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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.
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 effects of these agents. In most cases only review
particles, wood dust, chromium, arsenic, vinyl chlo- articles are cited. Since there are hundreds of such
ride, benzene, etc., are known to be associated with agents, this review includes only those commonly
cancer risk w1,2x. It has been estimated that occupa- found in the occupational setting or those to which a
tional exposure accounts for 4% of all human cancer significant number of workers are exposed. In certain
w3x. In the United States, approximately 500,000 chemical groups, only a few representatives are listed.
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 2. Occupational exposure to genotoxic agents
cause genetic alterations in germ cells and lead to
reproductive disorders. It has been estimated that up The genotoxic agents to which workers are poten-
to 50% of fetal deaths, 30% of mental retardation, tially exposed can be grouped into the following
20% of congenital defects and 2% of total male categories: dusts and particles, fumes and fluids,
infertility are associated with chromosomal aberra- fibers, chemicals and radiation.
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- 2.1. Dusts and particles
sisted mainly of epidemiologic surveys of pregnancy
outcomes following maternal exposures. Such stud- Silica, diesel emission particles, coal dusts and
ies have shown increased rates of spontaneous abor- wood dusts ŽTable 1. are the most common occupa-
tions in chemical and laboratory workers w7,8x, ethy- tionally related dusts and particles.
lene oxide, and anaesthetic gases w9,10x. In general,
relatively few studies have been conducted on repro- 2.1.1. Silica
ductive outcomes associated with paternal exposures Silica can either be crystalline or amorphous. The
w11x. size of crystalline silica varies from less than 1 mm
Occupational cancers and reproductive disorders to more than 50 mm in diameter. Approximately 3.2
have been listed on NORA master list of research million workers are potentially exposed to respirable
priorities as major occupational diseases and injuries crystalline silica w14,15x. Its abundance in the envi-
w3x. It has been suggested that 10% of all chronic ronment is second only to oxygen. Crystalline silica
diseases, including cardiovascular diseases, are the is probably one of the most documented workplace
result of mutations. The National Institute for Occu- contaminants. The severity and the widespread na-
pational Safety and Health has identified cardio- ture of exposure and the associated health effects
vascular diseases as one of the 10 leading occupa- have been documented in the literature w16,17x. Some
tional diseases and injuries w12,13x. Personal risk is of the industries in which workers may be exposed
one of the primary factors associated with an in- to crystalline silica are in mining-related milling
creased incidence of coronary heart disease. How- operations, iron and steel milling, quarrying, con-
ever, it is not known what fraction, if any, of the struction, glass and cement-making, ceramics Žin-
cardiovascular diseases among workers are due to cluding the making of pottery, porcelain, tiles, bricks,
exposure to genotoxic agents in the occupational etc.., silicon and ferro-silicon foundry work, metal
setting. A review of current information on the rela- manufacturing, manufacture of machinery, and in
tionship between workplace factors and cardio- agriculture. Occupational exposure to crystalline sil-
vascular disease shows that millions of workers are ica in mines mainly occurs from the dust generated
currently exposed to work-related factors, including from the ore that is being extracted or from its
chemicals, associated with an increased risk of car- associated rock. Exposure to silica in foundries oc-
diovascular disease w12x. curs mainly in the use of sands in the making of
This review discusses the exposure of workers in molds and cores.
different occupational settings to genotoxic agents Genotoxicity and clastogenicity of silica has re-
and briefly describes the genotoxic and carcinogenic 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- tal and epidemiologic studies of cancer in animals
ated and micronucleated cells in Syrian hamster em- and workers exposed to respirable crystalline silica
bryo cells treated with Min–U–Sil quartz w16,17x. and has concluded that there is sufficient evidence in
Min–U–Sil 5 and Min–U–Sil 10 silica samples humans to show genotoxicity and carcinogenicity of
were also shown to induce a significant dose-related inhaled crystalline silica in the forms of quartz or
increase in micronuclei in Chinese hamster lung cristobalite from occupational sources w16,17x.
