CHLOROMETHYL ETHER AND BIS(CHLOROMETHYL) ETHER

Used predominantly in industries to synthesize plastics, organic
chemicals, and exchange resins, chloromethyl methyl ether
(CMME) and an associated impurity, bis(chloromethyl) ether
(BCME) were initially produced and used in this country soon
after the end of World War II. Their potential role as carcinogen
was not realized until 1968 when van Duuren 86 demonstrated
the development of skin cancers in mice after exposing them to
CMME. Leong et al. 87 found that BCME and CMME were
pulmonary carcinogens after exposing A/Heston mice to vapors
of each chemical 6 hours a day, 5 days a week, for a total of 82
to 130 exposure days. Laskin et al. 88 confirmed this inhalation
effect of BCME on rats and hamsters.
The results of these initial animal studies prompted further
human investigation. Albert et al. 89 evaluated lung cancer
mortality at six of the seven U.S. companies that used
CMME at that time. They found a 2.5-fold increase in lung
cancer– related mortality among workers exposed to CMME
choosing nonexposed employees at those same plants as controls.
They also revealed an increase in lung cancer risk with
increasing duration and intensity of exposure. DeFonso et al. 90
found that CMME with 0.5% to 4% BCME resulted in a
3.8-fold increase in lung cancer risk at a Philadelphia chemical
plant, again using employees without an exposure history from
the same plant as controls. Numerous studies have provided
additional evidence supporting CMME and BCME’s role as
pulmonary carcinogens. 91–99
The literature suggests that the latency period for lung
cancer after exposure to BCME and CMME is between 21 to
25 years and is inversely related to exposure intensity and duration.
A predominance of small cell carcinomas (80% to 90% of
cases) is apparent in most studies.
In the 1970s, restrictions in the use of and safer handling
techniques for CMME and BCME were instituted with an apparent
decline in the incidence of associated cases of lung cancer. 99
Currently, the use of these substances is highly restricted, thereby
minimizing potential exposure. BCME breaks down easily and
quickly when exposed to sunlight or water and fortunately, does
not build up in the food chain. Consequently, the only likely
sources of exposure today are living near and/or working in
industries that still use BCME and CMME.
The IARC officially recognized CMME and BCME as
carcinogens in 1987. At this time, the EPA has set a tolerable
limit of 0.0000038 parts of BCME per billion parts of water
(0.0000038 ppb) in lakes and streams. Any release of more
than 10 lb of BCME into the environment must be reported to
the EPA. The OSHA has mandated that no more than 1 ppb
of BCME be present in the air of a work environment. 100
CHROMIUM
Chromium is a naturally occurring mineral found throughout
the environment. It is present in multiple forms and is used in
wood preserving, dyes, chrome plating, leather tanning, and
steel production.
In the United States, recognition of chromium as a potential
pulmonary carcinogen began when the chromate industry
acknowledged a concern over the incidence of lung
cancer among their employees. This prompted Machle and
Gregorius 101 to perform a retrospective mortality study encompassing
the years 1933 through 1946 of employees at seven
different plants located in New Jersey, New York, Maryland,
and Ohio. They compared their findings with mortality data
for industrial policyholders of the Metropolitan Life Insurance
Company for the first 10 months of 1947. They found a 16-
fold increase in the risk of lung cancer mortality among employees
(range 18 to 50). Several ensuing studies have confirmed
the increased risk of lung cancer associated with chromium
exposure in occupations ranging from chromate production to
the use of chromate-based pigments and/or spray paints. 102–113
Masonry, 114,115 hard-chrome plating, 116–118 and stainless steel
production 119 are other occupations associated with chromium
exposure and increased risks of lung cancer.
Regarding oral ingestion of chromium, a systematic review
of the available data does not support a carcinogenic role
for chromium (VI), especially at the current mandated maximal
contamination level in drinking water. 120 No data exists
supporting any increase in lung cancer among residents in
communities surrounding industries, which primarily produce
or utilize chromium. 121
The mean latency period for development of chromiumrelated
lung cancer varies between 13 and 30 years with a
duration-of-exposure dependent increase in the risk of cancer.
