Mutation Research 437 Ž1999.

175–194
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Occupational exposure to genotoxic agents

)
Nagalakshmi Keshava, Tong-man Ong
Toxicology and Molecular Biology Branch, Health Effects Laboratory DiÕision, National Institute for Occupational Safety and Health,
m r s 3014, 1095 Willowdale Road, Morgantown, WV 26505-2888, USA
Received 22 February 1999; accepted 4 May 1999

Abstract

Millions of workers in the United States are potentially exposed each year to hazardous chemicals, dusts, or fibers in
occupational settings. Some of these agents are genotoxic and may cause genetic alterations in the somatic or germ cells of
exposed workers. Such alterations, if they occur in proto-oncogenes or tumor suppressor genes, which are involved in
controlling cell growth or differentiation, may lead to the development of cancer. Genetic alterations in germ cells may also
lead to reproductive failure or genetic disorders in subsequent generations. It has been estimated that occupational exposure
accounts for 4% of all human cancers and up to 30% of cancer among blue-collar workers. Approximately 20,000 cancer
deaths each year are attributable to occupational exposure in the United States. Occupational cancer and reproductive
abnormalities have been listed on the National Occupational Research Agenda master list of research priorities as major
occupational diseases and injuries. q 1999 Elsevier Science B.V. All rights reserved.

Keywords: Genotoxic agents; Occupational exposure; Occupational cancer

1. Introduction foundry industries are exposed to complex chemical

mixtures or mixtures of chemical and physical agents.
Millions of workers in various occupational set-
Illness in some workers, however, can be attributed
tings in the United States have the potential to be
to exposure to a single chemical or physical agent.
exposed to hazardous substances. These substances,
Painters and laundromat workers may be exposed to
including dusts, fibers, and organic or inorganic
a specific solvent, some healthcare workers to a
chemicals, are used as raw materials, intermediates,
specific drug or radiation, some farmers to a specific
by-products or end products in industrial processes.
insecticide or herbicide, and some construction
They can exist in the form of gases, vapors, fumes,
workers to asbestos, man-made fibers or silica.
mists or particles. Inhalation is the primary route of
Many of these substances are now known to be
exposure, however, exposure can also take place
genotoxic and have the potential to cause genetic
through dermal absorption or ingestion. Most work-
alterations in the target tissues of exposed workers.
ers in construction, mining, manufacturing and
Such alterations, if they occur in proto-oncogenes or
tumor suppressor genes, which are involved in con-
)
Corresponding author. Tel.: q1-304-285-5817; fax: q1-304- trolling cell growth or differentiation, may lead to
285-6194; E-mail: too2@cdc.gov the development of cancer in the target organs.

1383-5742r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved.
PII: S 1 3 8 3 - 5 7 4 2 Ž 9 9 . 0 0 0 8 3 - 6
176 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
Industrial agents, such as asbestos, diesel emission
particles, wood dust, chromium, arsenic, vinyl chlo-
ride, benzene, etc., are known to be associated with
cancer risk w1,2x. It has been estimated that occupa-
tional exposure accounts for 4% of all human cancer
w3x. In the United States, approximately 500,000
deaths each year are due to cancer, and 20,000 of
these are attributable to occupational exposure w4x.
Exposure of workers to genotoxic agents may also
cause genetic alterations in germ cells and lead to
reproductive disorders. It has been estimated that up
to 50% of fetal deaths, 30% of mental retardation,
20% of congenital defects and 2% of total male
infertility are associated with chromosomal aberra-
tions w5x and hundreds of human diseases are also
known to be due to gene mutations w6x. Studies of
occupational reproductive hazards to date have con-
sisted mainly of epidemiologic surveys of pregnancy
outcomes following maternal exposures. Such stud-
ies have shown increased rates of spontaneous abor-
tions in chemical and laboratory workers w7,8x, ethy-
lene oxide, and anaesthetic gases w9,10x. In general,
relatively few studies have been conducted on repro-
ductive outcomes associated with paternal exposures
w11x.
Occupational cancers and reproductive disorders
have been listed on NORA master list of research
priorities as major occupational diseases and injuries
w3x. It has been suggested that 10% of all chronic
diseases, including cardiovascular diseases, are the
result of mutations. The National Institute for Occu-
pational Safety and Health has identified cardio-
vascular diseases as one of the 10 leading occupa-
tional diseases and injuries w12,13x. Personal risk is
one of the primary factors associated with an in-
creased incidence of coronary heart disease. How-
ever, it is not known what fraction, if any, of the
cardiovascular diseases among workers are due to
exposure to genotoxic agents in the occupational
setting. A review of current information on the rela-
tionship between workplace factors and cardio-
vascular disease shows that millions of workers are
currently exposed to work-related factors, including
chemicals, associated with an increased risk of car-
diovascular disease w12x.
This review discusses the exposure of workers in
different occupational settings to genotoxic agents
and briefly describes the genotoxic and carcinogenic
effects of these agents. In most cases only review
articles are cited. Since there are hundreds of such
agents, this review includes only those commonly
found in the occupational setting or those to which a
significant number of workers are exposed. In certain
chemical groups, only a few representatives are listed.
2. Occupational exposure to genotoxic agents
The genotoxic agents to which workers are poten-
tially exposed can be grouped into the following
categories: dusts and particles, fumes and fluids,
fibers, chemicals and radiation.
2.1. Dusts and particles
Silica, diesel emission particles, coal dusts and
wood dusts ŽTable 1. are the most common occupa-
tionally related dusts and particles.
2.1.1. Silica
Silica can either be crystalline or amorphous. The
size of crystalline silica varies from less than 1 mm
to more than 50 mm in diameter. Approximately 3.2
million workers are potentially exposed to respirable
crystalline silica w14,15x. Its abundance in the envi-
ronment is second only to oxygen. Crystalline silica
is probably one of the most documented workplace
contaminants. The severity and the widespread na-
ture of exposure and the associated health effects
have been documented in the literature w16,17x. Some
of the industries in which workers may be exposed
to crystalline silica are in mining-related milling
operations, iron and steel milling, quarrying, con-
struction, glass and cement-making, ceramics Žin-
cluding the making of pottery, porcelain, tiles, bricks,
etc.., silicon and ferro-silicon foundry work, metal
manufacturing, manufacture of machinery, and in
agriculture. Occupational exposure to crystalline sil-
ica in mines mainly occurs from the dust generated
from the ore that is being extracted or from its
associated rock. Exposure to silica in foundries oc-
curs mainly in the use of sands in the making of
molds and cores.