fibroblast ŽV79. cells and human embryonic lung
ŽHel 299. cells w19x. Also, a significant and dose-de- 2.1.2. Diesel emission particles
pendent increase in the frequency of morphologically It has been estimated that approximately 1.35
transformed Syrian hamster embryo cells was re- million workers are occupationally exposed to the
ported following treatment with Min–U–Sil 5 and combustion products of diesel fuel in about 80,000
other quartz samples w20,21x. Gene expression using workplaces across the United States w24x. Occupa-
nine proto-oncogenes and the p53 tumor suppressor tional exposure is common among transportation
gene in a small number of cell lines suggested an workers, operators of diesel-powered equipment and
increase in the mRNA expression of four proto- among some miners operating diesel-powered equip-
oncogenes Ž K-ras, H-ras, myc, abl . and of the p53 ment underground. Bus workers, bus-maintenance
gene in some quartz-transformed cell lines w22x. Ge- workers, railroad workers and truck drivers are also
nomic instability has also been found in transformed among those who are potentially exposed to diesel
BALBrc 3T3 cells induced by silica w23x. In addi- exhaust. Diesel exhaust consists of both gaseous and
tion to in vitro studies, genotoxic potential has also particulate fractions. The particulate is composed
been studied in silica-exposed workers. Significant mostly of carbon formed through the incomplete
increases in the levels of chromosomal aberrations combustion of fuel. Many of these substances are
ŽCAs. and sister chromatid exchanges ŽSCEs. in mutagenic or carcinogenic, containing chemicals such
peripheral blood lymphocytes of workers from a as 3-to-5-ring polycyclic aromatic hydrocarbons
stone crushing unit have been observed w16x. IARC ŽPAHs., aliphatic hydrocarbons, ketones and aldehy-
has also reviewed in detail the published experimen- 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 rock-dusters, coal drill operators, cutting machine
potential health hazard to exposed workers. operators, and blasters often are potentially exposed
Diesel exhaust has been classified as a potential to a high concentrations of respirable coal dust.
occupational carcinogenic agent in humans by the Other than mining, exposure to coal dust can also
National Institute for Occupational Safety and Health occur during bulk coal transfer and at sites where
w24x. McClellan et al. w26x have summarized the coal is used.
biological activity of diesel exhaust, concluding that Studies related to the genotoxicity of coal dusts
diesel exhaust particle extracts have a potency al- have been reviewed by IARC w16x. It has been shown
most equaling that of coke-oven emissions and, in- that organic solvent extracts of coal dust from differ-
terestingly, are more potent than cigarette smoke. ent types of coals are either non-mutagenic or weakly
Nitrosocompounds, chemicals found in diesel ex- mutagenic with microsomal activation. However,
haust particles, have been found to be major contrib- high mutagenic activities were found when extracts
utors to mutagenicity in the Salmonella typhimurium of bituminous, sub-bituminous and lignite coal dusts
assay w25x. Genotoxicity of diesel emission particles were reacted with nitrite under acidic conditions w39x.
has been reviewed in literature w26–28x. Diesel ex- The nitrosated extracts of coal dust induce gene
tract has been found to cause mutations in cultured mutations in bacteria and mammalian cells, induce
mammalian cells. Micronucleus induction by diesel SCEs and CAs in human peripheral lymphocytes and
extract has been observed in mammalian cells both induce morphological transformation in BALBrc-
in vitro and in vivo. Diesel emission particles have 3T3 cells w40,41x. In vivo genotoxicity studies using
also been known to induce MN, SCEs, CAs and peripheral blood lymphocytes show an elevated fre-
morphological cell transformation in various mam- quency of aberrant cells Žcells with chromatid or
malian cell systems. Animal studies have shown that chromosome breaks. in workers employed in digging
diesel exhaust is potentially co-tumorigenic w29–31x. operations w42x. Also, exposure to fumes in soft coal
Epidemiological studies indicate that heavy occupa- open-cast mining operations increased CAs com-
tional exposure to diesel exhaust increased MN and pared to controls w38x. Oxidative DNA damage has
SCE in traffic policemen w32x and also increased the also been observed in coal miners exposed to coal
risk of mortality for both lung cancer and non-cancer dust when compared to non-exposed controls w43x.
pulmonary disease w33–35x. The health effect of coal mine dust has been studied
in coal miners. The most common illnesses associ-
2.1.3. Coal dust ated with coal dust exposure are pneumoconiosis,
Coal mining was very popular at the turn of the progressive fibrosis, chronic bronchitis and acceler-
century with the invention of the steam engine. ated loss of lung function w38x. Increases in stomach
About 800,000 miners were employed in 1923 w36x, cancer among coal miners have been reported by
however, with the declining use of the coal for several epidemiological studies w17x.
transportation and steel mining, coal mining employ-
ment has dropped dramatically. Still, there are about 2.1.4. Wood dust
400,000 miners in the United States, and 2000 of The National Occupational Exposure Survey, car-
them die each year of lung disease w37x. Coal mine ried out in 1981-1983 in the United States, estimated
dust is a complex and heterogeneous mixture con- that about 600,000 workers were exposed to wood
taining more than 50 different organic or inorganic dust. The largest numbers of exposed workers were
chemicals and their oxides. Some of the minerals employed in the building trades and the lum-
occurring in coal are silicates, oxides, carbonates, berrwood product industries such as wood machin-
sulfides and sulfates. Some of these particles are ists, cabinet makers, chair makers, turners and
respirable and therefore increase the risk for health sanders. Exposure to wood dust is associated with an
hazards among coal miners w38x. The coal component increased risk of developing adenocarcinomas of the
of respirable dust in coal mines can be highly vari- nasal cavity w44x. Both occupation and type of wood
able depending on the stage of the mining operation. dust exposure influence the histological type of nasal
Occupations such as mine operators, jack-setters, cancer observed. For example, increased incidence
N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194 179
Genotoxicity of welding fumes has been reviewed chemical reactions between components. Compounds
by IARC w70x. Studies have shown both positive and such as N-nitrosodimethylamine, N-nitrosodiethy-
negative results for gene mutations in cultured mam- lamine, N-nitrosodiethanolamine, N-nitrodibutyla-
malian cells exposed to stainless-steel welding fumes. mine, N-nitrosomorpholine are known to be car-
Welding fumes induced morphological transforma- cinogens and have been found in MWFs. Some
tion in mammalian cells in vitro w71x as well as 3-to-5-ring PAHs found in MWFs, are known to
increased frequencies of CAs w72x andror SCEs be genotoxic.
