Occupational exposure to genotoxic agents

Mutation Research 437 Ž1999. 175–194 www.elsevier.comrlocaterreviewsmr Community address: www.elsevier.comrlocatermutres

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 Millions of workers in various occupational settings in the United States have the potential to be exposed to hazardous substances. These substances, including dusts, fibers, and organic or inorganic chemicals, are used as raw materials, intermediates, by-products or end products in industrial processes. They can exist in the form of gases, vapors, fumes, mists or particles. Inhalation is the primary route of exposure, however, exposure can also take place through dermal absorption or ingestion. Most workers in construction, mining, manufacturing and ) Corresponding author. Tel.: q1-304-285-5817; fax: q1-304285-6194; E-mail: [email protected]

foundry industries are exposed to complex chemical mixtures or mixtures of chemical and physical agents. Illness in some workers, however, can be attributed to exposure to a single chemical or physical agent. Painters and laundromat workers may be exposed to a specific solvent, some healthcare workers to a specific drug or radiation, some farmers to a specific insecticide or herbicide, and some construction workers to asbestos, man-made fibers or silica. Many of these substances are now known to be genotoxic and have the potential to cause genetic alterations in the target tissues 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 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

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Industrial agents, such as asbestos, diesel emission particles, wood dust, chromium, arsenic, vinyl chloride, benzene, etc., are known to be associated with cancer risk w1,2x. It has been estimated that occupational 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 aberrations w5x and hundreds of human diseases are also known to be due to gene mutations w6x. Studies of occupational reproductive hazards to date have consisted mainly of epidemiologic surveys of pregnancy outcomes following maternal exposures. Such studies have shown increased rates of spontaneous abortions in chemical and laboratory workers w7,8x, ethylene oxide, and anaesthetic gases w9,10x. In general, relatively few studies have been conducted on reproductive 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 Occupational Safety and Health has identified cardiovascular diseases as one of the 10 leading occupational diseases and injuries w12,13x. Personal risk is one of the primary factors associated with an increased incidence of coronary heart disease. However, 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 relationship between workplace factors and cardiovascular disease shows that millions of workers are currently exposed to work-related factors, including chemicals, associated with an increased risk of cardiovascular 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 potentially 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 occupationally 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 environment is second only to oxygen. Crystalline silica is probably one of the most documented workplace contaminants. The severity and the widespread nature 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, construction, glass and cement-making, ceramics Žincluding 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 silica 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 occurs mainly in the use of sands in the making of molds and cores. Genotoxicity and clastogenicity of silica has recently been reviewed by Gu and Ong w18x. In vitro

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Table 1 Occupational exposure to dusts and fibers and their genotoxic effects Dusts, fibers and radiation

Source of exposure

No. of workers exposed

Genotoxic effectsa

References

Silica

Ore mining, quarrying and granite workers, ceramics, pottery, glass, refractory brick, diatoaceous earth industries, foundries Transportation workers, operators of diesel-powered equipment, bus workers, truck drivers Mine operators, jack setters, rock-dusters, coal drill operators, cutting machine operators and blasters

3.2 million

CA, MN, SCEs

w14,17,19,22x

1.35 million

w24,25x

Wood dust

Wood workers, furniture workers, cutting oil users, leather workers, tailors, dressmakers and printers

600,000

Glass fibers

Thermal and acoustical insulation, construction and ship building, insulation in houses, thermal and sound insulation Asbestos textiles, roofing, asbestos paper industry, insulation, shipyard workers, miners

NrA

MN, SCEs, CAs, cell transformation Gene mutations, SCEs, CAs, cell transformation Gene mutations, DNA single-strand breaks, MN CA, MN, cell transformation MN, CA, gene mutations

w84x

Diesel emission particles Coal dust

Asbestos

400,000

27.5 million

w17,40–42x

w44x

w79,81,83x

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 binucleated and micronucleated cells in Syrian hamster embryo 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-dependent increase in the frequency of morphologically transformed Syrian hamster embryo cells was reported 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 protooncogenes Ž K-ras, H-ras, myc, abl . and of the p53 gene in some quartz-transformed cell lines w22x. Genomic instability has also been found in transformed BALBrc 3T3 cells induced by silica w23x. In addition 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. Occupational exposure is common among transportation workers, operators of diesel-powered equipment and among some miners operating diesel-powered equipment 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 aldehydes w25x. These particles, since they fall within the