Genotoxicity and clastogenicity of silica has re-
cently been reviewed by Gu and Ong w18x. In vitro
 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194 177

Table 1
Occupational exposure to dusts and fibers and their genotoxic effects
Dusts, fibers Source of exposure No. of workers Genotoxic effectsa References
and radiation exposed
Silica Ore mining, quarrying and granite workers, ceramics, 3.2 million CA, MN, SCEs w14,17,19,22x
pottery, glass, refractory brick, diatoaceous earth
industries, foundries
Diesel emission Transportation workers, operators of diesel-powered 1.35 million MN, SCEs, CAs, w24,25x
particles equipment, bus workers, truck drivers cell transformation
Coal dust Mine operators, jack setters, rock-dusters, coal drill 400,000 Gene mutations, w17,40–42x
operators, cutting machine operators and blasters SCEs, CAs,
cell transformation
Wood dust Wood workers, furniture workers, cutting oil users, 600,000 Gene mutations, w44x
leather workers, tailors, dressmakers and printers DNA single-strand
breaks, MN
Glass fibers Thermal and acoustical insulation, construction and NrA CA, MN, w79,81,83x
ship building, insulation in houses, thermal and cell transformation
sound insulation
Asbestos Asbestos textiles, roofing, asbestos paper industry, 27.5 million MN, CA, w84x
insulation, shipyard workers, miners gene mutations
a
Positive responses were observed for genotoxicity.
NrA, not available; CA, chromosomal aberrations; MN, micronucleus; SCEs, sister chromatid exchanges

studies have shown significant increases in binucle-
ated and micronucleated cells in Syrian hamster em-
bryo cells treated with Min–U–Sil quartz w16,17x.
Min–U–Sil 5 and Min–U–Sil 10 silica samples
were also shown to induce a significant dose-related
increase in micronuclei in Chinese hamster lung
fibroblast ŽV79. cells and human embryonic lung
ŽHel 299. cells w19x. Also, a significant and dose-de-
pendent increase in the frequency of morphologically
transformed Syrian hamster embryo cells was re-
ported following treatment with Min–U–Sil 5 and
other quartz samples w20,21x. Gene expression using
nine proto-oncogenes and the p53 tumor suppressor
gene in a small number of cell lines suggested an
increase in the mRNA expression of four proto-
oncogenes Ž K-ras, H-ras, myc, abl . and of the p53
gene in some quartz-transformed cell lines w22x. Ge-
nomic instability has also been found in transformed
BALBrc 3T3 cells induced by silica w23x. In addi-
tion to in vitro studies, genotoxic potential has also
been studied in silica-exposed workers. Significant
increases in the levels of chromosomal aberrations
ŽCAs. and sister chromatid exchanges ŽSCEs. in
peripheral blood lymphocytes of workers from a
stone crushing unit have been observed w16x. IARC
has also reviewed in detail the published experimen-
tal and epidemiologic studies of cancer in animals
and workers exposed to respirable crystalline silica
and has concluded that there is sufficient evidence in
humans to show genotoxicity and carcinogenicity of
inhaled crystalline silica in the forms of quartz or
cristobalite from occupational sources w16,17x.
2.1.2. Diesel emission particles
It has been estimated that approximately 1.35
million workers are occupationally exposed to the
combustion products of diesel fuel in about 80,000
workplaces across the United States w24x. Occupa-
tional exposure is common among transportation
workers, operators of diesel-powered equipment and
among some miners operating diesel-powered equip-
ment underground. Bus workers, bus-maintenance
workers, railroad workers and truck drivers are also
among those who are potentially exposed to diesel
exhaust. Diesel exhaust consists of both gaseous and
particulate fractions. The particulate is composed
mostly of carbon formed through the incomplete
combustion of fuel. Many of these substances are
mutagenic or carcinogenic, containing chemicals such
as 3-to-5-ring polycyclic aromatic hydrocarbons
ŽPAHs., aliphatic hydrocarbons, ketones and aldehy-
des w25x. These particles, since they fall within the
178 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
respirable range and are toxic compounds, pose a
potential health hazard to exposed workers.
Diesel exhaust has been classified as a potential
occupational carcinogenic agent in humans by the
National Institute for Occupational Safety and Health
w24x. McClellan et al. w26x have summarized the
biological activity of diesel exhaust, concluding that
diesel exhaust particle extracts have a potency al-
most equaling that of coke-oven emissions and, in-
terestingly, are more potent than cigarette smoke.
Nitrosocompounds, chemicals found in diesel ex-
haust particles, have been found to be major contrib-
utors to mutagenicity in the Salmonella typhimurium
assay w25x. Genotoxicity of diesel emission particles
has been reviewed in literature w26–28x. Diesel ex-
tract has been found to cause mutations in cultured
mammalian cells. Micronucleus induction by diesel
extract has been observed in mammalian cells both
in vitro and in vivo. Diesel emission particles have
also been known to induce MN, SCEs, CAs and
morphological cell transformation in various mam-
malian cell systems. Animal studies have shown that
diesel exhaust is potentially co-tumorigenic w29–31x.
Epidemiological studies indicate that heavy occupa-
tional exposure to diesel exhaust increased MN and
SCE in traffic policemen w32x and also increased the
risk of mortality for both lung cancer and non-cancer
pulmonary disease w33–35x.
2.1.3. Coal dust
Coal mining was very popular at the turn of the
century with the invention of the steam engine.
About 800,000 miners were employed in 1923 w36x,
however, with the declining use of the coal for
transportation and steel mining, coal mining employ-
ment has dropped dramatically. Still, there are about
400,000 miners in the United States, and 2000 of
them die each year of lung disease w37x. Coal mine
dust is a complex and heterogeneous mixture con-
taining more than 50 different organic or inorganic
chemicals and their oxides. Some of the minerals
occurring in coal are silicates, oxides, carbonates,
sulfides and sulfates. Some of these particles are
respirable and therefore increase the risk for health
hazards among coal miners w38x. The coal component
of respirable dust in coal mines can be highly vari-
able depending on the stage of the mining operation.
Occupations such as mine operators, jack-setters,
rock-dusters, coal drill operators, cutting machine
operators, and blasters often are potentially exposed
to a high concentrations of respirable coal dust.
Other than mining, exposure to coal dust can also
occur during bulk coal transfer and at sites where
coal is used.
Studies related to the genotoxicity of coal dusts
have been reviewed by IARC w16x. It has been shown
that organic solvent extracts of coal dust from differ-
ent types of coals are either non-mutagenic or weakly
mutagenic with microsomal activation. However,
high mutagenic activities were found when extracts
of bituminous, sub-bituminous and lignite coal dusts
were reacted with nitrite under acidic conditions w39x.
The nitrosated extracts of coal dust induce gene
mutations in bacteria and mammalian cells, induce
SCEs and CAs in human peripheral lymphocytes and
induce morphological transformation in BALBrc-
3T3 cells w40,41x. In vivo genotoxicity studies using
peripheral blood lymphocytes show an elevated fre-
quency of aberrant cells Žcells with chromatid or
chromosome breaks. in workers employed in digging
operations w42x. Also, exposure to fumes in soft coal
open-cast mining operations increased CAs com-
pared to controls w38x. Oxidative DNA damage has
also been observed in coal miners exposed to coal
dust when compared to non-exposed controls w43x.
The health effect of coal mine dust has been studied
in coal miners. The most common illnesses associ-
ated with coal dust exposure are pneumoconiosis,
progressive fibrosis, chronic bronchitis and acceler-
ated loss of lung function w38x. Increases in stomach
cancer among coal miners have been reported by
several epidemiological studies w17x.
