products. Such products include textiles,
cement, paper, wicks, ropes, floor and roofing tiles, water pipes,
wallboard, fireproof clothing, gaskets, brake linings, etc. 94
Various morphologic, biochemical, and molecular techniques
have been utilized to document events that might be associated
with asbestos toxicity at the cellular level. Prolonged exposure to
asbestos results in the accumulation of macrophages and inflammatory
cells in the alveoli, which is accompanied by the release
of oxygen free radicals, the peroxidation of cell membranes, and
damage to DNA and other macromolecules. Asbestos fibers that
cross the alveolar epithelium may be translocated to the pleura
by macrophages. The shape, length, and persistence of fibers
may be important in eliciting cellular responses intrinsic to carcinogenesis.
Longer, rodlike fibers (i.e., 5 to 10 m in length
and 0.25 m in diameter) appear to be more cytotoxic than
shorter, coarse fibers. Electrostatic charge on the fiber surface may
enhance deposition in lung tissue, and the surface biochemistry
may also impact the inflammatory response. Experimentally, in
tracheobronchial epithelial culture systems, asbestos exhibits the
characteristics of a tumor promoter; chronic exposure to asbestos,
subsequent to the introduction of subcarcinogenic amounts
of dimethyl benzanthracene (DMBA), has resulted in increased
DNA synthesis, basal cell hyperplasia, squamous metaplasia, and
squamous cell carcinoma. In the induction of mesotheliomas and
pleural sarcomas, asbestos is a complete carcinogen.
The risk of lung carcinoma in cigarette smokers has been
examined in several asbestos-exposed populations. In 1968,
Selikoff et al. 93 reported on the effects of combined exposures
to cigarette smoking and asbestos in insulation workers; the RR
for lung cancer significantly exceeded the level of risk expected
if each exposure were to have acted only independently (noninteractively).
The synergy resulting from combined exposures
to tobacco and asbestos has been demonstrated in asbestos
factory workers, Quebec miners and millers, amosite asbestos
factory workers, and Finnish anthophyllite miners and millers.
Although most studies have concluded that the RRs were close
to multiplicative, as in exposures to smoking and radon combined,
a study among Canadian chrysotile miners and millers
concluded that the effect of each agent was independent and
additive. Various sources have concluded that asbestos exposure,
in the absence of tobacco smoking, increases the risk of both
squamous cell carcinoma and adenocarcinoma of the lung. It
is assumed in risk assessment models that the dose–response relationship
may be linear or exponential, and without an apparent
threshold. On the assumption of synergy between asbestos
exposure and tobacco smoking, it has been emphasized that it is
especially important for asbestos-exposed persons to quit smoking
as a cost- effective preventive measure. 95
Mesothelioma has a protracted latency period averaging 35
to 40 years. Unlike carcinoma of the lung, smoking does not contribute
to the development of mesothelioma in asbestos workers.
Statistics on the incidence and mortality of mesothelioma are not
reported routinely because of problems in histopathologic classification
of mesothelial cell hyperplasia and malignant neoplasia
and the distinction from metastatic sarcomas or adenocarcinomas.
A combination of histochemistry, immunocytochemistry,
and electron microscopy may be necessary to achieve a precise
and valid diagnosis. In the SEER program consisting of various
state, county and metropolitan population-based cancer registries
that cover currently about 14% of the total U.S. population,
the average annual age-adjusted incidence of mesothelioma
(per 100,000 population) in white men nearly doubled from
1978 to 1992 (from 1.3 to 2.5), whereas the rates among white
women remained stable at about 0.4. Rates in men aged 75 to
84 years increased from 6.3 to 18.2. In developed countries, approximately
one mesothelioma case occurs concurrently with
100 lung carcinoma cases. The rates in nonwhites were too low
to yield reliable estimates during this period of time. As reported
in other countries, pleural exceeded peritoneal mesotheliomas by
a ratio of 9:1 in men and 3:1 in women. The incidence rates appeared
to have peaked among those born around 1910 and have
declined among cohorts born subsequently. 96
There are well-documented areas of elevated incidence
of mesothelioma, such as the coastal area of Virginia, San
Francisco-Oakland, Hawaii, and Seattle in the United States;
England and Wales; and Japan, where there were shipbuilding
centers; among women in areas where, during World War II,
gas masks with asbestos filters were manufactured; or in South
Africa, where excess mesothelioma incidence was concentrated
in mining districts. Mesotheliomas may result from neighborhood
or environmental (nonoccupational) exposures to asbestos
industries and from household contact with asbestos dust,
primarily through the laundering of work clothing. 97–101
All types of asbestos have the potential for causing mesothelioma,
although the risks in humans are two to four times
more significant for amphibole fibers, such as crocidolite and
amosite, than for the serpentine fibers of chrysotile. The mechanisms
of induction appear related to the physical properties
of fiber size and dimension. The amphibole straight rodlike fibers
can more readily be transported or penetrate to peripheral
segments of the lung. The pathogenesis in mesothelial cells is
accompanied by induced proto-oncogene expression and the
formation of oxygen radical species.
The association between the physical structure of asbestos
fibers and carcinogenicity has raised concerns regarding possible
hazards of other fibers, whether natural or synthetic. Inorganic
synthetic vitreous substances derived from glass, rock, slag,
or clay are used primarily in the manufacture of thermal and
acoustic insulation materials. Intrapleural injection of such fibers
is associated with mesothelioma or sarcoma of the pleura
of laboratory animals. In 1987, the WHO declared that glass
wool, rock wool, slag wool, and ceramic fibers were to be classified
as 2B agents, namely, agents possibly carcinogenic to humans.
This category is generally used for agents for which there
is limited evidence in humans and where there is the absence
of sufficient evidence in experimental animals. Epidemiologic
studies of the association of occupational exposures to synthetic
vitreous fibers and the risk of lung cancer have not shown a
consistent pattern of risk in relation to duration of employment,
average intensity and cumulative exposure dose levels,
or latency interval. Further, many of the studies have not controlled
adequately for confounding by cigarette smoking habits
or exposure to other workplace respiratory carcinogens