The predominant histologic cell types are small cell and squamous
cell carcinoma, but all cell types have been reported in
the literature.
Animal studies demonstrated a mild increase in lung cancer
risk after exposure to inhaled forms of chromium. Levy et al. 122
found that intrabronchial implantation of two different samples
of strontium chromate in rats resulted in a significant number
of lung cancers (43 of 99 and 62 of 99), almost all of which
were squamous cell carcinomas. Implantation of zinc chromate
resulted in a significant increase in lung cancer development as
well, but with many fewer malignancies (5 of 100).
The molecular mechanisms underlying the carcinogenicity
of chromium carcinogen are still being investigated, but the
preponderance of evidence points toward oxidative DNA damage.
Cheng et al. 123 found that chromium (VI) in the form of
potassium chromate administered to Big Blue transgenic mice
by intratracheal instillation resulted in a dose- and glutathionedependent
mutation frequency within 2 weeks of initial exposure.
This group suggested that the potential carcinogenic mechanism
is mediated through oxidative damage of DNA.
Additional support for an oxidative DNA damage mechanism
was provided by Hodges et al. 124 They found that exposing
human lung epithelial cells (A549) to sodium dichromate
for 1 hour resulted in a significant number of DNA-strand
breaks. Immunohistochemistry analysis found that levels of a
DNA-repair glycosylase 8-oxodeoxyguanosine (OGG1), were
increased in treated cells. In a follow-up study, Hodges et al. 125
found that treating A549 cells with sodium dichromate for 16
hours resulted in a concentration-dependent decrease in levels
of OGG1 mRNA expression and OGG1 protein in nuclear extracts.
The authors found that these findings demonstrated that
sodium dichromate carcinogenesis may be in part mediated by
suppression of DNA-repair mechanisms performed by OGG1.
One study offered a potential cocarcinogenic mechanism for
chromium exposure and smoking. Feng et al. 126 noted that preexposure
of normal human lung fibroblasts to chromium (VI) enhances
the binding of benzo(a)pyrene diol epoxide to mutational
hotspots in the p53 gene, specifically codons 248, 273, and 282.
In the 1950s and 1960s, several steps were taken to decrease
worker exposure to chromium—removal of calcium
chromate by changing to lime-free processes and better environmental
controls. Studies attempting to evaluate these
modifications have not found any significant change in lung
cancer-associated mortality but were often underpowered. 127
In 1990, the IARC 128 concluded that chromium was a
human pulmonary carcinogen. The OSHA currently mandates
a PEL for chromate or chromic acid of 100- g CrO 3 /m 3 . The
NIOSH recommends a 10-hour time-weighted average exposure
limit of 1- g Cr(VI)/m 3 . With respect to drinking water,
the EPA 129 has established a maximum contamination level of
100 g/mL (100 ppb).
DIESEL EXHAUST
Diesel particulate matter is composed of a core of elemental
carbon and adsorbed organic compounds, including polycyclic
aromatic hydrocarbons and nitrate, metals, sulfate, and other
trace elements. Diesel particulates consist largely of respirable
range particulates that have a large surface area where
organic substances can adsorb easily. Lung cancer risk has been
shown to be elevated among workers in occupations where
diesel engines have been used. 130 Concerns over the potential
carcinogenicity of diesel exhaust arose as a result of studies
demonstrating the development of different carcinomas after
exposure to diesel particle extracts 131 and other studies showing
mutagenic effects of diesel particulate matter. 132–137
Garshick et al. 138 performed a case-control study of U.S.
railroad workers with at least 10 years of service and born
in or after 1900. Using deaths between March 1, 1981 and
February 28, 1982 and work history data available from the
U.S. Railroad Retirement Board (RRB), they demonstrated an
OR for lung cancer of 1.41 (95% CI, 1.06, 1.88) for railroad
workers younger than age 65 at death exposed to diesel exhaust
for more than 20 years after adjustment for cigarette smoking
and asbestos exposure. However, another study published by
Garshick 139 in 2004 failed to find an association between the
lung cancer mortality and the duration of time that subjects
spent as railroad workers. In this study, the increase in lung
cancer mortality was restricted to those subjects who worked
specifically on locomotives powered by diesel engines.
