Nontobacco-Related Lung Carcinogenesis

Lung cancer is estimated to cause 17,000 to 26,000 deaths
among nonsmokers annually in the United States. 1 Secondhand
smoke exposure explains some deaths among nonsmokers, but
many deaths are unrelated to tobacco smoke. Occupational and
environmental exposures and genetic characteristics have been
identified as risk factors for the development of lung cancer in
both smokers and nonsmokers. In this chapter, we review important
toxicants, other than tobacco, for which the evidence for
pulmonary carcinogenic potential is strong and the population
health effects data support a causal relationship between exposure
and lung cancer. These toxicants share the common feature of
being respirable carcinogens, but otherwise have widely different
physicochemical characteristics. The substances include minerals
(asbestos and silica), radioactive gas (radon), and products of
fossil fuel combustion (diesel-exhaust particles).
Historically, occupational settings have been among the
most important sources of exposure to the nontobacco pulmonary
carcinogens. Accordingly, many cases of lung cancer
attributable to nontobacco carcinogens are work related and,
in turn, preventable. Moreover, we review data on some exposures
mainly encountered in industrial settings, which are most
persuasively linked with lung cancer. It is important to note,
however, that since the beginning of the 20th century, an estimated
85,000 chemicals have been introduced into industrial
applications, many of which may be encountered in respirable
states. 2 Data on the carcinogenic potential of most of these
chemicals are limited or nonexistent. Some cases of lung cancer
may be attributable to occupational or environmental exposures
yet to be recognized as carcinogenic. However, such
speculation should not alter the fact that strategies to reduce
the total burden of lung cancer worldwide must remain sharply
focused on preventing exposure to established pulmonary carcinogens,
including tobacco and nontobacco exposures.
ARSENIC
Arsenic is a naturally occurring element found throughout the
earth’s crust. Inorganic arsenic complexes are used predominantly
to preserve wood, whereas organic arsenic is used in pesticides.
In addition, arsenic trioxide (arsenite) is used in the treatment of
promyelocytic leukemia.
Concerns over the potential carcinogenicity of arsenic were
first raised as early as 1820 when Paris 3 first described its association
with skin cancer. In 1930, Saupe 4 described two cases
of lung cancer in association with arsenic exposure. Since then,
a large amount of data has been published linking arsenic and
lung cancer in humans. Blot and Fraumeni Jr 5 uncovered an increased
risk of lung cancer–related mortality in smelter workers
exposed to arsenic trioxide between 1938 and 1963. Tokudome
and Kuratsune 6 found a significantly increased mortality rate
from lung cancer in copper smelters employed at a metal
refinery in Japan between 1949 and 1971. The average latency
period for lung cancer was 37.6 years and was unrelated to the
estimated levels of arsenic exposure. Rencher et al. 6a conducted
a retrospective mortality study at a copper smelter in Utah and
demonstrated that 7% of all worker deaths were caused by lung
cancer compared to 2.7% in the state of Utah and 2.2% at the
smelter’s associated mine and concentrator. Other investigators
have confirmed the association between lung cancer and working
directly with copper smelters.7–11 Other studies have found
increased risks of lung cancer in association with exposure to
pesticides containing inorganic arsenic 12,13 and even the use of
arsenic as a medicinal. 14 Of note, Guo et al. 15 concluded arsenic
exposure is most strongly associated with the development
of either squamous cell or small cell lung cancer.
Most studies assumed that only inhalational exposures are
associated with arsenic-related lung cancer. However, along
the southwest and northeast coasts of Taiwan, in the Niigata
Prefecture of Japan, in Northern Chile, and in Bangladesh,
ground water is heavily contaminated by arsenic, and its ingestion
has been associated with increased incidences of lung cancer.
