4
CANCER

Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells (ACS 2003g; WHO 2003). Cancer can affect almost any tissue of the body. Known causes include external factors (such as chemicals, radiation, and infectious agents) and internal factors (such as mutations, hormones, and immune conditions). Such factors may act together or in sequence to initiate or promote carcinogenesis (ACS 2003g). In adults, a latent period of 10 years or more may elapse between exposure or mutation and the detection of cancer.

Cancer is the second-leading cause of death in the United States, exceeded only by heart disease. Among the member states of the World Health Organization (WHO), cancer is the third-leading cause of death, after heart disease and infectious or parasitic diseases (WHO 2003). In the United States in 2000, lung cancer was the leading cause of cancer deaths among both men and women, followed by prostatic cancer in men and breast cancer in women (Jemal et al. 2003). Each year, cancer leads to 12% of deaths worldwide, equivalent to about 6 million deaths (WHO 2003). Among men, lung and stomach cancers are the most common worldwide; among women, breast and cervical cancers are the most common (WHO 2003).

This chapter summarizes the results of epidemiologic studies of cancer outcomes related to exposure to fuels and combustion products. The committee considered the findings of those investigations as a means of determining what types of cancers Gulf War veterans might be at increased risk for as a consequence of exposure to fuels in the course of using military equipment, to tent heater fumes, and to smoke from oil-well fires. Because only a dozen years have passed since the Gulf War, studies of the Gulf War veterans themselves for cancer outcomes, which are characterized by considerable latent periods, would not yet be expected to be informative. Chapter 3 presented a general introduction on fuels and combustion products and a summary of toxicologic information on them. Appendix D contains tables that describe studies of populations exposed to relevant agents; many of the studies are referred to repeatedly in this chapter because their findings are related to several cancers of the specific anatomic sites and tissues reviewed.

In this chapter, the section on each type of cancer contains pertinent findings from cohort studies and then from case-control studies, first for fuels and then for combustion products, followed by the committee’s conclusions regarding the relationship between cancer of the specific type and exposure to fuels or combustion products. The tables included at the end of this chapter contain results from the primary studies on which the committee bases its conclusions.



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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 4 CANCER Cancer is a group of diseases characterized by uncontrolled growth and spread of abnormal cells (ACS 2003g; WHO 2003). Cancer can affect almost any tissue of the body. Known causes include external factors (such as chemicals, radiation, and infectious agents) and internal factors (such as mutations, hormones, and immune conditions). Such factors may act together or in sequence to initiate or promote carcinogenesis (ACS 2003g). In adults, a latent period of 10 years or more may elapse between exposure or mutation and the detection of cancer. Cancer is the second-leading cause of death in the United States, exceeded only by heart disease. Among the member states of the World Health Organization (WHO), cancer is the third-leading cause of death, after heart disease and infectious or parasitic diseases (WHO 2003). In the United States in 2000, lung cancer was the leading cause of cancer deaths among both men and women, followed by prostatic cancer in men and breast cancer in women (Jemal et al. 2003). Each year, cancer leads to 12% of deaths worldwide, equivalent to about 6 million deaths (WHO 2003). Among men, lung and stomach cancers are the most common worldwide; among women, breast and cervical cancers are the most common (WHO 2003). This chapter summarizes the results of epidemiologic studies of cancer outcomes related to exposure to fuels and combustion products. The committee considered the findings of those investigations as a means of determining what types of cancers Gulf War veterans might be at increased risk for as a consequence of exposure to fuels in the course of using military equipment, to tent heater fumes, and to smoke from oil-well fires. Because only a dozen years have passed since the Gulf War, studies of the Gulf War veterans themselves for cancer outcomes, which are characterized