w72,73x. Also, fumes from manual metal arc welding Genotoxicity and carcinogenicity studies have
of mild steel or cast iron using a nickel electrode shown that a significant increase in the number of
increased the frequency of SCEs, in mammalian cells DNA strand breaks in mononuclear blood cells was
in vitro ŽRef. w70x and references therein.. Genotoxic- observed in workers exposed to MWFs w78x. Skin
ity studies have shown increased levels of SCEs and cancer of hands, forearms and scrotum has been
CAs in peripheral blood lymphocytes of workers reported due to long-term exposure of workers to
exposed during stainless-steel welding w74x. Carcino- poorly or non-refined mineral oils w78x. Primary ex-
genicity studies have shown an excessive risk for posure to straight oil MWFs has been associated
lung cancer among welders and flame cutters w75x. In with an increased risk for laryngeal, rectal, pancre-
a large study of shipyard welders in Finland, a atic and bladder cancer w78x.
moderately increased incidence of lung cancer was
found. Also, five other studies conducted in United 2.3. Fibers
States and Europe indicated about 30% increased
risk for lung cancer among welders ŽRef. w70x and Fibers are classified as either natural or man-made.
references therein.. Man-made mineral fibers are inorganic substances
primarily made from rock, clay, slag or glass. These
2.2.3. Metal-working fluids fibers can be further classified into three general
An estimated 1.2 million workers are potentially groups: glass fibers, rock wool and slag wool, and
exposed to agents collectively referred to as metal- ceramic fibers. Very little information is available
working fluids ŽMWFs. w76x. These agents are com- regarding the genotoxicity of rock wool, slag wool
monly used in a variety of industrial machining and and ceramic fibers.
grinding operations. MWFs are primarily used to
cool and lubricate both machinery and working sur- 2.3.1. Glass fibers
faces. They are also used to provide corrosion pro- The primary use of glass fibers is for thermal and
tection and removal of metal chips. MWFs are clas- acoustical insulation in construction and ship-build-
sified into four major classes: Ž1. straight oil MWFs, ing. They are also used as insulation in houses,
which are made from naphthenic or paraffinic oils incorporated into ceiling tile for fire resistance as
and contain no water; Ž2. soluble oil MWFs, which well as for thermal and sound insulation. Small-di-
are naphthenic or paraffinic oils emulsified in water; ameter glass fibers are used in air and liquid filtra-
Ž3. synthetic MWFs, which are chemical fluids con- tion and glass fiber air filters have been used in
taining no petroleum-based oils; and Ž4. semisyn- furnaces and air-conditioning systems. Glass fibers
thetic MWFs, which are emulsions containing small are also used for aerospace engineering in the form
amounts of oil w77x. The types and amounts of of batts, blankets and molded parts. In addition, glass
chemical constituents may vary between the different fibers are sold as chopped strand mats rovings,
classes of MWFs. Limited information exists about chopped fibers, yarns, yarn fabrics and roofing mats.
the chemical components of specific MWFs. A wide Occupational exposure occurs in the fibrous glass
variety of chemicals and contaminants may be pre- industry during production, manufacturing, mainte-
sent in each of the MWF classes, and the hazard that nance, quality control and shipping. Workers in-
these chemicals pose to workers may vary widely volved in general manufacturing operations, such as
because of different manufacturing processes, vari- trimming, sawing, cutting, finishing, painting and
ous degrees of refining, recycling and potential molding are potentially exposed to glass fibers.
N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194 181
Maintenance workers, including those who sweep turing Žprocessing asbestos-manufactured products to
floors or clean dust collectors and machinery, as well make other products. and consumer industries Žutiliz-
as those who do general cleaning within the plant, ing a finished product containing asbestos without
may also be exposed to glass fibers. modification. w85x.