Swanson et al. 140 demonstrated significantly increased risks
of lung cancer after adjustment for age at diagnosis, smoking,
and race among truck drivers and railroad workers employed
for more than or equal to 20 and 10 years. Their adjusted ORs
were 2.5 (95% CI, 1.1, 4.4) and 2.4 (95% CI, 1.1, 5.1), respectively.
They also found statistically significant trends for
lung cancer in farmers. They are the first investigators to document
this group as being at risk. In 2003, Jarvholm et al. 141
confirmed these findings in truck drivers.
Brüske-Hohlfeld et al. 142 described an elevated risk in
farmers and found an OR of 6.81 (95% CI, 1.17, 39.51) for
exposures of greater than 30 years. The increase in the OR has
been attributed to the repeated exposure of farmers to exhaust
as they drive tractors back and forth through their fields,
thereby possibly increasing the concentration of exhaust and
consequently their exposure.
With the amount of evidence linking diesel exhaust to lung
cancer, in 2002, the EPA 143 concluded that diesel exhaust is a
potential causative agent of lung cancer. By 2007, they required
that the sulfur content of diesel fuel be less than 15 ppm. 144
MINERAL OIL
Mineral oil has been in use in the textile and metalworking
industries since the latter half of the 19th century. Initial concerns
over its potential role as a carcinogen were raised after an
epidemic of scrotal cancers among mule spinners in the cotton
industry.
Jones 144a was the first to describe abnormalities on chest
radiographs of workers exposed to mineral oil aerosols.145 Several
case reports of lung cancer in association with a mineral oilexposure
history appeared between 1940 and 1970 prompting
epidemiologic studies to clarify this apparent connection. 146–148
Other case-control studies in the 1980s found significant
associations between lung cancer and mineral oil exposure
in workers in the metal industry and in workers using rotary
letterpress printing machines. 149 More recently, an association
has also been found in aerospace workers. 150 Mineral oil contains
varying amounts of polycyclic aromatic hydrocarbons,
known carcinogens. These molecules are the presumed carcinogenic
component of mineral oil.
In 1984, the IARC 151 concluded that there was sufficient
evidence from human studies that mineral oil is a human
carcinogen. Currently, OSHA has set a PEL for mineral oil of
5 mg/m 3 of air as a time-weighted average concentration over
an 8-hour period. The NIOSH has established similar exposure
standards. 152
NICKEL
Nickel is a naturally occurring element found in the environment
in combination with sulfur or arsenic. It is a silvery white
metal initially prized for its ability to color glass green. Nickel
is hard yet malleable, magnetic, and inert; consequently, it has
multiple uses. Presently, most mined nickel is used to produce
austenitic stainless steel, whereas the remainder is used for the
production of different alloys, rechargeable batteries, catalysts,
plating, coins, chemicals, and foundry products.