by considerable latent periods, would not yet be expected to be informative. Chapter 3 presented a general introduction on fuels and combustion products and a summary of toxicologic information on them. Appendix D contains tables that describe studies of populations exposed to relevant agents; many of the studies are referred to repeatedly in this chapter because their findings are related to several cancers of the specific anatomic sites and tissues reviewed. In this chapter, the section on each type of cancer contains pertinent findings from cohort studies and then from case-control studies, first for fuels and then for combustion products, followed by the committee’s conclusions regarding the relationship between cancer of the specific type and exposure to fuels or combustion products. The tables included at the end of this chapter contain results from the primary studies on which the committee bases its conclusions.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Those tables are presented in reverse chronological order by each type of study design. The committee reviewed over 500 epidemiologic studies on cancer related to exposure to fuels and combustion products and selected studies that met its inclusion criteria for more thorough evaluation. Briefly, the studies had to appear in peer-reviewed publications, identify exposure relevant to the committee’s charge, and identify a specific health outcome (for example, the study must specify a type of cancer as opposed to considering all cancers together). Chapter 2 discusses the committee’s inclusion criteria in more detail. This chapter reviews epidemiologic studies of cancer in adults, which would be pertinent to the occurrence of cancer in Gulf War veterans themselves; studies of childhood cancer are reviewed in Chapter 7, on reproductive and developmental effects, because the committee was concerned with such outcomes in the offspring of Gulf War veterans as a possible result of parental exposure. Epidemiologic studies assessing gender-specific cancers (for example, female breast cancer and prostate cancer) are included in the committee’s review. Seven percent of the 697,000 US military personnel sent to the Persian Gulf were women. For the combustion products of crude oil and petroleum-derived fuels, the epidemiologic data complement the vast amount of toxicologic information on poly cyclic aromatic hydrocarbons (PAHs) (particularly benzo[a]pyrene), other combustion products, and soot. There are numerous studies of occupational cohorts heavily exposed to PAHs (for example, from coal tar and asphalt), usually in combination with other products of combusted petroleum-derived fuels (for example, exhausts from various sources and metals) and soot. The conclusions from that large, complex body of information have been addressed by several expert bodies, including the International Agency for Research on Cancer (IARC 1985), which (IARC 1984a, 1984b) have been virtually unanimous in judging that PAHs and soot are most probably human carcinogens, particularly for skin after dermal exposure. Urban firefighter studies were not included in the committee’s review. The committee agreed that urban fire fighters are likely exposed to a number of compounds that are not found in combustion products produced from oil-well fires, tent heaters, and vehicles (for example, plastics, asbestos, and PCBs). It would not be possible for the committee to distinguish between health effects in urban firefighters attributable to those compounds versus combustion products as were experienced in the Gulf War. Therefore, the committee made a decision not to include urban firefighter studies in this report. Cancer sites or types are addressed in this chapter largely according to the ninth revision of the International Classification of Disease (ICD-9).1 That approach is taken in an effort to organize the multitude of site-specific evidence presented in the chapter. In many cases, the findings by various investigators do not follow the strict categorization of the ICD-9. CANCERS OF THE ORAL CAVITY AND OROPHARYNX The cancers reviewed in this section include those of the oral cavity, that is, the lips, the lining of the lips and cheeks, the teeth, the gums, the tongue, the floor and roof of the mouth, and the area behind the wisdom teeth) (ICD-9 140–145); and the oropharynx and hypopharynx, the parts of the throat just behind the mouth (ICD-9 146 and 148, respectively). With cancers of the 1   ICD codes are revised and updated by WHO. Although ICD-10 codes have been published, ICD-9 codes remain the most widely recognized and used. ICD codes were established by WHO to promote international comparability in the collection, processing, classification, and presentation of mortality statistics. The codes group cancers according to their organ or tissue of origin and their histologic features.