The genotoxic effects of glass fibers have been Genotoxicity studies have shown that asbestos
reviewed in the literature w79x. Fine and coarse glass fibers can induce gross CAs and micronuclei in
fibers were found not to induce mutations in S. mammalian cells w86–90x. An increase in unsched-
typhimurium. An increase in CAs was observed in uled DNA synthesis has been reported in rat
CHO-K1 cells after treatment with JM 100 glass mesothelial cells exposed to crocidolite and chryso-
wool w80x. Other in vitro studies have shown that lite w91x. Increased frequencies of CAs andror SCEs
glass fibers are capable of inducing micronucleated were observed in peripheral blood lymphocytes of
andror multinucleated cells in cultured Chinese asbestos cement workers w92–94x and leukocytes
hamster lung fibroblasts w81x and cultured human from asbestos workers w94x. Asbestos may induce
primary mesothelial cells w82x. It has also been shown cancer directly in humans by causing CAs, or indi-
that two of the three microfibers studied were capa- rectly by the production of free radicals, which lead
ble of inhibiting cytokinesis and were principally to genetic damage or an altered immune response
aneuploidogens. Interestingly, large fibers neither w95x. All types of asbestos are considered to cause
induce micronuclei nor inhibit cytokinesis. This lung cancer in humans. It is estimated that about one
indicates that size may play an important role in third as many deaths will occur from asbestosis as
genotoxicity w81x. Significant increases in numerical from mesothelioma w84x. Although it is not clear if
chromosomal changes as well as in the number of asbestos is the only cause for mesothelioma and
binucleated and micronucleated cells were observed cancer of the lung in asbestos-exposed workers, the
after treatment of Syrian hamster embryo cells with majority of the workers who die working in as-
JM 100 glass wool w83x. Both JM 100 and JM 110 bestos-related plants are mesothelioma and lung can-
glass wool induced a linear, dose-dependent increase cer patients. In addition, cancers of the stomach,
in the frequency of transformed colonies in Syrian colon, rectum, esophagus, larynx, pharynx, buccal
hamster embryo cells in culture after a single cavity, and the kidney are each elevated significantly
treatment of the cells w79x. Glass wool-induced mor- compared with rates expected for these sites in the
phological transformation was also found to be de- general population. Exposure of the mesothelial tis-
pendent on fiber length and diameter w18x. Human sue and kidney may occur since fibers readily pene-
carcinogenicity data indicate no increase in the oc- trate into lung lymphatics and reach the pleural
currence of lung cancer w79x. A slight increase in mesothelium or can also be transported to the kidney
mortality from respiratory cancer was observed in or the peritoneal mesothelium w84,96x.
glass wool workers in the United States. However, a
study of Canadian glass wool workers showed a 2.4. Chemicals
substantially raised mortality from lung cancer w79x.
Occupationally related chemicals can be broadly
2.3.2. Asbestos classified into three types: organic chemicals, inor-
According to Nicholson et al. w84x, 27.5 million ganic chemicals and specific chemical groups. The
individuals have had past occupational exposure to following is a brief discussion of several selected
asbestos ŽTable 1.. Workers are exposed to asbestos chemicals and specific chemical groups. Genotoxic-
in a wide variety of industrial settings, consisting ity of common occupationally related chemicals are
primarily of maintenance and construction workers also listed in Table 2.
exposed to asbestos insulation and mechanics ex-
posed to asbestos in brake linings. Other industrial 2.4.1. Organic chemicals
settings where workers may also be exposed include Among the most common organic chemicals found
primary manufacturing Žproducing manufactured in occupational settings are vinyl chloride, tetra-
goods from raw asbestos fibers., secondary manufac- 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. after metabolic activation. VC is mutagenic in the
accounts for 20% of plastic material usage and is Ames Salmonella microsomal assay system. VC ex-
found in most industrial sectors w97,98x. Vinyl chlo- posure also induced unscheduled DNA synthesis in
ride ŽVC. and dioxin are the most toxic byproducts rat hepatocytes and increased SCEs in human lym-
in PVC manufacture. The main route of occupational phocytes after addition of an exogenic activation
exposure is via inhalation and occurs primarily in system. VC exposure induced gene mutations and
VCrPVC plants. Agency for Toxic Substances and mitotic recombination in Drosophila melanogaster.
Disease Registry has provided an extensive review Cytogenetic studies have shown that the levels of
w99x on the genotoxicity and carcinogenicity of VC. CAs, micronuclei and SCEs in peripheral blood lym-
The genotoxic activities of VC have been detected in phocytes of workers exposed to VC are higher com-
a number of in vitro test systems, predominantly pared to control subjects ŽRef. w99x and references
N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194 183
therein.. Point mutations have also been detected in urinary bladder cancer, esophageal cancer, lung can-
the p53 and ras genes from tumors Žangiosarcoma cer and cervical cancer has been observed w102x.