The carcinogenicity of nickel only became apparent in
Europe after case reports of cancer among nickel-refinery
workers. Doll 153 provided the first epidemiologic evidence for
lung and nose cancer after occupational exposure to nickel;
however, his study did not have adequate data on duration of
nickel exposure or information on exposure to other potential
pulmonary carcinogens such as smoking. Studies of nickel
workers continued to demonstrate increased risks for lung cancer,
the largest of which was conducted by the International
Committee on Nickel Carcinogenesis in Man (ICNCM) in
1990. 154–157 This study evaluated 140,888 nickel workers with
a minimum employment period ranging between 6 months
and 5 years. The committee concluded that most of the lung
cancer risk was associated with exposure to oxidic and sulfidic
nickel at high concentration or to a high concentration of the
oxidic form alone. Soluble-nickel exposure at low levels was associated
with high risks of lung cancer, and metallic nickel had
no appreciable associated risk. However, Grimsrud et al. 158
evaluated a group of Norwegian nickel-refinery workers and
found that a dose-related effect was evident for lung cancer
risk, as well as exposure to water-soluble nickel species but
not to sulfidic, oxidic, or metallic forms. In additional studies,
Grimsrud et al. 159,160 continued to demonstrate an increase in
lung cancer mortality associated with process work at nickel
factories. At this time, the controversy over the risks of each
specific type of nickel persists. 161,162
As in all occupational lung cancer studies, smoking has
presented a problem in ascertaining the true role of nickel exposure
in lung cancer risk. Attempts to tease out the contribution
of smoking in lung cancer risk among nickel workers have
suggested an additive effect. 163
The latency period for nickel-related lung cancer is about
15 years. A review of the literature did not reveal any predominance
of a particular histologic cell type.
Animal data have not been entirely consistent in supporting
the hypothesis that nickel is a pulmonary carcinogen.
Ottolenghi et al. 164 were able to induce lung cancers in rats
after inhalation of nickel subsulfide. However, Dunnick et al. 165
failed to demonstrate such a response. They also evaluated the
inhalational effects of oxidic nickel and again, failed to demonstrate
an increase in the development of lung cancer in rats. At
higher doses, an increase was found but not statistically significant.
Soluble nickel inhalational studies had not been conducted
prior to the National Toxicology Program 2-year inhalation
study. Again, no significant increase in lung cancer incidence was
found after exposure to soluble nickel. 166 Exposing animals to
metallic forms of nickel have not demonstrated the development
of lung cancer either, except for one study, which did produce
lung cancer after intratracheal instillation of elemental nickel in
rats. 167 On a molecular level, nickel has been shown to damage
and mutate DNA while also preventing DNA repair. 168,169
In 1990, the IARC concluded that nickel compounds were
carcinogenic to humans. The EPA has set a long-term PEL of
0.2 mg of nickel per kilogram of body weight per day in food
and drinking water. The OSHA has established an occupational
level of exposure to be 1 mg on nickel per cubic meter
over an 8-hour workday, 40-hour workweek. The NIOSH has
set a recommended exposure level of 0.015 mg/m 3 . 170
RADON
Radon is an odorless, colorless gas, which is derived from the
radioactive decay of uranium. Radon itself undergoes radioactive
decay with a half-life of about 4 hours and generates two
progeny or radon daughters. Radon daughters, with a half-life
of about one-half hours, attach easily to dust and other airborne
particles, permitting their inhalation and deposition along the
respiratory airways. The daughters continue to decay until they
become nonradioactive particles. During each decay cycle,
release of alpha, beta, and gamma radiation occurs, thereby
predisposing nearby living cells to potential DNA damage
and/or mutation and subsequent development of malignancy.
Numerous studies have demonstrated the mutagenic effects of
radiation on cellular DNA 171–173 and the generation of lung
cancers in Sprague-Dawley rats 174,175 and A/J mice. 176
In the 1800s, uranium was used primarily as a dye, and
uranium miners in Schneeberg, Germany and Joachimsthal,
Czechoslovakia were known to develop lung disease and lung
cancer. 177 In fact, the relationship was significant enough that
by 1932, both Germany and Czechoslovakia had designated
lung cancer in these miners as a compensatable disease. 178
Studies conducted by the U.S. Public Health Service in the
1950s raised concerns about the possibility of increased risks
of lung cancer among uranium miners. 179 By 1964, reports
were circulating about the high concentrations of radon in uranium
mines, 180 and there were concerns regarding the risk of
lung cancer being related to the amount of exposure to radon
daughters. 181 However, controversy existed over the influence
of smoking on the risk of lung cancer.
Numerous studies among Navajo men were performed to
evaluate the effects of uranium/radon on lung cancer. Mining
around the Navajo Nation began in 1948, peaked around 1956,
and declined to zero by 1967. 182 Several studies demonstrated
an excess in lung cancer–related mortality among Navajo
Indians. Archer et al. 183 found 11 lung cancer–related deaths
in a follow-up study of 780 predominantly Navajo Native
American Indians compared to an expected number of 2.6.