2.1.4. Wood dust
The National Occupational Exposure Survey, car-
ried out in 1981-1983 in the United States, estimated
that about 600,000 workers were exposed to wood
dust. The largest numbers of exposed workers were
employed in the building trades and the lum-
berrwood product industries such as wood machin-
ists, cabinet makers, chair makers, turners and
sanders. Exposure to wood dust is associated with an
increased risk of developing adenocarcinomas of the
nasal cavity w44x. Both occupation and type of wood
dust exposure influence the histological type of nasal
cancer observed. For example, increased incidence
 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
of nasal cancer in furniture makers is limited mainly
to adenocarcinomas of the nasal cavity, however,
squamous cell carcinoma of the nasal cavity has
been observed in furniture workers, joiners, carpen-
ters and loggers exposed exclusively to soft wood
dust. The chemical components andror properties of
the carcinogenic factorŽs. in wood dust are not very
well understood. From reported literature, one can
conclude that carcinogenic agents are most likely
substances in the wood itself, since machinists and
cabinet makers have only minor exposure to lac-
quers, sprays and polishes w45–47x. There is addi-
tional evidence from epidemiological studies that the
factors responsible for induction of adenocarcinomas
of the nasal cavity in hardwood workers exist in the
wood itself w47–49x. The natural constituents of wood
are numerous. The following agents have been sug-
gested as possible contributing agents to the induc-
tion of nasal cancer: native mutagenic components of
wood dust Žsuch as tannins and tannic acids, 2,6-di-
methoxy-1,4-benzoquinone, unsaturated aldehydes
and their oxidation products, coniferyl and sinapic
alcohols, etc.., pyrolytic substances created during
sanding and sawing of wood products, and metabo-
lites produced by wood-covering fungi w50–52x.
Attempts to evaluate the genotoxic and carcino-
genic potential of wood dust and wood shavings both
in animal and human exposures have been summa-
rized in IARC w53x. Mutations were observed in S.
typhimurium when exposed to beech wood w54x.
Chemically andror bacterially degraded beech wood
lignin also significantly induced mutations w55x. Other
extracts of beech and oak increased number of DNA
single strand breaks in rat hepatocytes in vitro w56x.
Also, various chemical substances found in plant and
wood extracts have been tested for their toxicity and
carcinogenicity in animals. However, few animal
studies, in vitro or in vivo, have adequately ad-
dressed the genotoxicity and carcinogenicity of wood
dust andror wood dust extracts.
2.2. Fumes and fluids
In several occupational settings, workers are ex-
posed to fumes or fluids such as asphalt fumes,
welding fumes and metal-working fluids.
179
2.2.1. Asphalt fumes
Asphalt is used widely in paving, roofing, water-
proofing and other industrial applications w57x. In
1983, it was estimated that more than 55 million tons
of asphalt was produced w58x, and at least 500,000
workers were potentially exposed to asphalt fumes in
the United States w59x. Asphalt contains high levels
of PAHs, many of which are known genotoxicants
and carcinogens. In a study of asphalt road paving
operations, benzow axnthracene and chrysene cons-
tituted majority of the PAH emissions. Asphalt
compounds used in roadwork can be applied hot
Žapproximately 1508C–1808C., and at these tempera-
tures, PAH compounds volatilize creating the poten-
tial for inhalation exposure w60x. In another study of
occupational exposure to asphalt rubber fumes, other
PAHs such as fluorene, phenanthrene, anthracene,
fluoranthene, pyrene and benzow b xfluoranthene were
found w61x. In vitro studies have shown asphalt fume
condensates to be mutagenic to bacteria w62x and
clastogenic in cultured mammalian cells w63x. Studies
have also shown that asphalt fume condensates in-
duce DNA adducts in vivo in rat lung cells w64x.
Genotoxicity studies have shown significant increase
in cytogenetic damage in peripheral lymphocytes of
workers exposed to bitumen fumes w65x. Carcino-
genicity studies in animals by dermal treatment with
roofing asphalt fume condensates have produced skin
cancers in mice w66,67x. Results of epidemiological
studies seem to suggest that there is an association
between cancer risk and exposure to asphalt fumes.
Studies regarding the exposure of workers to asphalt
fumes, the genotoxicity and potential carcinogenicity
of asphalt fumes can also be found in a document
published by NIOSH w68x.
2.2.2. Welding fumes
In the United States, more than 185,000 workers
are employed as welders, brazers or thermal cutters,
and it is estimated that up to 700,000 US workers
carry out some welding during their work w69x.
Welders are exposed to a variety of airborne contam-
inants and gaseous pollutants arising from the weld-
ing process and other operations w70x. Fume particles
contain a wide variety of oxides and salts of metals
and other compounds, which are produced mainly
from electrodes, filler wire and flux materials.
180 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
Genotoxicity of welding fumes has been reviewed
by IARC w70x. Studies have shown both positive and
negative results for gene mutations in cultured mam-
malian cells exposed to stainless-steel welding fumes.
Welding fumes induced morphological transforma-
tion in mammalian cells in vitro w71x as well as
increased frequencies of CAs w72x andror SCEs
w72,73x. Also, fumes from manual metal arc welding
of mild steel or cast iron using a nickel electrode
increased the frequency of SCEs, in mammalian cells
in vitro ŽRef. w70x and references therein.. Genotoxic-
ity studies have shown increased levels of SCEs and
CAs in peripheral blood lymphocytes of workers
exposed during stainless-steel welding w74x. Carcino-
genicity studies have shown an excessive risk for
lung cancer among welders and flame cutters w75x. In
a large study of shipyard welders in Finland, a
moderately increased incidence of lung cancer was
found. Also, five other studies conducted in United
States and Europe indicated about 30% increased
risk for lung cancer among welders ŽRef. w70x and
references therein..
2.2.3. Metal-working fluids
An estimated 1.2 million workers are potentially
exposed to agents collectively referred to as metal-
working fluids ŽMWFs. w76x. These agents are com-
monly used in a variety of industrial machining and
grinding operations. MWFs are primarily used to
cool and lubricate both machinery and working sur-
faces. They are also used to provide corrosion pro-
tection and removal of metal chips. MWFs are clas-
sified into four major classes: Ž1. straight oil MWFs,
which are made from naphthenic or paraffinic oils
and contain no water; Ž2. soluble oil MWFs, which
are naphthenic or paraffinic oils emulsified in water;
Ž3. synthetic MWFs, which are chemical fluids con-
taining no petroleum-based oils; and Ž4. semisyn-
thetic MWFs, which are emulsions containing small
amounts of oil w77x. The types and amounts of
chemical constituents may vary between the different
classes of MWFs. Limited information exists about
the chemical components of specific MWFs. A wide
variety of chemicals and contaminants may be pre-
sent in each of the MWF classes, and the hazard that
these chemicals pose to workers may vary widely
because of different manufacturing processes, vari-
ous degrees of refining, recycling and potential
chemical reactions between components. Compounds
such as N-nitrosodimethylamine, N-nitrosodiethy-
lamine, N-nitrosodiethanolamine, N-nitrodibutyla-
mine, N-nitrosomorpholine are known to be car-
cinogens and have been found in MWFs. Some
3-to-5-ring PAHs found in MWFs, are known to
be genotoxic.