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 nasopharynx (ICD-9 147) and of the nasal cavity and paranasal sinuses (ICD-9 160)—the next section is on cancers of the nasal cavity and nasopharynx—these cancers were formerly denoted “head and neck cancers”. Recently, some cancer epidemiologists (for example, Berrino et al. 2003; Boffetta et al. 2003) have chosen to consider the hypopharynx with the larynx (ICD-9 161), which it is next to, when assessing risks at that site associated with occupational exposure. In discussing the epidemiologic literature on cancer of the oral, nasal, and upper respiratory tissues, the committee has decided to specify exactly which sites individual researchers were reporting on. The committee has opted to draw conclusions related to the separate tissues that would be exposed during inhalation: along the oral pathway, along the nasal pathway, and their juncture near the larynx. As for all head and neck cancers, the most important risk factor for cancers of the oral cavity and oropharynx is tobacco use, particularly cigarette-smoking (ACS 2003b, 2003c, 2003d). Additional risk factors for this site are alcohol consumption, vitamin A deficiency, exposure to ultraviolet radiation (sunlight), and increasing age. Some genetic factors, a weakened immune system, chronic irritation, and infection with human papillomavirus also may contribute to the occurrence of oral cancers. In 2000, there were 10.6 new cases of cancer of the oral cavity and oropharynx per 100,000 people (15.9 among men and 6.2 among women) and 2.7 deaths per 100,000 (4.1 among men and 1.6 among women) in the United States (Ries et al. 2004). Fuels Table 4.1 presents the most relevant findings reviewed by the committee in drawing its conclusion on the possibility of an association between exposure to fuels and cancers of the oral cavity and oropharynx. Cohort Studies With the assistance of industrial hygienists and others familiar with a uranium-processing facility in Fernald, Ohio, Ritz (1999) conducted a secondary exposure assessment by using available data on the exposure of 4,128 male workers to kerosene (and to cutting fluids and trichloroethylene). The potential confounding effects of smoking were assessed by examining whether smoking habits were related to chemical exposure in a subset of 20% of the workers on whom smoking information was available in recent personnel files. There was no clear pattern of smoking behavior and exposure, so differences in smoking habits among exposure groups probably did not explain study results. Compared with the US population, the risk of death from oropharyngeal cancers (ICD-8 140–149) in the entire cohort was not notably increased (standardized mortality ratio [SMR] 1.05, 95% confidence interval [CI] 0.48–1.99). Among workers exposed to kerosene, the risks of oropharyngeal cancers derived with conditional logistic regression adjusted for pay status, time of hire, and cumulative radiation dose increased with exposure, but were imprecise (low kerosene exposure relative risk [RR] 1.85, 95% CI 0.37–9.36; moderate kerosene exposure RR 2.87, 95% CI 0.43–19.2; no workers had been categorized with heavy kerosene exposure). Lagorio et al. (1994) tracked the mortality experience of 2,308 men through 1992; the men had been managers of Italian service stations in 1980. The effort complemented a detailed assessment of exposure at service stations in which 111 attendants were monitored in 1992 (Lagorio et al. 1993). Observation of only a single death from oropharyngeal cancer (ICD-9 140–

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 149) (SMR 0.38, 90% CI 0.02–1.79) during the follow-up period rendered this study uninformative. Jarvholm et al. (1997) investigated cancer morbidity in a cohort of 4,128 male Swedish workers found by reviewing personnel files of 26 different refineries, distribution companies, lubrication-oil manufacturing industries, tank-cleaning companies, and companies that handled fuel. Exposure was determined from job titles combined with a retrospective review of air monitoring of work areas and personal exposure. The cohort was linked to the Swedish cancer and mortality registers. When the full array of oropharyngeal cancers were grouped (ICD-9 140–149), only six cases were identified in the cohort, so the somewhat increased risk estimates could not be distinguished from no effect, even for the subgroup of distribution workers with long duration and