Gottlieb et al. 184 documented that between February 1965 and
May 1979, 16 of 17 male Navajo patients admitted with lung
cancer were uranium miners (94.1%). Samet et al. 185 were able
to demonstrate a significantly elevated risk of lung cancer in
predominantly nonsmoking Navajo Indians. Of the 32 Navajo
men with documented lung cancer between 1969 and 1981, 23
had been uranium miners. Information regarding smoking status
was available for 21 of these 23 miners: 8 were nonsmokers;
2 smoked less than one cigarette per day; 6 smoked between
one to three cigarettes daily; and 5 smoked between four and
eight cigarettes per day. In the same issue of the New England
Journal of Medicine , Radford et al. 186 also demonstrated an increased
incidence of lung cancer in Swedish iron miners who
had been exposed to low doses of radon daughters, not affected
by smoking status.
In an editorial, Harley 187 discussed the potential implication
of environmental exposure to radon. The average environmental
radon exposure has been estimated to be about 0.2
working-level months (WLM) per year. 188 A working level is
equivalent to 100 pCi/L of air at equilibrium. A WLM is the
exposure derived from spending 170 hours (1 month’s working
hours) exposed to a working level. Based on a risk projection
generated by Radford et al., 186 this level of exposure translates
into a lung cancer risk of 15 cases per 1000 persons. Lubin
et al. 189 pooled the results from two case-control studies of
residential radon exposure in China and found increased ORs
for the risk of lung cancer. Specifically, for subjects living in
the same home for 30 years or more exposed to 100 Bq/m 3 of
radon, the OR for lung cancer was 1.32 (95% CI, 1.07, 1.91)
where 1 Ci is equivalent to 3.7 10 10 Bq. In 2005, Darby et
al. 190 and Krewski et al. 191 also found increases in the risk of
lung cancer after pooling 13 European and 7 North American
case-control studies, respectively.
The highest recorded environmental radon-related exposure
occurred in Pennsylvania at the home of Stanley Watras.
His home level of radon was 2700 pCi/L. Geologic surveys of
his home revealed that the structure was located on the Reading
Prong, a large naturally occurring granite deposit. Other natural
soil sources of radon include shale, phosphate, and pitchblende.
It has been estimated that 1 in 15 homes have higher than acceptable
radon levels as determined by the EPA (4 pCi/L). The
average level in the U.S. homes is about 1 pCi/L.
Commercial kits are available to measure radon levels
in homes, but consumers should be aware that only certain
testing devices are certified as “meeting EPA requirements.”
Testing should be performed if the home is located over large
deposits of granite, shale, phosphate, or pitchblende, as well as
if a young patient without a significant smoke-exposure history
or significant family history presents with a lung cancer.
Removing radon sources from the home requires professional
certified contractors. Options include sealing cracks in floors
and walls, installing pipes and fans to ventilate the ground
below home foundations (subslab depressurization), and/or
soil depressurization. One of the most important interventions
is smoking cessation, especially inside the dwelling.
SILICA
Crystalline silica is the cause of silicosis, an inhalational occupational
disease. The list of occupations associated with crystalline
silica exposure is extensive and includes any occupation
that aerosolizes crystal dusts. Mining, sandblasting, ceramic
production, and stone working are a few examples.