Genotoxicity and carcinogenicity studies have
shown that a significant increase in the number of
DNA strand breaks in mononuclear blood cells was
observed in workers exposed to MWFs w78x. Skin
cancer of hands, forearms and scrotum has been
reported due to long-term exposure of workers to
poorly or non-refined mineral oils w78x. Primary ex-
posure to straight oil MWFs has been associated
with an increased risk for laryngeal, rectal, pancre-
atic and bladder cancer w78x.
2.3. Fibers
Fibers are classified as either natural or man-made.
Man-made mineral fibers are inorganic substances
primarily made from rock, clay, slag or glass. These
fibers can be further classified into three general
groups: glass fibers, rock wool and slag wool, and
ceramic fibers. Very little information is available
regarding the genotoxicity of rock wool, slag wool
and ceramic fibers.
2.3.1. Glass fibers
The primary use of glass fibers is for thermal and
acoustical insulation in construction and ship-build-
ing. They are also used as insulation in houses,
incorporated into ceiling tile for fire resistance as
well as for thermal and sound insulation. Small-di-
ameter glass fibers are used in air and liquid filtra-
tion and glass fiber air filters have been used in
furnaces and air-conditioning systems. Glass fibers
are also used for aerospace engineering in the form
of batts, blankets and molded parts. In addition, glass
fibers are sold as chopped strand mats rovings,
chopped fibers, yarns, yarn fabrics and roofing mats.
Occupational exposure occurs in the fibrous glass
industry during production, manufacturing, mainte-
nance, quality control and shipping. Workers in-
volved in general manufacturing operations, such as
trimming, sawing, cutting, finishing, painting and
molding are potentially exposed to glass fibers.
 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
Maintenance workers, including those who sweep
floors or clean dust collectors and machinery, as well
as those who do general cleaning within the plant,
may also be exposed to glass fibers.
The genotoxic effects of glass fibers have been
reviewed in the literature w79x. Fine and coarse glass
fibers were found not to induce mutations in S.
typhimurium. An increase in CAs was observed in
CHO-K1 cells after treatment with JM 100 glass
wool w80x. Other in vitro studies have shown that
glass fibers are capable of inducing micronucleated
andror multinucleated cells in cultured Chinese
hamster lung fibroblasts w81x and cultured human
primary mesothelial cells w82x. It has also been shown
that two of the three microfibers studied were capa-
ble of inhibiting cytokinesis and were principally
aneuploidogens. Interestingly, large fibers neither
induce micronuclei nor inhibit cytokinesis. This
indicates that size may play an important role in
genotoxicity w81x. Significant increases in numerical
chromosomal changes as well as in the number of
binucleated and micronucleated cells were observed
after treatment of Syrian hamster embryo cells with
JM 100 glass wool w83x. Both JM 100 and JM 110
glass wool induced a linear, dose-dependent increase
in the frequency of transformed colonies in Syrian
hamster embryo cells in culture after a single
treatment of the cells w79x. Glass wool-induced mor-
phological transformation was also found to be de-
pendent on fiber length and diameter w18x. Human
carcinogenicity data indicate no increase in the oc-
currence of lung cancer w79x. A slight increase in
mortality from respiratory cancer was observed in
glass wool workers in the United States. However, a
study of Canadian glass wool workers showed a
substantially raised mortality from lung cancer w79x.
2.3.2. Asbestos
According to Nicholson et al. w84x, 27.5 million
individuals have had past occupational exposure to
asbestos ŽTable 1.. Workers are exposed to asbestos
in a wide variety of industrial settings, consisting
primarily of maintenance and construction workers
exposed to asbestos insulation and mechanics ex-
posed to asbestos in brake linings. Other industrial
settings where workers may also be exposed include
primary manufacturing Žproducing manufactured
goods from raw asbestos fibers., secondary manufac-
181
turing Žprocessing asbestos-manufactured products to
make other products. and consumer industries Žutiliz-
ing a finished product containing asbestos without
modification. w85x.
Genotoxicity studies have shown that asbestos
fibers can induce gross CAs and micronuclei in
mammalian cells w86–90x. An increase in unsched-
uled DNA synthesis has been reported in rat
mesothelial cells exposed to crocidolite and chryso-
lite w91x. Increased frequencies of CAs andror SCEs
were observed in peripheral blood lymphocytes of
asbestos cement workers w92–94x and leukocytes
from asbestos workers w94x. Asbestos may induce
cancer directly in humans by causing CAs, or indi-
rectly by the production of free radicals, which lead
to genetic damage or an altered immune response
w95x. All types of asbestos are considered to cause
lung cancer in humans. It is estimated that about one
third as many deaths will occur from asbestosis as
from mesothelioma w84x. Although it is not clear if
asbestos is the only cause for mesothelioma and
cancer of the lung in asbestos-exposed workers, the
majority of the workers who die working in as-
bestos-related plants are mesothelioma and lung can-
cer patients. In addition, cancers of the stomach,
colon, rectum, esophagus, larynx, pharynx, buccal
cavity, and the kidney are each elevated significantly
compared with rates expected for these sites in the
general population. Exposure of the mesothelial tis-
sue and kidney may occur since fibers readily pene-
trate into lung lymphatics and reach the pleural
mesothelium or can also be transported to the kidney
or the peritoneal mesothelium w84,96x.
2.4. Chemicals
Occupationally related chemicals can be broadly
classified into three types: organic chemicals, inor-
ganic chemicals and specific chemical groups. The
following is a brief discussion of several selected
chemicals and specific chemical groups. Genotoxic-
ity of common occupationally related chemicals are
also listed in Table 2.
2.4.1. Organic chemicals
Among the most common organic chemicals found
in occupational settings are vinyl chloride, tetra-
chloroethylene, benzene and styrene.
182 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194

Table 2
Genotoxicity of common occupationally related chemicals
Chemicals Type of occupation No. of workers Genotoxic activity a References
exposed
Acrylamide Chemical production, construction 10,700 employees DNA adducts, SCEs, w170x
and maintenance involving pipe were exposed CA, mitotic distur-
grouting and sealing, water and between 1981 and bances
waste water treatment 1983
Arsenic Non-ferrous smelting, arsenic pro- 55,000 employees CA, DNA damage, w166x
duction, wood preservation, glass gene mutations
manufacturing, and arsenical pesti-
cide production and application
Benzene Petroleum distillates, coal tar distil- 238,000 CA, clastogenic, MN w108,167x
lates
Benzidine and dyes Benzidine manufacturing plant, 79,000 SCEs, gene mutations w173–175x
manufacture or using dye based on
benzidine
1,3-butadiene Production of polymers and ; 10,000 DNA alkylation, w111,168,176x
synthetic rubber SCEs, MN, CA
Bis-chloromethyl- Petrochemical-based industry NrA Gene mutations w169x
ethyl–ether
Ethylene oxide Chemical and allied products manu- 270,000 US employ- MN, SCEs, CA, gene w170x
facturing industry, production work- ees were exposed be- mutations, UDS
ers, maintenance workers, laboratory tween 1981 and 1983
workers
Formaldehyde Production of resin in urea and 1.5 million Gene mutations, w53,171x
phenol. Textile, leather, rubber and SCEs, CAs
cement industry
Propylene oxide Chemical industry, starch industry 421,000 employees DNA adducts, gene w170x
exposed between mutations, SCEs, CA
1981 and 1983
Styrene Styrene production, production of 1 million DNA adducts, strand w109,110,112,172x
polystyrenes, plastic and rubber pro- breaks, CA, SCEs,
duction fabrication MN
Toluene Petroleum refining operations 1.2 million CA, SCEs w146,147x
Vinyl chloride Packaging, building, electrical appli- NrA CA, SCEs, MN, gene w99x
ances, medical equipments, automo- mutations
biles, toys
a
Positive responses were observed for genotoxicity.