16–20 Chen et al. 21 evaluated the dose–response relationship
between ingested arsenic and lung cancer risk as it relates to
smoking. They found an increase in the relative risk of lung cancer
of 3.29 (95% confidence interval [CI], 1.60, 2.78) among
populations exposed to the highest (700 g/L) relative to the
lowest ( 10 g/L) arsenic levels in drinking water. In addition,
after the instillation of a tap-water system in southwestern
Taiwan, lung cancer mortality declined, further bolstering the
likely relationship between ingested arsenic and lung cancer. 22
The most significant confounding factor in these studies of
arsenic and lung cancer is the contribution of smoking. Some
more recent studies have tried to adjust for the effect of smoking
and have demonstrated a persistent carcinogenic effect of
arsenic. 23 In addition, a synergistic interaction between arsenic
and smoking likely exists as suggested by Pershagen et al. 24 This
study evaluated Swedish copper smelter workers and found that
the age-standardized rate ratio for lung cancer death in arsenicexposed
nonsmokers was 3.0. Among those smokers without
occupational arsenic exposure, the ratio was 4.9. In arsenicexposed
smokers, the age-standardized rate ratio for lung cancer
was 14.6. 24 A metaanalysis by Hertz-Picciotto et al. 25 and
the previously described study by Chen et al. 21 also support a
synergistic effect.
Nonoccupational exposure to copper smelters (i.e., residential
proximity) may also pose a carcinogenic risk. However,
most studies failed to establish a statistically significant link
within this setting suggesting that arsenic alone may either be
a weak carcinogen or may require a cocarcinogen to induce the
development of cancer. 26–28
Reviews of the literature suggest that the average latency
for lung cancer diagnosis after exposure to arsenic is about
30 years. In addition, arsenic-related pulmonary malignancies
appear to have a predilection for the upper lobes. 29 All histologic
cell types are represented in arsenic-related lung cancer
and the relative frequencies of each cell type seem to mimic
that of the general nonexposed population. 30,31
Animal data supporting a carcinogenic role for arsenic are
limited. Ishinishi et al. 32 found that intratracheal instillation
of three forms of arsenic (copper ore, flue dust, and arsenic
trioxide) to Wistar-King rats was associated with the formation
of lung adenomas and/or adenocarcinomas. In another
publication, Ishinishi et al. 33 demonstrated a 10% to 30% lifetime
risk of lung adenocarcinoma in Syrian golden hamsters
after weekly intratracheal instillation of 3.75 or 5.25 mg of
arsenic trioxide. Ivankovic et al. 34 demonstrated the induction
of multifocal bronchogenic adenocarcinomas and bronchoalveolar
cell carcinomas in 9 of 15 (60%) rats after intratracheal
instillation of 0.1 mL of a vineyard pesticide containing calcium
arsenate. Soucy et al. 35 found dose-dependent effects
of arsenic trioxide on animal models of angiogenesis, as well
as melanoma tumor growth and metastasis. Interestingly, the
form of arsenic appears to influence the risk of lung cancer in
animal studies. Specifically, calcium arsenate appears to have
the strongest tumorigenic potential, whereas arsenic trioxide is
of questionable carcinogenicity. 36,37
Arsenic has been shown to induce preneoplastic changes in
human fetal lung tissue. 38 The mechanism behind such changes
may lie in arsenic-induced overmethylation of DNA. Mass and
Wang 39 found that exposure of human lung adenocarcinoma
A549 cells to sodium arsenite or sodium arsenate resulted in a
significant level of methylation of a fragment of p53, a tumor
suppressor gene. This may alter the function of p53 as a checkpoint
in the cell cycle permitting eventual transformation into
an immortal cell line. Other mouse studies have suggested that
arsenic augments the ability of the tobacco-derived carcinogen,
benzo(a)pyrene, to increase the number of DNA adducts in
both skin and lung, the initiation step in mutagenesis. 40
In 1980, the International Agency for Research on Cancer
(IARC) concluded that the available human data were sufficient
to implicate arsenic as a pulmonary carcinogen. In October
2001, the U.S. Environmental Protection Agency (EPA) announced
that on January 2006, a permissible exposure limit
(PEL) of 10 ppb in drinking water would be enforced. 41
The National Institute for Occupational Safety and
Health (NIOSH) has established a PEL of 2 g/m 3 during
a 15-minute ceiling, whereas the Occupational Safety
and Health Administration (OSHA) has established a PEL
of 10 g/m 3 during any 8-hour period for a 40-hour workweek.