latency (standardized incidence ratio [SIR] 2.5, 95% CI 0.44–7.9). Case-Control Studies Zheng et al. (1996) conducted a case-control study to investigate the risk of salivary gland cancer (ICD-9 142) among residents of urban Shanghai. Cases were ascertained from 1988 and 1990. A total of 44 cases and 414 controls (frequency matched by sex and age) were interviewed to determine use of specific cooking fuels. Self-reported use of kerosene was associated with the risk of salivary gland cancer in models adjusted for sex, age, and income (odds ratio [OR] 3.5, 95% CI 1.6–7.4). Similar associations were found in multivariate models that included other possible risk factors but were not adjusted for smoking, which had not been found to be associated with salivary gland cancer. A large population-based case-control study relying on several cancer registries was conducted in New Jersey, Los Angeles, Atlanta, and Santa Clara and San Mateo Counties, California, in January 1984–April 1985 (Huebner et al. 1992). Data were obtained on 1,114 cases (762 men and 352 women) of histologically confirmed primary oral and pharyngeal cancers (ICD-9 141, 143–146, 148, 149) diagnosed in January 1984–April 1985. The results for men working in selected industries were imprecise with some suggestion of an increased risk in petroleum-industry workers (OR 1.79, 95% CI 0.75–4.25). Employment history was obtained through interviews, and exposure was determined by job category. Smoking did not have an effect on the results. Combustion Products Table 4.2 presents the most relevant findings reviewed by the committee in drawing its conclusion on the possibility of an association between exposure to combustion products and cancers of the oral cavity and oropharynx. Case-Control Studies Gustavsson et al. (1998) identified incident cancers of the oral cavity (ICD-9 141, 143–145) or of the oropharynx or hypopharynx (ICD-9 146, 148) diagnosed in Sweden in 1988–1991. A total of 545 cases in men were identified by monitoring weekly medical reports and verified with the regional cancer registry; 641 controls were matched to the cases by region and age. Each case and control was interviewed by a trained interviewer according to a standardized protocol. Work histories were reviewed by industrial hygienists blinded to case status to estimate occupational exposure to 17 agents, including PAHs in a job-exposure matrix (JEM) approach. After adjustment for region, age, alcohol consumption, and smoking, high PAH exposure was

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 associated with both cancer at all sites (RR 1.48, 95% CI 1.09–2.01) and pharyngeal cancer (RR 1.52, 95% CI 0.94–2.45). No dose-response relationship, however, was evident in the case of PAH exposure. Pintos et al. (1998) conducted a study in Sao Paulo, Curitiba, and Loiania, Brazil, to examine the risk of oral cancer (ICD-9 140–145) or pharyngeal cancer (ICD-9 146–149) in relation to the use of wood stoves. The researchers identified 784 incident cases of cancer of the pharynx and mouth from local hospitals and selected two controls for each case from among other hospital inpatients (patients with other cancers or mental disorders were excluded), matching them to cases on age, sex, and trimester of hospital admission. Exposure to products of wood stoves was ascertained with a single yes-no question. After adjustment for lifetime cumulative tobacco use (pack-years), alcohol consumption (kilograms of ethanol), sociodemographic variables, diet, and history of employment in specific industries, the reported use of wood stoves was associated with an increased risk of cancer of the mouth (OR 2.73, 95% CI 1.76–4.24) and pharynx (OR 3.82, 95% CI 1.96–7.42). The Shanghai case-control study of salivary gland cancer (ICD-9 142) (Zheng et al. 1996) found self-reported use of kerosene for cooking was associated with risk of salivary gland cancer in models adjusted for sex, age, and income (OR 3.5, 95% CI 1.6–7.4). The increases in risk associated with use of coal, gas, and wood for cooking were not as precise. Dietz et al. (1995) identified incident cancers of the oral cavity (ICD-9 141–145), oropharynx (ICD-9 146), or hypopharynx (ICD-9 148) in Heidelberg, Germany, and evaluated the effects of using fossil-fuel stoves for heating and cooking. Cases were ascertained in 1989–1992 from all patients seeking treatment at the Otorhinolaryngology Department at the University of Heidelberg within 3 years after first diagnosis. They identified 100 and 105 cases of oral cavity and pharyngeal cancer, respectively. Controls were recruited from the same medical center and general outpatient department and