NrA, not available; CA, chromosomal aberrations; MN, micronucleus; SCEs, sister chromatid exchanges; UDS, unscheduled DNA
synthesis

2.4.1.1. Vinyl chloride. Polyvinyl chloride ŽPVC.
accounts for 20% of plastic material usage and is
found in most industrial sectors w97,98x. Vinyl chlo-
ride ŽVC. and dioxin are the most toxic byproducts
in PVC manufacture. The main route of occupational
exposure is via inhalation and occurs primarily in
VCrPVC plants. Agency for Toxic Substances and
Disease Registry has provided an extensive review
w99x on the genotoxicity and carcinogenicity of VC.
The genotoxic activities of VC have been detected in
a number of in vitro test systems, predominantly
after metabolic activation. VC is mutagenic in the
Ames Salmonella microsomal assay system. VC ex-
posure also induced unscheduled DNA synthesis in
rat hepatocytes and increased SCEs in human lym-
phocytes after addition of an exogenic activation
system. VC exposure induced gene mutations and
mitotic recombination in Drosophila melanogaster.
Cytogenetic studies have shown that the levels of
CAs, micronuclei and SCEs in peripheral blood lym-
phocytes of workers exposed to VC are higher com-
pared to control subjects ŽRef. w99x and references
 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
therein.. Point mutations have also been detected in
the p53 and ras genes from tumors Žangiosarcoma
of liver and hepatocellular carcinoma. of vinyl chlo-
ride exposed workers. Animal studies have also
shown that VC is carcinogenic, causing a wide spec-
trum of tumors in various animal species w99,100x.
VC exposure has been particularly associated with a
rare tumor, angiosarcoma of the liver ŽASL., in
humans and in animals w99,101x. Other tumors that
have been found, at least in animal species, include
liver tumors Žother than ASL., mammary gland car-
cinoma, nephroblastoma, and lung tumors.
2.4.1.2. Tetrachloroethylene. Commercial dry clean-
ing makes up the largest segment of the cleaning
industry. The chemicals used mostly include chlori-
nated solvents, amyl acetate, bleaching agents, acetic
acid, aqueous ammonia, oxalic acid, hydrogen perox-
ide and dilute hydrogen fluoride solutions. Tetra-
chloroethylene comprises about 82% of the solvents
used in dry cleaning. In 1991, tetrachloroethylene
was used in estimated 28,181 dry cleaning plants in
the United States. The National Occupational Expo-
sure Survey indicated that about 566,000 employees
in 42,700 plants were potentially exposed to tetra-
chloroethylene w102x. Occupational exposure to tetra-
chloroethylene occurs through inhalation, skin ab-
sorption and ingestion. Most occur by inhalation
whenever tetrachloroethylene vapors escape from a
dry cleaning machine in the form of process or
fugitive emissions. Improper storage of hazardous
waste, including still residues, dirty filters or contam-
inants in lint and water separator run-off can increase
background levels of tetrachloroethylene. Tetra-
chloroethylene clearly increased the number of rever-
tants in S. typhimurium in the presence of rat liver
enzymes w103x. In another study, tetrachloroethylene
induced cell transformation in Fischer rat embryo
cells but not in mouse BALBrc-3T3 cells in the
absence of exogenous metabolic activation w102x.
Other genotoxicity studies have shown a significant
correlation between the tetrachloroethylene content
of air and urinary mutagenicity in 24 Estonian dry
cleaners w104x. An increase in SCEs was seen in
dry-cleaners when compared to control groups, how-
ever the dry-cleaners in the study were smokers, so a
definitive conclusion could not be made w105x. In-
creased risk for certain types of cancer, such as
183
urinary bladder cancer, esophageal cancer, lung can-
cer and cervical cancer has been observed w102x.
2.4.1.3. Benzene. It has been estimated that approxi-
mately 238,000 workers may be occupationally ex-
posed to benzene in the United States w106x. They are
primarily exposed during the production of petro-
chemicals, petroleum refining, coke and coal chemi-
cal manufacturing, rubber tire manufacturing, and
storage or transport of benzene and petroleum prod-
ucts containing benzene. Steel workers, printers, rub-
ber workers, shoe makers, laboratory technicians,
firefighters and gas station employees may also be
exposed to benzene to certain extent.
Studies on genotoxicity show that benzene is
clastogenic in humans and induces CAs in peripheral
lymphocytes w106x. In another study, workers ex-
posed to benzene for various time periods showed a
significantly higher proportion of chromosome breaks
w107x. Some studies involving individuals with long-
term occupational exposure to benzene also suggest
that benzene damage chromosomes in hematopoietic
cells. A slight increase in SCEs was observed in
peripheral lymphocytes from workers exposed to
benzene w108x. Other evidence of genotoxicity in-
duced by benzene is the inhibition of DNA synthesis
in certain cell types w109x. Epidemiological studies
have shown acute myeloid leukemia in benzene ex-
posed workers w110x.
2.4.1.4. Styrene. NIOSH estimates that approxi-
mately 300,000 workers at 22,000 facilities may be
exposed to styrene w111x. Exposure primarily occurs
in the reinforced-plastics industry where there may
be a high air concentration for inhalation and dermal
contact with liquid styrene or resins w112,113x. Sig-
nificant occupational exposures may also occur in
other industrial settings, such as styrene polymeriza-
tion, rubber manufacturing and styrene–polyester
resin facilities w113,114x.
The genotoxic effects of styrene have been well
studied w115,116x. CAs have been reported in several
studies of workers exposed to styrene w117x.
Styrene-exposed men showed an increase in the
number of aberrant cells along with an increase in
the frequency of micronuclei w117x. In another study
of exposed workers, an increase in the incidence of
chromosome breaksrgaps and SCEs was seen w118x.
184 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
With regard to causing cancer, although there are
several epidemiological studies that suggest there
may be an association between styrene exposure and
an increased risk of leukemia and lymphoma, the
evidence is generally inconclusive because of multi-
ple chemical exposures and inadequate documenta-
tion of the levels and durations of exposure to styrene.