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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 almost equaling that of coke-oven emissions and, interestingly, are more potent than cigarette smoke. Nitrosocompounds, chemicals found in diesel exhaust particles, have been found to be major contributors to mutagenicity in the Salmonella typhimurium assay w25x. Genotoxicity of diesel emission particles has been reviewed in literature w26–28x. Diesel extract 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 mammalian cell systems. Animal studies have shown that diesel exhaust is potentially co-tumorigenic w29–31x. Epidemiological studies indicate that heavy occupational 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 employment 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 containing 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 variable 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 different 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 BALBrc3T3 cells w40,41x. In vivo genotoxicity studies using peripheral blood lymphocytes show an elevated frequency 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 compared 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 associated with coal dust exposure are pneumoconiosis, progressive fibrosis, chronic bronchitis and accelerated 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, carried 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 lumberrwood product industries such as wood machinists, 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, carpenters 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 lacquers, sprays and polishes w45–47x. There is additional 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 suggested as possible contributing agents to the induction of nasal cancer: native mutagenic components of wood dust Žsuch as tannins and tannic acids, 2,6-dimethoxy-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 metabolites produced by wood-covering fungi w50–52x. Attempts to evaluate the genotoxic and carcinogenic potential of wood dust and wood shavings both in animal and human exposures have been summarized 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 addressed the genotoxicity and carcinogenicity of wood dust andror wood dust extracts.

2.2. Fumes and fluids In several occupational settings, workers are exposed to fumes or fluids such as asphalt fumes, welding fumes and metal-working fluids.

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2.2.1. Asphalt fumes Asphalt is used widely in paving, roofing, waterproofing 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 constituted majority of the PAH emissions. Asphalt compounds used in roadwork can be applied hot Žapproximately 1508C–1808C., and at these temperatures, PAH compounds volatilize creating the potential 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 induce 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. Carcinogenicity 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 contaminants and gaseous pollutants arising from the welding 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.

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Genotoxicity of welding fumes has been reviewed by IARC w70x. Studies have shown both positive and negative results for gene mutations in cultured mammalian cells exposed to stainless-steel welding fumes. Welding fumes induced morphological transformation 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.. Genotoxicity studies have shown increased levels of SCEs and CAs in peripheral blood lymphocytes of workers exposed during stainless-steel welding w74x. Carcinogenicity 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 metalworking fluids ŽMWFs. w76x. These agents are commonly used in a variety of industrial machining and grinding operations. MWFs are primarily used to cool and lubricate both machinery and working surfaces. They are also used to provide corrosion protection and removal of metal chips. MWFs are classified 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 containing no petroleum-based oils; and Ž4. semisynthetic 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 present in each of the MWF classes, and the hazard that these chemicals pose to workers may vary widely because of different manufacturing processes, various degrees of refining, recycling and potential

chemical reactions between components. Compounds such as N-nitrosodimethylamine, N-nitrosodiethylamine, N-nitrosodiethanolamine, N-nitrodibutylamine, N-nitrosomorpholine are known to be carcinogens 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 exposure to straight oil MWFs has been associated with an increased risk for laryngeal, rectal, pancreatic 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-building. They are also used as insulation in houses, incorporated into ceiling tile for fire resistance as well as for thermal and sound insulation. Small-diameter glass fibers are used in air and liquid filtration 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, maintenance, quality control and shipping. Workers involved in general manufacturing operations, such as trimming, sawing, cutting, finishing, painting and molding are potentially exposed to glass fibers.

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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 capable 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 morphological transformation was also found to be dependent on fiber length and diameter w18x. Human carcinogenicity data indicate no increase in the occurrence 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 exposed 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 Žutilizing 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 unscheduled DNA synthesis has been reported in rat mesothelial cells exposed to crocidolite and chrysolite 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 indirectly 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 asbestos-related plants are mesothelioma and lung cancer 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 tissue and kidney may occur since fibers readily penetrate 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, inorganic chemicals and specific chemical groups. The following is a brief discussion of several selected chemicals and specific chemical groups. Genotoxicity 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, tetrachloroethylene, benzene and styrene.

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Table 2 Genotoxicity of common occupationally related chemicals Chemicals

Type of occupation

No. of workers exposed

Genotoxic activity a

References

Acrylamide

Chemical production, construction and maintenance involving pipe grouting and sealing, water and waste water treatment Non-ferrous smelting, arsenic production, wood preservation, glass manufacturing, and arsenical pesticide production and application Petroleum distillates, coal tar distillates Benzidine manufacturing plant, manufacture or using dye based on benzidine Production of polymers and synthetic rubber Petrochemical-based industry

10,700 employees were exposed between 1981 and 1983 55,000 employees

DNA adducts, SCEs, CA, mitotic disturbances

w170x

CA, DNA damage, gene mutations

w166x

238,000

CA, clastogenic, MN

w108,167x

79,000

SCEs, gene mutations

w173–175x

; 10,000

DNA alkylation, SCEs, MN, CA Gene mutations

w111,168,176x

270,000 US employees were exposed between 1981 and 1983

MN, SCEs, CA, gene mutations, UDS

w170x

1.5 million

Gene mutations, SCEs, CAs

w53,171x

421,000 employees exposed between 1981 and 1983 1 million

DNA adducts, gene mutations, SCEs, CA

w170x

DNA adducts, strand breaks, CA, SCEs, MN CA, SCEs CA, SCEs, MN, gene mutations

w109,110,112,172x

Arsenic

Benzene Benzidine and dyes

1,3-butadiene Bis-chloromethylethyl–ether Ethylene oxide

Formaldehyde

Propylene oxide

Styrene

Toluene Vinyl chloride

Chemical and allied products manufacturing industry, production workers, maintenance workers, laboratory workers Production of resin in urea and phenol. Textile, leather, rubber and cement industry Chemical industry, starch industry