Potential household exposures to arsenic through ant
pesticides containing sodium arsenate and arsenic-treated
pressurized wood prompted the EPA to begin phasing out
these products in 1989.
ASBESTOS
Asbestos, derived from a Greek adjective meaning inextinguishable
or unquenchable, is a naturally occurring mineral used
widely in the 20th century for its insulating and corrosionand
fire-resistant properties. In the late 1800s, the British
discovered that asbestos fibers could be woven into textiles
permitting its use in everything from brake pads to ship boiler
insulators. 42 Asbestos had already been in use for centuries, and
its associated adverse health effects had been recognized since
at least the time of the Roman Empire when Pliny the Elder, a
Roman citizen, noticed that slaves working in asbestos mines
succumbed early to lung diseases. It was not until the United
Kingdom Annual Report of the Chief Inspector of Factories
in 1898 that the potential deleterious effects of asbestos were
recognized again. 43
Doll 44 published the landmark epidemiologic study linking
lung cancer and asbestos exposure when he evaluated
the autopsy results of 105 employees of an asbestos factory.
Selikoff 45 provided further supportive epidemiologic evidence
after reviewing the medical records of 1522 members of the
asbestos workers unions in New York City and New Jersey.
Wagner et al. 46 and Newhouse et al. 47 determined that even
casual nonoccupational exposure to asbestos was sufficient to
cause lung cancer by recognizing epidemics of mesothelioma
among communities surrounding asbestos mines and neighborhoods
located near asbestos textile mills.
Recent reports suggest that the mutagenic effect of asbestos
involves proto-oncogenes, such as k- ras 48 and c- ras, 49 as well as
tumor suppressor genes, such as p53. Nelson et al. 50 found a
fivefold increase in the presence of k- ras mutations in patients
diagnosed with lung adenocarcinoma who had occupational
asbestos-exposure history compared to those patients with lung
cancer without exposure history. Panduri et al. 51 found that p53
induces alveolar epithelial cell apoptosis in cells damaged by
asbestos exposure. Supporting the important protective role of
p53, Morris et al. 52 demonstrated a fivefold increase in the incidence
of asbestos-associated lung cancer in mice after disrupting
intrinsic p53 function. Additional findings include alterations in
the insulin receptor pathway and associated downregulation of
deleted in colorectal cancer (DCC) gene, KU70, and heat shock
protein 27. 53 The effects of these gene alterations are the constitutive
expression of proteins promoting cell division and the
downregulation or removal of proteins involved in checkpoints
during the cell cycle.
Possible mechanisms by which asbestos damages DNA
appear to involve the production of reactive oxygen species
and the activation of mitogen-activated protein kinases. Iwata
et al. 54 detected the generation of reactive oxygen species by
polymorphonuclear lymphocytes after exposure to anthophyllite
asbestos fibers. Schabath et al. 55 demonstrated that homozygotes
for the G-myeloperoxidase allele (G/G) exhibited an
increased risk of asbestos-related lung cancer (odds ratio [OR]
1.72, 95% CI, 1.09 to 2.66) compared to those subjects with
G/A and A/A genotypes. Another possible mechanism proposed
by MacCorkle et al. 56 involves the interaction of asbestos
fibers with cell’s cytoskeletal proteins or proteins involved
in cell division resulting in an increase in aneuploid cells.