2.4.2. Inorganic chemicals
Some of the important occupational inorganic
chemicals are beryllium, chromium, cadmium, ar-
senic and nickel. Most of these inorganic compounds
exist in several different forms such as alloys, ox-
ides, chlorides, sulphates, carbonates and nitrates.
2.4.2.1. Beryllium. Occupational exposure to beryl-
lium and beryllium compounds occur in a range of
industrial processes. In 1971, approximately 30,000
employees were potentially exposed to beryllium
w119x. Beryllium is used in many manufacturing
industries such as ceramics, non-ferrous foundries,
non-ferrous smelters, sand blasting, electronics, fab-
rication, welding or flame cutting, and metal plating.
It is also used in the recycling industry and for
processing, such as in hazardous waste processing
w120,121x. Exposure to fumes, dusts and mists of
beryllium compounds can also occur during produc-
tion of beryllium metal.
Studies on genotoxicity as reviewed by IARC
w122x show that beryllium sulfate is mutagenic to
Bacillus subtilis, however, it is inactive in most other
bacterial mutagenesis assays. Beryllium chloride and
beryllium nitrates have been shown to induce SCEs
in V79 cells. In cultured mammalian cells, low-tem-
perature-fired beryllium oxide induced single strand
breaks in DNA w122x. Beryllium sulfate has also
been shown to induce morphological transformation
in BALBrc-3T3 and Syrian hamster embryo cells.
Beryllium sulfate also increased the frequency of
SCEs in Syrian hamster embryo cells and cultured
human lymphocytes w123x.
Human carcinogenicity data show an increased
incidence of mortality from lung cancer in beryllium
plant workers w124x. The risk of lung cancer was
consistently higher in those plants in which there
was also an excess mortality from non-malignant
respiratory disease. Also, it has been concluded that
the work environment of workers involved in refin-
ing, machining and producing beryllium metal and
alloys was associated with an increased risk of lung
cancer.
2.4.2.2. Chromium. The National Institute for Occu-
pational Safety and Health w125x estimated that about
two million workers are exposed to chromium and
chromium compounds. Potential occupational expo-
sure to chromium occurs through inhalation, inges-
tion or skin contact w126x. Occupations with potential
exposures to chromium include cement workers,
chromium platers, dye manufacturers, electroplaters,
leather finishers, lithographers, metal cleaners, oil
drillers, painters, pencil manufacturers, photogra-
phers, printers, shingle manufacturers, corrosion-in-
hibitor workers, furniture polishers, glass frosters,
welders, textile workers, wood stainers and several
others w126x.
Elevated levels of SCEs were observed in workers
exposed to chromium wIVx compounds in electroplat-
ing factories w70x. CAs were also found in studies of
exposed workers. Several other forms of chromate
induced a variety of genetic effects including DNA
damage, gene mutation, SCEs, CAs, cell transforma-
tion and dominant lethal mutations in a number of
targets, including animal cells in vivo and animal
and human cells in vitro w70x. Epidemiological stud-
ies of workers in the chromate production industry
have consistently shown an excess risk for lung
cancer w70x. Increased risk for lung cancer has also
been observed in facilities where zinc chromate was
produced Že.g., in the chromate plating industry, and
in stainless-steel welding. w70x.
2.4.2.3. Cadmium. Approximately 500,000 workers
in the United States are exposed to cadmium w127x.
Workers may be exposed to cadmium and cadmium
compounds in a variety of occupational settings. The
major sources of such exposure are smelting, refin-
ing of zinc, lead and copper ores, electroplating,
manufacturing of cadmium alloys, pigments, plastic
stabilizers, nickel–cadmium batteries, and welding.
Cadmium may enter the body by ingestion, inhala-
tion and, to a very limited extent, by passage through
the skin.
The genotoxic and carcinogenic related activities
of cadmium and related compounds have been re-
viewed by IARC w122x. DNA strand breaks, muta-
 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
tions, chromosomal damage and cell transformation
have been observed in vitro as a result of cadmium
exposure. Cadmium compounds inhibit the repair of
DNA damaged by other agents, thereby enhancing
their genotoxicity. Studies using cultured animal cells
have shown that exposure to cadmium compounds
damages genetic material. CAs and aneuploidy were
seen in animals exposed to cadmium chloride in
vivo. Frequencies of CAs were increased in periph-
eral blood lymphocytes of workers exposed to cad-
mium in the metal industry w122x. Excess mortality
from lung cancer has been reported among workers
employed in a cadmium recovery plant ŽRef. w122x
and references therein.. An increased risk for lung
cancer is associated in cadmium-related occupational
exposures. A number of early studies have reported
an increased risk for prostatic cancer among cad-
mium workers, however, the results are inconsistent.
2.4.2.4. Nickel. It has been estimated that about 1.5
million workers in the United States are potentially
exposed to nickel and nickel compounds w128x. Oc-
cupational exposure to nickel may occur by skin
contact or by inhalation of dusts, fumes or mists
containing nickel or by inhalation of gaseous nickel
carbonyl. Occupations with potential exposure to
nickel include battery makers, ceramic makers, dy-
ers, electroplaters, jewellers, nickel-alloy makers,
nickel refiners, nickel smelters, nickel miners, or-
ganic chemical synthesizers, paint makers, petroleum
refinery workers, textile dyers, varnish makers and
welders.
Genotoxic and carcinogenic related activities of
nickel and related compounds have also been re-
viewed by IARC w70x. Ground nickel powder has
been shown to cause a dose-dependent increase in
morphological transformation of Syrian hamster em-
bryo cells w129x. It also inhibited progression through
S phase in Chinese hamster ovary cells. Similar
effects on cell transformation were seen with nickel
monoxide and nickel trioxide. Crystalline nickel sul-
fide and nickel subsulfide induced DNA strand breaks
in rat primary hepatocytes and cultured mammalian
cells w130x. Crystalline nickel sulfide was also muta-
genic in Chinese hamster V79 cells. The frequency
of SCEs was increased in cultured human lympho-
cytes treated with nickel subsulfide. A dose- and
time-dependent increase in the frequency of CAs
185
including gaps, breaks, exchanges and dicentrics were
seen in Chinese hamster ovary cells w70x. Crystalline
nickel sulfide and subsulfide induced cell transfor-
mation, gene mutation and DNA damage in cultured
mammalian cells w70x CAs were induced in mouse
mammary carcinoma cells. Nickel sulfate and nickel
acetate induced anchorage-independent growth in
human cells in vitro. Increased risks for lung and
nasal cancers have been found to be associated with
exposures to nickel and its compounds w70x. The
highest risk for lung and nasal cancer has been
observed among calcining workers, who are heavily
exposed to oxidic nickel ŽRef. w70x and references
therein..
2.4.2.5. Arsenic. Approximately 55,000 workers may
be occupationally exposed to arsenic w131x. Occupa-
tional exposure to arsenic may be significant in
several industries, mainly nonferrous smelting, ar-
senic production, wood preservation, glass manufac-
turing, and arsenical pesticide production and appli-
cation. Workers in industry where gallium arsenide
is used can also be exposed to substances such as
arsenic, arsine and various other acids w132x.