of liver and hepatocellular carcinoma. of vinyl chlo-
ride exposed workers. Animal studies have also 2.4.1.3. Benzene. It has been estimated that approxi-
shown that VC is carcinogenic, causing a wide spec- mately 238,000 workers may be occupationally ex-
trum of tumors in various animal species w99,100x. posed to benzene in the United States w106x. They are
VC exposure has been particularly associated with a primarily exposed during the production of petro-
rare tumor, angiosarcoma of the liver ŽASL., in chemicals, petroleum refining, coke and coal chemi-
humans and in animals w99,101x. Other tumors that cal manufacturing, rubber tire manufacturing, and
have been found, at least in animal species, include storage or transport of benzene and petroleum prod-
liver tumors Žother than ASL., mammary gland car- ucts containing benzene. Steel workers, printers, rub-
cinoma, nephroblastoma, and lung tumors. ber workers, shoe makers, laboratory technicians,
firefighters and gas station employees may also be
2.4.1.2. Tetrachloroethylene. Commercial dry clean- exposed to benzene to certain extent.
ing makes up the largest segment of the cleaning Studies on genotoxicity show that benzene is
industry. The chemicals used mostly include chlori- clastogenic in humans and induces CAs in peripheral
nated solvents, amyl acetate, bleaching agents, acetic lymphocytes w106x. In another study, workers ex-
acid, aqueous ammonia, oxalic acid, hydrogen perox- posed to benzene for various time periods showed a
ide and dilute hydrogen fluoride solutions. Tetra- significantly higher proportion of chromosome breaks
chloroethylene comprises about 82% of the solvents w107x. Some studies involving individuals with long-
used in dry cleaning. In 1991, tetrachloroethylene term occupational exposure to benzene also suggest
was used in estimated 28,181 dry cleaning plants in that benzene damage chromosomes in hematopoietic
the United States. The National Occupational Expo- cells. A slight increase in SCEs was observed in
sure Survey indicated that about 566,000 employees peripheral lymphocytes from workers exposed to
in 42,700 plants were potentially exposed to tetra- benzene w108x. Other evidence of genotoxicity in-
chloroethylene w102x. Occupational exposure to tetra- duced by benzene is the inhibition of DNA synthesis
chloroethylene occurs through inhalation, skin ab- in certain cell types w109x. Epidemiological studies
sorption and ingestion. Most occur by inhalation have shown acute myeloid leukemia in benzene ex-
whenever tetrachloroethylene vapors escape from a posed workers w110x.
dry cleaning machine in the form of process or
fugitive emissions. Improper storage of hazardous 2.4.1.4. Styrene. NIOSH estimates that approxi-
waste, including still residues, dirty filters or contam- mately 300,000 workers at 22,000 facilities may be
inants in lint and water separator run-off can increase exposed to styrene w111x. Exposure primarily occurs
background levels of tetrachloroethylene. Tetra- in the reinforced-plastics industry where there may
chloroethylene clearly increased the number of rever- be a high air concentration for inhalation and dermal
tants in S. typhimurium in the presence of rat liver contact with liquid styrene or resins w112,113x. Sig-
enzymes w103x. In another study, tetrachloroethylene nificant occupational exposures may also occur in
induced cell transformation in Fischer rat embryo other industrial settings, such as styrene polymeriza-
cells but not in mouse BALBrc-3T3 cells in the tion, rubber manufacturing and styrene–polyester
absence of exogenous metabolic activation w102x. resin facilities w113,114x.
Other genotoxicity studies have shown a significant The genotoxic effects of styrene have been well
correlation between the tetrachloroethylene content studied w115,116x. CAs have been reported in several
of air and urinary mutagenicity in 24 Estonian dry studies of workers exposed to styrene w117x.
cleaners w104x. An increase in SCEs was seen in Styrene-exposed men showed an increase in the
dry-cleaners when compared to control groups, how- number of aberrant cells along with an increase in
ever the dry-cleaners in the study were smokers, so a the frequency of micronuclei w117x. In another study
definitive conclusion could not be made w105x. In- of exposed workers, an increase in the incidence of
creased risk for certain types of cancer, such as 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 ing, machining and producing beryllium metal and
several epidemiological studies that suggest there alloys was associated with an increased risk of lung
may be an association between styrene exposure and cancer.
an increased risk of leukemia and lymphoma, the
evidence is generally inconclusive because of multi- 2.4.2.2. Chromium. The National Institute for Occu-
ple chemical exposures and inadequate documenta- pational Safety and Health w125x estimated that about
tion of the levels and durations of exposure to styrene. two million workers are exposed to chromium and
chromium compounds. Potential occupational expo-
2.4.2. Inorganic chemicals sure to chromium occurs through inhalation, inges-
Some of the important occupational inorganic tion or skin contact w126x. Occupations with potential
chemicals are beryllium, chromium, cadmium, ar- exposures to chromium include cement workers,
senic and nickel. Most of these inorganic compounds chromium platers, dye manufacturers, electroplaters,
exist in several different forms such as alloys, ox- leather finishers, lithographers, metal cleaners, oil
ides, chlorides, sulphates, carbonates and nitrates. drillers, painters, pencil manufacturers, photogra-
phers, printers, shingle manufacturers, corrosion-in-
2.4.2.1. Beryllium. Occupational exposure to beryl- hibitor workers, furniture polishers, glass frosters,
lium and beryllium compounds occur in a range of welders, textile workers, wood stainers and several
industrial processes. In 1971, approximately 30,000 others w126x.