Another theory regarding the carcinogenicity of asbestos
hypothesizes that the asbestos fiber’s role is to facilitate the introduction
of other carcinogens like those in cigarette smoke
to cells. The fibers do so by adhering to surfactant, which then
creates a lipid bilayer permitting solubilization of hydrophobic
carcinogens such as polycyclic hydrocarbons. This would then
permit long-term high concentration exposure of the lung
epithelium to carcinogenic substances. 57–59
The latency period for the development of asbestos- related
lung cancer is in excess of 20 years. 60 Asbestos has been linked to
all cell types of lung cancer. 61 The risk of lung cancer in persons
exposed to asbestos seems to depend on the fiber type (greater
with nonchrysotile fibers even though chrysotile exposure is associated
with lung cancer), 62 fiber size (greater with longer fibers), 63
exposure environment (greater in textile than in cement industries),
and evidence of asbestosis on chest radiograph (greater in
patients with opacities). 64–66 The estimated risk of lung cancer
in some studies is about fivefold compared to the nonexposed
general population. Smoking acts synergistically with asbestos
and increases the risk of lung cancer almost 50-fold. 45,67
The Asbestos Regulations of 1931 were the first attempt
to regulate asbestos exposure in the workplace. Unfortunately,
the permitted exposure levels were based on a study of workers
at a North Carolina asbestos factory, all of whom had
been employed for less than 10 years. Another methodologic
problem occurred when about 150 workers were fired prior
to the initiation of the study because of concerns that they
may have had asbestosis. The Asbestos Regulations of 1969 decreased
the permitted exposure level 15-fold to 2 fibers/mL of
air. However, a company physician untrained in epidemiology
based this “safe” level of exposure on an industry-sponsored
study. In 1994, the United States lowered the “safe” exposure
level to 0.1 fibers/mL of air, whereas Great Britain banned the
use of the substance altogether in 1999. In 2001, the World
Trade Organization stated that no safe level of asbestos exposure
existed. 68 In 1973, the IARC concluded that asbestos was
a human lung carcinogen. 69
As of year 2000, based on data obtained from death certificates
in the United Kingdom, deaths from asbestos-related lung
cancer and mesothelioma continue to rise. The implication is
that those exposed to the substance over the preceding 20 to
40 years will continue to be at risk for developing lung and/or
pleural cancers despite cessation of exposure. 42
Recognition that asbestos is the underlying etiology of a
patient’s illness should prompt physicians to make the appropriate
notifications. In addition, it would be prudent to instruct
the patient on the importance of avoiding further exposure to
asbestos preferably by changing jobs or using protective respiratory
equipment.
Asbestos-Related Mesothelioma Asbestos is the predominant
cause of mesothelioma worldwide. In about two
thirds of cases, an asbestos-exposure history is present. The
risk of mesothelioma varies with the duration and intensity of
exposure, as well as the type of asbestos fiber inhaled (highest
with amosite and crocidolite). The latency period for mesothelioma
is at least 25 to 30 years, and there have been reports
of cases occurring more than 40 years after exposure. 70
Diagnosis often requires open-lung biopsy and unfortunately,
mesotheliomas are notorious for growing along needle tracts
and through surgical incisions. The most important step in
evaluating a possible mesothelioma involves distinguishing it
from benign mesothelioma, primary bronchogenic adenocarcinomas,
and metastatic disease given the potentially different
treatment options and outcomes.
BERYLLIUM
Beryllium is a naturally occurring element found in soil, rocks,
coal, and oil. It was first discovered more than 2 centuries
ago but was not widely used in industry until the 1940s and
1950s. Beryllium can withstand extreme heat, remain stable
over a wide range of temperatures, and act as an excellent
thermal conductor. It also enhances other metals when combined
with them as alloys. It is essential for numerous items
used in our day-to-day activities. Electrical connections in our
cell phones, battery contacts, high-definition and cable television,
power steering, electronic ignition systems, and air bag
sensors are all modern-day systems and/or appliances that rely
on beryllium to function. Mancuso et al. 71–76 first reported
a potential link between beryllium and human lung cancer
followed by other reports. However, other reports found no
such relationship. 77–82
Early animal studies suggested the possible role of beryllium
in lung cancer; however, the mechanism is still unknown.
83 Studies have attempted to demonstrate a genotoxic
event but have been mostly unsuccessful. 80–82 One study
suggests a potential role for overmethylation of p16, a tumor
suppressor gene; however, further work is needed to clarify its
possible contribution. 84
The varying results of beryllium studies have prompted
four IARC meetings regarding the element’s classification as
a pulmonary carcinogen. In 1993, the working group of the
IARC concluded that the evidence in human studies is sufficient
to implicate beryllium as a carcinogen. The EPA has
established that industries may release a total of 0.01 g of
beryllium per cubic meter averaged over 30 days. The OSHA
has set a PEL of 2 g of beryllium per cubic meter of air over
an 8-hour workday.