There have been a large number of studies on the
genotoxic effects of arsenic. Inhalation exposure to
arsenic trioxide has been found to increase the fre-
quency of CAs in peripheral lymphocytes of smelter
workers w133,134x. Arsenic was also capable of pro-
ducing SCEs in most in vitro systems tested w135x.
An increased frequency of CAs in peripheral lym-
phocytes was also seen in a worker with oral expo-
sure w136x. There is clear evidence from studies in
humans that exposure to inorganic arsenic may also
increase the risk of cancer. In workers exposed by
inhalation, the predominant effect was an increased
risk of lung cancer w137,138x, although some studies
have noted increased incidences of tumors at other
sites w139,140x.
2.4.3. Specific chemical groups
In certain occupational settings, workers are ex-
posed to specific groups of chemicals. For example,
agricultural workers are exposed to insecticides,
fungicides andror herbicides; painters and some lab-
oratory workers are exposed to solvents; and health-
care workers are exposed to certain drugs.
186 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
2.4.3.1. Insecticides, fungicides and herbicides.
Worldwide consumption of insecticides in 1985 was
estimated at about 3 million tons, more than 75% of
this is being in the United States, Japan and in
Europe. Occupational exposures to insecticides,
fungicides and herbicides occur during manufacture
and processing as well as during their intended us-
ages. In addition, pesticide residues on plants or
fruits may cause significant exposure to farm work-
ers picking or handling the products. Exposure of
workers to insecticides, fungicides and herbicides
may be through skin contact, inhalation or ingestion.
The level of exposure depends on the type of appli-
cation and the specific job. Some of the most com-
monly used insecticides with potential genotoxic and
carcinogenic effects are aldicarb w141x, chlordane
w141,142x, heptachlor w141,142x, DDT w141x and as-
sociated compounds Žalthough DDT and its associ-
ated compounds have been banned from use for a
while, their residue still exists in the environment
and populations are potentially being exposed to
these compounds., deltamethrin and permethrin.
Fungicides such as captafol, pentachlorophenol, thi-
ram, ziram and herbicides such as atrazine, monuron,
picloram and simazine are in use and are potentially
genotoxic and, to a certain extent, carcinogenic w141x.
Aldicarb is highly toxic and induced CAs in rat
bone marrow cells in vivo w141,143x. It also induced
chromosomal damages and gene mutations in cul-
tured mammalian cells. Chlordane and heptachlor
have also been shown to induce gene mutations in
mammalian cells. IARC w141x classifies chlordane
and heptachlor as possible carcinogens to humans.
DDT increased frequencies of chromatid-type aberra-
tions in peripheral lymphocytes of workers with
increased plasma levels of DDT, however, conflict-
ing data are available with regard to other genetic
endpoints w141,144x. DDT has been tested adequately
for carcinogenicity in animal experiments and has
been proven to be carcinogenic in animals w141x.
Pentachlorophenol, a fungicide, significantly in-
creased the incidence of dicentric chromosomes and
acentric fragments in peripheral lymphocytes of
workers exposed occupationally to pentachloro-
phenol. It was also weakly positive for somatic gene
mutations in a mouse spot test and induced CAs in
cultured rodent cells. For additional information on
other chemicals listed, please refer to IARC w141x.
2.4.3.2. SolÕents. There are several organic solvents
to which workers are occupationally exposed.
Petroleum solvents, toluene, cyclohexanone,
dimethylformamide and certain products in paint
manufacturing are some examples that are poten-
tially genotoxic. The National Institute for Occupa-
tional Safety and Health w145x has estimated that
3500 workers are potentially exposed to petroleum
ether and about 26,400 workers are exposed to rub-
ber solvent. About 327,000 workers were potentially
exposed to varnish materials and paints w146x, about
160,000 to white spirits and 521,800 to Stoddard
solvent in the United States between 1981 and 1983.
Some of these solvents have genotoxic effects. A
rubber solvent induced CAs but not SCEs in human
whole-blood culture w147x. Potential long, high expo-
sure to mineral spirits was associated with increased
risks for squamous-cell lung cancer and prostatic
cancer w148x.
NIOSH w146x has estimated that 1,278,000 work-
ers were potentially exposed to toluene in the United
States between 1981 and 1983. Toluene is mainly
used in the production of benzene via the hydro-
demethylation process. The second largest use is in
solvent applications, especially in the painting and
coating industry. Significant amounts are also used
in inks, adhesives and in the leather industry w149x.
Cytogenetically, an excess of CAs were reported in
lymphocytes in Swedish workers exposed to toluene
w150x. Increases in the frequency of SCEs, chromatid
breaks, chromatid exchanges and gaps were reported
in the peripheral lymphocytes of workers in Ger-
many exposed to toluene w151x.
About one million workers were potentially ex-
posed to xylene in the United States between 1981
and 1983 w146x. Xylenes are primarily used for gaso-
line blending. They are also used in the manufacture
of perfumes, insecticides, pharmaceuticals and adhe-
sives and in the painting, printing, rubber, plastics
and leather industries w148x. Most genotoxicity stud-
ies indicate that xylene is not a genotoxic agent, and
there is also inadequate evidence for the carcino-
genicity of xylene in humans.
Paints and paint products are another group of
organic solvents that may pose potential health haz-
ards to exposed workers. Paints mainly consist of
pigments, binders Žresins., solvents and additives.
They are mainly used in exterior and interior paint-
 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
ing, masonry painting and waterproofing on un-
painted concrete, brick, surface coating in the wood
industry, painting in the metal industry and automo-
bile coatings. NIOSH estimates about 362,000 work-
ers are employed in construction or maintenance
painting. Workers are mainly exposed during the
manufacture of paints and related products, however,
exposure to industrial dusts during construction
painting and lacquering, during painting, varnishing
and lacquering in the wood industry and during
painting in the metal industry is also common. Occu-
pational exposure to paint products results predomi-
nantly from the inhalation of gases and vapors,
complex inorganic and organic mixtures such as
dusts from dried coatings and mists generated during
the spraying of paint. The other major route of
occupational exposure is through cutaneous contact
with various paint compounds, many of which can
be absorbed through the skin. Genotoxicity studies
did not show an increase in frequency of SCEs in
peripheral lymphocytes in painters or in paint manu-
facturing workers. However, an increased risk for
lung cancer among painters has been observed. Also,
an excess risk for bladder, oesophageal and stomach
cancers has been observed w148x.
2.4.3.3. Drugsr medicines. An increasing number of
agents, including pharmaceutical drugs and
medicines, are being used for the treatment of vari-
ous kinds of diseases. Recently, great attention has
been given to antineoplastic drugs that have new
possibilities for cancer treatment and prevention.
However, toxicological testing have shown that some
of these antineoplastic agents may be genotoxic. The
primary source of human exposure to these drugs is
from their use in therapy. Exposure may also occur
in persons employed in the manufacture of drugs as
well as nursing and other staff responsible for the
preparation and administration of compounds and
staff responsible for the care of treated patients.