Styrene production, production of polystyrenes, plastic and rubber production fabrication Petroleum refining operations Packaging, building, electrical appliances, medical equipments, automobiles, toys

NrA

1.2 million NrA

w169x

w146,147x w99x

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 chloride 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 exposure also induced unscheduled DNA synthesis in rat hepatocytes and increased SCEs in human lymphocytes 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 lymphocytes of workers exposed to VC are higher compared 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 chloride exposed workers. Animal studies have also shown that VC is carcinogenic, causing a wide spectrum 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 carcinoma, nephroblastoma, and lung tumors. 2.4.1.2. Tetrachloroethylene. Commercial dry cleaning makes up the largest segment of the cleaning industry. The chemicals used mostly include chlorinated solvents, amyl acetate, bleaching agents, acetic acid, aqueous ammonia, oxalic acid, hydrogen peroxide and dilute hydrogen fluoride solutions. Tetrachloroethylene 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 Exposure Survey indicated that about 566,000 employees in 42,700 plants were potentially exposed to tetrachloroethylene w102x. Occupational exposure to tetrachloroethylene occurs through inhalation, skin absorption 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 contaminants in lint and water separator run-off can increase background levels of tetrachloroethylene. Tetrachloroethylene clearly increased the number of revertants 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, however the dry-cleaners in the study were smokers, so a definitive conclusion could not be made w105x. Increased risk for certain types of cancer, such as

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urinary bladder cancer, esophageal cancer, lung cancer and cervical cancer has been observed w102x. 2.4.1.3. Benzene. It has been estimated that approximately 238,000 workers may be occupationally exposed to benzene in the United States w106x. They are primarily exposed during the production of petrochemicals, petroleum refining, coke and coal chemical manufacturing, rubber tire manufacturing, and storage or transport of benzene and petroleum products containing benzene. Steel workers, printers, rubber 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 exposed to benzene for various time periods showed a significantly higher proportion of chromosome breaks w107x. Some studies involving individuals with longterm 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 induced by benzene is the inhibition of DNA synthesis in certain cell types w109x. Epidemiological studies have shown acute myeloid leukemia in benzene exposed workers w110x. 2.4.1.4. Styrene. NIOSH estimates that approximately 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. Significant occupational exposures may also occur in other industrial settings, such as styrene polymerization, 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.

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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 multiple chemical exposures and inadequate documentation 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, arsenic and nickel. Most of these inorganic compounds exist in several different forms such as alloys, oxides, chlorides, sulphates, carbonates and nitrates. 2.4.2.1. Beryllium. Occupational exposure to beryllium 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, fabrication, 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 production 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-temperature-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 Occupational Safety and Health w125x estimated that about two million workers are exposed to chromium and chromium compounds. Potential occupational exposure to chromium occurs through inhalation, ingestion 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, photographers, printers, shingle manufacturers, corrosion-inhibitor 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 electroplating 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 transformation and dominant lethal mutations in a number of targets, including animal cells in vivo and animal and human cells in vitro w70x. Epidemiological studies 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, refining 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, inhalation and, to a very limited extent, by passage through the skin. The genotoxic and carcinogenic related activities of cadmium and related compounds have been reviewed by IARC w122x. DNA strand breaks, muta-

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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 peripheral blood lymphocytes of workers exposed to cadmium 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 cadmium 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. Occupational 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, dyers, electroplaters, jewellers, nickel-alloy makers, nickel refiners, nickel smelters, nickel miners, organic 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 reviewed by IARC w70x. Ground nickel powder has been shown to cause a dose-dependent increase in morphological transformation of Syrian hamster embryo 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 sulfide and nickel subsulfide induced DNA strand breaks in rat primary hepatocytes and cultured mammalian cells w130x. Crystalline nickel sulfide was also mutagenic in Chinese hamster V79 cells. The frequency of SCEs was increased in cultured human lymphocytes treated with nickel subsulfide. A dose- and time-dependent increase in the frequency of CAs

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including gaps, breaks, exchanges and dicentrics were seen in Chinese hamster ovary cells w70x. Crystalline nickel sulfide and subsulfide induced cell transformation, 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. Occupational exposure to arsenic may be significant in several industries, mainly nonferrous smelting, arsenic production, wood preservation, glass manufacturing, and arsenical pesticide production and application. 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 frequency of CAs in peripheral lymphocytes of smelter workers w133,134x. Arsenic was also capable of producing SCEs in most in vitro systems tested w135x. An increased frequency of CAs in peripheral lymphocytes was also seen in a worker with oral exposure 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 exposed to specific groups of chemicals. For example, agricultural workers are exposed to insecticides, fungicides andror herbicides; painters and some laboratory workers are exposed to solvents; and healthcare workers are exposed to certain drugs.