employees were potentially exposed to beryllium Elevated levels of SCEs were observed in workers
w119x. Beryllium is used in many manufacturing exposed to chromium wIVx compounds in electroplat-
industries such as ceramics, non-ferrous foundries, ing factories w70x. CAs were also found in studies of
non-ferrous smelters, sand blasting, electronics, fab- exposed workers. Several other forms of chromate
rication, welding or flame cutting, and metal plating. induced a variety of genetic effects including DNA
It is also used in the recycling industry and for damage, gene mutation, SCEs, CAs, cell transforma-
processing, such as in hazardous waste processing tion and dominant lethal mutations in a number of
w120,121x. Exposure to fumes, dusts and mists of targets, including animal cells in vivo and animal
beryllium compounds can also occur during produc- and human cells in vitro w70x. Epidemiological stud-
tion of beryllium metal. ies of workers in the chromate production industry
Studies on genotoxicity as reviewed by IARC have consistently shown an excess risk for lung
w122x show that beryllium sulfate is mutagenic to cancer w70x. Increased risk for lung cancer has also
Bacillus subtilis, however, it is inactive in most other been observed in facilities where zinc chromate was
bacterial mutagenesis assays. Beryllium chloride and produced Že.g., in the chromate plating industry, and
beryllium nitrates have been shown to induce SCEs in stainless-steel welding. w70x.
in V79 cells. In cultured mammalian cells, low-tem-
perature-fired beryllium oxide induced single strand 2.4.2.3. Cadmium. Approximately 500,000 workers
breaks in DNA w122x. Beryllium sulfate has also in the United States are exposed to cadmium w127x.
been shown to induce morphological transformation Workers may be exposed to cadmium and cadmium
in BALBrc-3T3 and Syrian hamster embryo cells. compounds in a variety of occupational settings. The
Beryllium sulfate also increased the frequency of major sources of such exposure are smelting, refin-
SCEs in Syrian hamster embryo cells and cultured ing of zinc, lead and copper ores, electroplating,
human lymphocytes w123x. manufacturing of cadmium alloys, pigments, plastic
Human carcinogenicity data show an increased stabilizers, nickel–cadmium batteries, and welding.
incidence of mortality from lung cancer in beryllium Cadmium may enter the body by ingestion, inhala-
plant workers w124x. The risk of lung cancer was tion and, to a very limited extent, by passage through
consistently higher in those plants in which there the skin.
was also an excess mortality from non-malignant The genotoxic and carcinogenic related activities
respiratory disease. Also, it has been concluded that of cadmium and related compounds have been re-
the work environment of workers involved in refin- viewed by IARC w122x. DNA strand breaks, muta-
N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194 185
tions, chromosomal damage and cell transformation including gaps, breaks, exchanges and dicentrics were
have been observed in vitro as a result of cadmium seen in Chinese hamster ovary cells w70x. Crystalline
exposure. Cadmium compounds inhibit the repair of nickel sulfide and subsulfide induced cell transfor-
DNA damaged by other agents, thereby enhancing mation, gene mutation and DNA damage in cultured
their genotoxicity. Studies using cultured animal cells mammalian cells w70x CAs were induced in mouse
have shown that exposure to cadmium compounds mammary carcinoma cells. Nickel sulfate and nickel
damages genetic material. CAs and aneuploidy were acetate induced anchorage-independent growth in
seen in animals exposed to cadmium chloride in human cells in vitro. Increased risks for lung and
vivo. Frequencies of CAs were increased in periph- nasal cancers have been found to be associated with
eral blood lymphocytes of workers exposed to cad- exposures to nickel and its compounds w70x. The
mium in the metal industry w122x. Excess mortality highest risk for lung and nasal cancer has been
from lung cancer has been reported among workers observed among calcining workers, who are heavily
employed in a cadmium recovery plant ŽRef. w122x exposed to oxidic nickel ŽRef. w70x and references
and references therein.. An increased risk for lung therein..
cancer is associated in cadmium-related occupational
exposures. A number of early studies have reported 2.4.2.5. Arsenic. Approximately 55,000 workers may
an increased risk for prostatic cancer among cad- be occupationally exposed to arsenic w131x. Occupa-
mium workers, however, the results are inconsistent. tional exposure to arsenic may be significant in
several industries, mainly nonferrous smelting, ar-
2.4.2.4. Nickel. It has been estimated that about 1.5 senic production, wood preservation, glass manufac-
million workers in the United States are potentially turing, and arsenical pesticide production and appli-
exposed to nickel and nickel compounds w128x. Oc- cation. Workers in industry where gallium arsenide
cupational exposure to nickel may occur by skin is used can also be exposed to substances such as
contact or by inhalation of dusts, fumes or mists arsenic, arsine and various other acids w132x.
containing nickel or by inhalation of gaseous nickel There have been a large number of studies on the
carbonyl. Occupations with potential exposure to genotoxic effects of arsenic. Inhalation exposure to
nickel include battery makers, ceramic makers, dy- arsenic trioxide has been found to increase the fre-
ers, electroplaters, jewellers, nickel-alloy makers, quency of CAs in peripheral lymphocytes of smelter
nickel refiners, nickel smelters, nickel miners, or- workers w133,134x. Arsenic was also capable of pro-
ganic chemical synthesizers, paint makers, petroleum ducing SCEs in most in vitro systems tested w135x.