Some of the common antineoplastic drugs are cyclo-
phosphamide, methotrexate, azacitidine, chlorozo-
tocin and thiotepa. Other drugs such as niridazole
and metronidazole are used in the treatment of para-
sitic disease in man. Hycanthone, lucanthone, nirida-
zole and furapromidium are used as antischistosomal
drugs. Representative drugs have been briefly dis-
cussed in the following paragraph. For additional
187
information on other drugs listed, refer to IARC
w152x.
Cyclophosphamide has been tested extensively for
genetic effects in a wide variety of tests in vivo and
in vitro, giving consistently positive results. It in-
duces CAs, micronuclei, SCEs and DNA damage in
human cells in vitro w152x. In rodent cells in vitro, it
induced cell transformation, CAs, SCEs, mutation
and unscheduled DNA synthesis. In bacteria, it in-
duced mutation and DNA damage w152x. Methotrex-
ate, another antineoplastic agent, induced CAs and
SCEs in vitro. It also caused morphological cell
transformation in C3H 10T1r2 cells and was muta-
genic to mouse lymphoma cells w152x. Hycanthone is
mutagenic in several mammalian and sub-mam-
malian test systems. It induced transformation in
RMV-infected mammalian cells and also increased
the incidence of tumors in schistosome-infected mice
and hamsters w153x.
2.5. Radiation
Exposure to radiation, such as X-rays, gamma
radiation, and UV radiation can produce increases in
the incidence of cancer. Radiation can be classified
as ionizing radiation and non-ionizing radiation. Ion-
izing radiation includes X-rays and gamma rays,
while UV light, low frequency, radio frequency and
microwave radiations are non-ionizing.
2.5.1. X-rays
The most common occupations with the potential
for exposure to X-rays are in healthcare. The geno-
toxic effects of exposure to X-rays are well docu-
mented. In vitro studies have shown increased fre-
quency of micronuclei and CAs in V79 cells when
exposed to different concentrations of X-rays w154x.
In vivo genotoxicity studies showed an increased
frequency of micronuclei and CAs in populations
exposed to X-rays. Occupationally exposed individu-
als in personnel handling diagnostic X-ray machines
showed a higher frequency of CAs than unexposed
controls w155x. In another study where medical staff
workers in the X-ray department were tested, an
increased number of micronuclei and CAs were ob-
served. Also, a synergistic effect was observed when
the subjects were exposed to both X-rays and ultra-
sound equipment w156x.
188 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
2.5.2. UV radiation
Exposure to UV radiation may occur in certain
occupational settings although it is not a major con-
tributor for occupational diseases. Artificial sources
of UV radiation are used in many different ways in
the working environment. In some cases, the UV
source presents no risk of exposure to personnel. In
other applications of UV radiation, it is inevitable
that workers are exposed to some radiation. Workers
may also be exposed to a UV source during indus-
trial photoprocesses; sterilization and disinfection,
such as germicidal lamps, bactericidal lamps or UVC
lamps; electric arc welding; in operating theaters;
research laboratories; UV photography; UV lasers;
insect traps; and in sunbed salons.
All three types of UV rays, ŽUVA, UVB, and
UVC. are mutagenic and induce DNA damage, SCEs,
CAs and morphological transformation in mam-
malian cells, human cells in vitro and induce DNA
damage in mammalian skin cells irradiated in vivo
w157x. Solar UVR also induces a variety of photo-
products in DNA, including cyclobutane-type pyrim-
idine dimers, pyrimidine–pyrimidone photoproducts,
cytosine damage, purine damage, DNA strand breaks
and DNA–protein cross-links w157x. The results of
epidemiological studies suggest that people who work
primarily outdoors have higher mortality from non-
melanocytic skin cancer. In a study of US fishermen,
estimates of individual, annual and cumulative expo-
sure to UVB were positively associated with the
occurrence of squamous-cell carcinoma. A positive
relationship between melanoma of the skin and ex-
posure to fluorescent lights at work among women
was observed w157x. Molecular studies have shown
base substitutions in the tumor suppressor gene, p53,
in human squamous-cell skin carcinomas that were
developed at sites exposed to sun. UVR also pro-
duces erythema, melanin pigmentation and acute and
chronic cells and histological changes in humans
2.5.3. Radon
Approximately 15,000 annual lung cancer deaths
in the United States are attributed to occupational
radon exposures and interestingly, the EPA estimates
approximately 14,000 lung cancer deaths due to
residential radon exposures w158x. Exposure to the
radioactive radon gas and its progeny has recently
been linked to a variety of cancers, including lung
cancer in geographic correlation studies of domestic
radon exposure and in individual cohorts of occupa-
tionally exposed miners. Occupational exposures to
radon and its progeny occur in underground mining
of uranium and other metals, and in processing
certain minerals, ores and radioactive materials w79x.
Workers in buildings in areas with high radon levels
are also at risk. Although radon concentrations in
homes and buildings are far lower than in mines, the
long periods of time that people spend at home and
at work can result in significant cumulative expo-
sures, but generally far less than a miner’s exposure.
The effects of radon are largely attributable to the
inhalation of its decay products. In a study of groups
either occupationally exposed to or resident in areas
of high natural radiation, including elevated levels of
radon and its decay products, an increase in CAs has
been observed w159x. Gene mutation studies have
shown elevated levels of specific p53 mutations
Žcodon 249. in lung cancer tissues of uranium miners
w160x, however, this finding has not been confirmed.
Increased lung cancer rates have been reported from
a number of cohorts and case-control studies of
underground uranium and other metal miners ex-
posed to radon and its decay product w79x.
2.5.4. MicrowaÕe
Not many data are available on the effects of
microwave radiation. Occupationally, certain groups
such as air traffic controllers, and those using cellu-
lar telephones and their associated broadcast equip-
ments, have raised concerns about exposures to radio
frequency or microwaves. Basically, four types of
effects have been described w161x, increased sponta-
neous abortion, shifts in red and white blood cell
counts, increased somatic mutation rates in lympho-
cytes, and increased childhood testicular and other
cancers. In one study, Garaj-Vrohac et al., w162x
examined six men accidentally exposed while repair-
ing microwave devices used for air traffic control in
Zagreb. The results of this study showed that mi-
crowave irradiation can produce genotoxic effects.
Both chromosomal and chromatid changes were ob-
served. Also, a series of studies from Croatia and
Italy have demonstrated that radar exposures are
mutagenic both in vitro and in vivo w162–165x.
These findings suggest that microwaves may be po-
tentially genotoxic to the exposed workers.
 N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194
3. Conclusions
Occupational exposure to genotoxic agents is a
major concern regarding millions of workers’ health
and well being. Although several regulatory mea-
sures have been taken by agencies such as the Occu-
pational Safety Health Administration and the Mine
Safety and Health Administration, workers are still
being exposed to certain genotoxic agents. Workers
in many occupational settings may not be aware that
they have been exposed to genotoxic agents, nor do
they know the type and amount of agent to which
they have been exposed. Efforts need to be made to
detect andror identify genotoxic agents in occupa-
tional settings and to establish disease-related
biomarkers for molecular epidemiology and surveil-
lance studies to facilitate prevention of occupational
cancer.
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