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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 usages. In addition, pesticide residues on plants or fruits may cause significant exposure to farm workers 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 application and the specific job. Some of the most commonly used insecticides with potential genotoxic and carcinogenic effects are aldicarb w141x, chlordane w141,142x, heptachlor w141,142x, DDT w141x and associated compounds Žalthough DDT and its associated 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, thiram, 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 cultured 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 aberrations in peripheral lymphocytes of workers with increased plasma levels of DDT, however, conflicting 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 increased the incidence of dicentric chromosomes and acentric fragments in peripheral lymphocytes of workers exposed occupationally to pentachlorophenol. 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 potentially genotoxic. The National Institute for Occupational Safety and Health w145x has estimated that 3500 workers are potentially exposed to petroleum ether and about 26,400 workers are exposed to rubber 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 exposure 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 workers were potentially exposed to toluene in the United States between 1981 and 1983. Toluene is mainly used in the production of benzene via the hydrodemethylation 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 Germany exposed to toluene w151x. About one million workers were potentially exposed to xylene in the United States between 1981 and 1983 w146x. Xylenes are primarily used for gasoline blending. They are also used in the manufacture of perfumes, insecticides, pharmaceuticals and adhesives and in the painting, printing, rubber, plastics and leather industries w148x. Most genotoxicity studies indicate that xylene is not a genotoxic agent, and there is also inadequate evidence for the carcinogenicity of xylene in humans. Paints and paint products are another group of organic solvents that may pose potential health hazards to exposed workers. Paints mainly consist of pigments, binders Žresins., solvents and additives. They are mainly used in exterior and interior paint-

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ing, masonry painting and waterproofing on unpainted concrete, brick, surface coating in the wood industry, painting in the metal industry and automobile coatings. NIOSH estimates about 362,000 workers 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. Occupational exposure to paint products results predominantly 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 manufacturing 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 various 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 cyclophosphamide, methotrexate, azacitidine, chlorozotocin and thiotepa. Other drugs such as niridazole and metronidazole are used in the treatment of parasitic disease in man. Hycanthone, lucanthone, niridazole and furapromidium are used as antischistosomal drugs. Representative drugs have been briefly discussed in the following paragraph. For additional

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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 induces 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 induced mutation and DNA damage w152x. Methotrexate, another antineoplastic agent, induced CAs and SCEs in vitro. It also caused morphological cell transformation in C3H 10T1r2 cells and was mutagenic to mouse lymphoma cells w152x. Hycanthone is mutagenic in several mammalian and sub-mammalian 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. Ionizing 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 genotoxic effects of exposure to X-rays are well documented. In vitro studies have shown increased frequency 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 individuals 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 observed. Also, a synergistic effect was observed when the subjects were exposed to both X-rays and ultrasound equipment w156x.

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2.5.2. UV radiation Exposure to UV radiation may occur in certain occupational settings although it is not a major contributor 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 industrial 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 mammalian cells, human cells in vitro and induce DNA damage in mammalian skin cells irradiated in vivo w157x. Solar UVR also induces a variety of photoproducts in DNA, including cyclobutane-type pyrimidine 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 nonmelanocytic skin cancer. In a study of US fishermen, estimates of individual, annual and cumulative exposure to UVB were positively associated with the occurrence of squamous-cell carcinoma. A positive relationship between melanoma of the skin and exposure 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 produces 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 occupationally 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 exposures, 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 exposed 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 cellular telephones and their associated broadcast equipments, have raised concerns about exposures to radio frequency or microwaves. Basically, four types of effects have been described w161x, increased spontaneous abortion, shifts in red and white blood cell counts, increased somatic mutation rates in lymphocytes, and increased childhood testicular and other cancers. In one study, Garaj-Vrohac et al., w162x examined six men accidentally exposed while repairing microwave devices used for air traffic control in Zagreb. The results of this study showed that microwave irradiation can produce genotoxic effects. Both chromosomal and chromatid changes were observed. 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 potentially genotoxic to the exposed workers.

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3. Conclusions Occupational exposure to genotoxic agents is a major concern regarding millions of workers’ health and well being. Although several regulatory measures have been taken by agencies such as the Occupational 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 occupational settings and to establish disease-related biomarkers for molecular epidemiology and surveillance studies to facilitate prevention of occupational cancer.

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