refinery workers, textile dyers, varnish makers and An increased frequency of CAs in peripheral lym-
welders. phocytes was also seen in a worker with oral expo-
Genotoxic and carcinogenic related activities of sure w136x. There is clear evidence from studies in
nickel and related compounds have also been re- humans that exposure to inorganic arsenic may also
viewed by IARC w70x. Ground nickel powder has increase the risk of cancer. In workers exposed by
been shown to cause a dose-dependent increase in inhalation, the predominant effect was an increased
morphological transformation of Syrian hamster em- risk of lung cancer w137,138x, although some studies
bryo cells w129x. It also inhibited progression through have noted increased incidences of tumors at other
S phase in Chinese hamster ovary cells. Similar sites w139,140x.
effects on cell transformation were seen with nickel
monoxide and nickel trioxide. Crystalline nickel sul-
fide and nickel subsulfide induced DNA strand breaks 2.4.3. Specific chemical groups
in rat primary hepatocytes and cultured mammalian In certain occupational settings, workers are ex-
cells w130x. Crystalline nickel sulfide was also muta- posed to specific groups of chemicals. For example,
genic in Chinese hamster V79 cells. The frequency agricultural workers are exposed to insecticides,
of SCEs was increased in cultured human lympho- fungicides andror herbicides; painters and some lab-
cytes treated with nickel subsulfide. A dose- and oratory workers are exposed to solvents; and health-
time-dependent increase in the frequency of CAs 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. 2.4.3.2. SolÕents. There are several organic solvents
Worldwide consumption of insecticides in 1985 was to which workers are occupationally exposed.
estimated at about 3 million tons, more than 75% of Petroleum solvents, toluene, cyclohexanone,
this is being in the United States, Japan and in dimethylformamide and certain products in paint
Europe. Occupational exposures to insecticides, manufacturing are some examples that are poten-
fungicides and herbicides occur during manufacture tially genotoxic. The National Institute for Occupa-
and processing as well as during their intended us- tional Safety and Health w145x has estimated that
ages. In addition, pesticide residues on plants or 3500 workers are potentially exposed to petroleum
fruits may cause significant exposure to farm work- ether and about 26,400 workers are exposed to rub-
ers picking or handling the products. Exposure of ber solvent. About 327,000 workers were potentially
workers to insecticides, fungicides and herbicides exposed to varnish materials and paints w146x, about
may be through skin contact, inhalation or ingestion. 160,000 to white spirits and 521,800 to Stoddard
The level of exposure depends on the type of appli- solvent in the United States between 1981 and 1983.
cation and the specific job. Some of the most com- Some of these solvents have genotoxic effects. A
monly used insecticides with potential genotoxic and rubber solvent induced CAs but not SCEs in human
carcinogenic effects are aldicarb w141x, chlordane whole-blood culture w147x. Potential long, high expo-
w141,142x, heptachlor w141,142x, DDT w141x and as- sure to mineral spirits was associated with increased
sociated compounds Žalthough DDT and its associ- risks for squamous-cell lung cancer and prostatic
ated compounds have been banned from use for a cancer w148x.
while, their residue still exists in the environment NIOSH w146x has estimated that 1,278,000 work-
and populations are potentially being exposed to ers were potentially exposed to toluene in the United
these compounds., deltamethrin and permethrin. States between 1981 and 1983. Toluene is mainly
Fungicides such as captafol, pentachlorophenol, thi- used in the production of benzene via the hydro-
ram, ziram and herbicides such as atrazine, monuron, demethylation process. The second largest use is in
picloram and simazine are in use and are potentially solvent applications, especially in the painting and
genotoxic and, to a certain extent, carcinogenic w141x. coating industry. Significant amounts are also used
Aldicarb is highly toxic and induced CAs in rat in inks, adhesives and in the leather industry w149x.
bone marrow cells in vivo w141,143x. It also induced Cytogenetically, an excess of CAs were reported in
chromosomal damages and gene mutations in cul- lymphocytes in Swedish workers exposed to toluene
tured mammalian cells. Chlordane and heptachlor w150x. Increases in the frequency of SCEs, chromatid
have also been shown to induce gene mutations in breaks, chromatid exchanges and gaps were reported
mammalian cells. IARC w141x classifies chlordane in the peripheral lymphocytes of workers in Ger-
and heptachlor as possible carcinogens to humans. many exposed to toluene w151x.