Hippocrates recognized the development of pulmonary
disease in the setting of occupational exposure to crystalline
silica dust as early as 400 BC . Silica was not thought of as a
carcinogen until the 1980s after several investigators noted the
development of lung and pleural cancers in rats after exposure
to crystalline silica. Wagner 192–194 demonstrated an increase in
the development of lymphosarcomas after intrapleural injection
of crystalline silica in Wistar rats, injection of alkaline-washed
quartz, cristobalite, and Min-U-Sil in Wistar rats, and injection
of six different forms of crystalline silica in three different rat
strains. Stenbäck and Rowland 195 demonstrated an increased
incidence of respiratory tumors (44%) with intratracheal instillation
of silica in combination with benzo(a)pyrene in
Syrian golden hamsters compared with benzo(a)pyrene alone
(10%). Holland et al.196 also showed an increased incidence of
respiratory tumors (16.7%) in Sprague-Dawley rats after intratracheal
administration of silica. His group also showed that
Fischer-344 rats, after inhalational exposure to silica, had an
increased incidence of respiratory cancers (66.7%) compared
to none in the controls.197
The potential role of silica in human lung cancer was
brought to light with the work of several epidemiologists. In
the 1500s, miners from Schneeberg and Joachimsthal had a
high mortality rate, and it was recognized only later that the
likely cause of this increase was lung cancer. 198 Milham Jr 199
found a threefold increase in the risk of bronchial and lung
cancers in metal molders from Washington State based on
death certificates between 1950 and 1971. Westerholm 200
examined the Swedish Pneumoconiosis Register and found
that those who developed silicosis had a significantly elevated
risk of lung cancer–related mortality. The relationship between
silicosis and lung cancer has been supported by additional
studies. 201–203 Finkelstein et al. 204 also demonstrated a twofold
increase in lung cancer–related deaths in patients receiving
workmen’s compensation for silicosis between 1940 and 1975
from data obtained from the Ontario Ministry of Labor.
Attfield et al. 205 found a dose–response relationship between
silica exposure and lung cancer in Vermont granite workers.
These case-control studies did not document the prevalence of
smoking in the study population, but it was presumed to be
significantly higher than that of the control population, which
was the general public. In addition, demonstration of pneumoconiosis
or silicosis was required in the studies by Westerholm
and Finkelstein, respectively, thereby preventing conclusions
regarding the risk of lung cancer in workers exposed to silica
without evidence of disease on radiographs.
The controversy over the potential role of silica in lung
cancer pathogenesis stems from numerous studies, which failed
to find an increase in cancer risk after attempting to account for
smoking and exposure to radon daughters, arsenic, and other
occupational carcinogens. 206,207 Becker and Chatgidakis 208 did
not find a significant difference in the incidence of bronchogenic
carcinoma in white male gold miners compared to nonminers.
Other studies found that the degree of silicosis did not
correlate with the incidence of bronchogenic carcinoma. 209,210
In response to this controversy, Checkoway et al. 211 evaluated
the incidence of lung cancer in diatomaceous earth mining and
processing facility employees. They found that lung cancer incidence
was associated with cumulative crystalline silica exposure
and was not dependent on the presence of radiographically evident
silicosis. They attempted to further bolster their findings
by reviewing the available literature, but found that the design
of most studies attempting to better describe the link between
silica and lung cancer were potentially confounded by the use
of compensation claims to identify patients with silicosis and
the lack of adequate quantification of exposure. 212 A recent
study concluded that silica exposure in North American industrial
sand workers was associated with an increase in lung cancer
after controlling for smoking. 213
Despite these contradictory studies, in 1996, the IARC
concluded that the available literature provided sufficient evidence
implicating the inhalation of crystalline silica as a carcinogen.
The American Thoracic Society (ATS) followed that same
year with a statement describing the potential adverse effects of
inhaled silica exposure, including lung cancer. However, ATS
qualified the statement by questioning the carcinogenicity of
silica dust in nonsmokers and in those exposed to silica dust
without evidence of silicosis. In 1989, the NIOSH concurred
with the findings of the IARC and ATS after conducting their
own review of the literature and recommended that crystalline
silica be listed as a potential occupational carcinogen.
Occupational exposure controls have been established by
government agencies for silica but as part of a group of fibers
labeled as synthetic vitreous fibers. The PEL set by OSHA is
5 mg/m 3 for the inhalable fraction and 15 mg/m 3 for the total
dust exposure. The NIOSH has set a recommended exposure
limit (REL) of 3 fibers per cubic centimeter for fibrous glass