DDT increased frequencies of chromatid-type aberra- About one million workers were potentially ex-
tions in peripheral lymphocytes of workers with posed to xylene in the United States between 1981
increased plasma levels of DDT, however, conflict- and 1983 w146x. Xylenes are primarily used for gaso-
ing data are available with regard to other genetic line blending. They are also used in the manufacture
endpoints w141,144x. DDT has been tested adequately of perfumes, insecticides, pharmaceuticals and adhe-
for carcinogenicity in animal experiments and has sives and in the painting, printing, rubber, plastics
been proven to be carcinogenic in animals w141x. and leather industries w148x. Most genotoxicity stud-
Pentachlorophenol, a fungicide, significantly in- ies indicate that xylene is not a genotoxic agent, and
creased the incidence of dicentric chromosomes and there is also inadequate evidence for the carcino-
acentric fragments in peripheral lymphocytes of genicity of xylene in humans.
workers exposed occupationally to pentachloro- Paints and paint products are another group of
phenol. It was also weakly positive for somatic gene organic solvents that may pose potential health haz-
mutations in a mouse spot test and induced CAs in ards to exposed workers. Paints mainly consist of
cultured rodent cells. For additional information on pigments, binders Žresins., solvents and additives.
other chemicals listed, please refer to IARC w141x. They are mainly used in exterior and interior paint-
N. KeshaÕa, T. Ong r Mutation Research 437 (1999) 175–194 187
ing, masonry painting and waterproofing on un- information on other drugs listed, refer to IARC
painted concrete, brick, surface coating in the wood w152x.
industry, painting in the metal industry and automo- Cyclophosphamide has been tested extensively for
bile coatings. NIOSH estimates about 362,000 work- genetic effects in a wide variety of tests in vivo and
ers are employed in construction or maintenance in vitro, giving consistently positive results. It in-
painting. Workers are mainly exposed during the duces CAs, micronuclei, SCEs and DNA damage in
manufacture of paints and related products, however, human cells in vitro w152x. In rodent cells in vitro, it
exposure to industrial dusts during construction induced cell transformation, CAs, SCEs, mutation
painting and lacquering, during painting, varnishing and unscheduled DNA synthesis. In bacteria, it in-
and lacquering in the wood industry and during duced mutation and DNA damage w152x. Methotrex-
painting in the metal industry is also common. Occu- ate, another antineoplastic agent, induced CAs and
pational exposure to paint products results predomi- SCEs in vitro. It also caused morphological cell
nantly from the inhalation of gases and vapors, transformation in C3H 10T1r2 cells and was muta-
complex inorganic and organic mixtures such as genic to mouse lymphoma cells w152x. Hycanthone is
dusts from dried coatings and mists generated during mutagenic in several mammalian and sub-mam-
the spraying of paint. The other major route of malian test systems. It induced transformation in
occupational exposure is through cutaneous contact RMV-infected mammalian cells and also increased
with various paint compounds, many of which can the incidence of tumors in schistosome-infected mice
be absorbed through the skin. Genotoxicity studies and hamsters w153x.
did not show an increase in frequency of SCEs in
peripheral lymphocytes in painters or in paint manu- 2.5. Radiation
facturing workers. However, an increased risk for
lung cancer among painters has been observed. Also, Exposure to radiation, such as X-rays, gamma
an excess risk for bladder, oesophageal and stomach radiation, and UV radiation can produce increases in
cancers has been observed w148x. the incidence of cancer. Radiation can be classified
as ionizing radiation and non-ionizing radiation. Ion-
2.4.3.3. Drugsr medicines. An increasing number of izing radiation includes X-rays and gamma rays,
agents, including pharmaceutical drugs and while UV light, low frequency, radio frequency and
medicines, are being used for the treatment of vari- microwave radiations are non-ionizing.
ous kinds of diseases. Recently, great attention has
been given to antineoplastic drugs that have new 2.5.1. X-rays
possibilities for cancer treatment and prevention. The most common occupations with the potential
However, toxicological testing have shown that some for exposure to X-rays are in healthcare. The geno-
of these antineoplastic agents may be genotoxic. The toxic effects of exposure to X-rays are well docu-
primary source of human exposure to these drugs is mented. In vitro studies have shown increased fre-
from their use in therapy. Exposure may also occur quency of micronuclei and CAs in V79 cells when
in persons employed in the manufacture of drugs as exposed to different concentrations of X-rays w154x.
well as nursing and other staff responsible for the In vivo genotoxicity studies showed an increased
preparation and administration of compounds and frequency of micronuclei and CAs in populations
staff responsible for the care of treated patients. exposed to X-rays. Occupationally exposed individu-
Some of the common antineoplastic drugs are cyclo- als in personnel handling diagnostic X-ray machines
phosphamide, methotrexate, azacitidine, chlorozo- showed a higher frequency of CAs than unexposed
tocin and thiotepa. Other drugs such as niridazole controls w155x. In another study where medical staff
and metronidazole are used in the treatment of para- workers in the X-ray department were tested, an
sitic disease in man. Hycanthone, lucanthone, nirida- increased number of micronuclei and CAs were ob-
zole and furapromidium are used as antischistosomal served. Also, a synergistic effect was observed when
drugs. Representative drugs have been briefly dis- the subjects were exposed to both X-rays and ultra-
cussed in the following paragraph. For additional sound equipment w156x.
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