matched to cases on sex, age, and size of place of residence. All subjects were interviewed to ascertain risk-factor information, including alcohol consumption (grams/day), smoking (tobacco-years), and use of fossil-fuel stoves and cookers (coal, briquette, coke, peat, gas, and oil). After adjustment for tobacco and alcohol, use of fossil-fuel single stove heating units for more than 40 years vs 0–20 years was associated with pharyngeal cancer (OR 3.3, 95% CI 1.43–7.55). Fossil-fuel stove use for cooking in kitchen units also increased risk (OR 2.5, 95% CI 1.03–6.30) for more than 40 years of stove use (compared with 0–20 years). The OR for oral cavity cancer (ICD-9 141–145), adjusted for tobacco and alcohol, was 2.4 (95% CI 1.26–4.40) for more than 40 years (compared with 0–20 years) of exposure to fossil-fuel heating units. For exposure to kitchen cooking units, the OR for oral cavity cancer, adjusted for tobacco and alcohol, was 1.6 (95% CI 0.90–2.97) for more than 40 years of stove use (compared with 0–20 years). Pukkala (1994) examined cancer incidence in Finland in 1971–1985 in 2,369 men and 809 women employed in various occupations. Occupation was ascertained by linking cancer-registry data with occupational and social-class data from the 1970 Finnish Population Census. SIRs were calculated from sex, age, site, and calendar-year-specific rates in the general Finnish population and were adjusted for social class. Risks of various cancers among men employed in transport and communications (lip cancer SIR 0.91, 95% CI 0.73–1.12; tongue cancer SIR 1.17, 95% CI 0.74–1.76; oral cavity cancer SIR 1.17, 95% CI 0.71–1.81; pharyngeal cancer SIR 0.97, 95% CI 0.66–1.39) were not found to be increased; there was a small increase in motor vehicle drivers (tongue cancer SIR 1.56, 95% CI 0.94–2.44), but the 95% CI contained the null.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 In the study by Huebner et al. (1992) of fuel exposures described above, the relationship between job categories potentially involving exposure to combustion products and primary cancers of the oral cavity and pharyngeal region were also assessed. The effect estimates derived for boiler or furnace and heavy-equipment operators (OR 1.50, 95% CI 0.68–3.34), heavy-equipment operators only (OR 1.25, 95% CI 0.78–2.01), motor-vehicle operators (OR 1.01, 95% CI 0.75–1.35), railroad transport workers (OR 1.00, 95% CI 0.30–3.35), mechanics or repairers (OR 0.86, 95% CI 0.66–1.12), and firefighters (OR 0.65, 95% CI 0.23–1.85) were imprecise and suggested no increases for these jobs. Similarly, the results for men working in selected industries were imprecise; no increased risk was observed for transportation workers (OR 1.07, 95% 0.74–1.56) and trucking or warehousing workers (OR 0.86, 95% CI 0.56–1.31). Among women, point estimates exceeded 1 for oral or pharyngeal cancer in association with employment as a motor-vehicle operator, but results were imprecise because of the small numbers (OR for motor-vehicle operator 2.80, 95% CI 0.61–12.9). Incident oral and pharyngeal cancer was assessed in Shanghai, China (Zheng et al. 1992). A total of 204 cases 20–75 years old were ascertained in 1988–1990 and matched to 414 controls on age and sex. Exposure to potential risk factors was ascertained by interview. The prevalence of men using kerosene stoves among cases was reported to be 27.0% compared with 14.1% of controls (p≤0.01), but no difference was reported for women. Merletti et al. (1991) conducted a population-based case-control study in Turin, Italy. From July 1982 to December 1984, 103 incident male cases of oral cavity or oropharyngeal cancer were identified. The questionnaire included a detailed occupational history. That information was reviewed by industrial hygienists and physicians experienced in occupational medicine, who determined the probability and intensity of exposure to 16 agents, including PAHs. After adjustment for age, education, geographic region of birth, tobacco-smoking, and alcohol consumption, probable or definite exposure to PAHs was not associated with cancer risk (OR 0.6; study authors stated that confidence interval included 1). Patient records were abstracted for a case-control study at the Roswell Park Memorial Institute in Buffalo, New York (Decoufle and Stanislawczyk 1977; Viadana et al. 1976). All persons referred to the Institute in 1956–1965 were asked to report their lifetime occupational history and job activities. Their risk of cancer of the buccal cavity and pharynx was compared with that of noncancer controls according to jobs they had ever held or had held for 5 years or more. Data were analyzed and stratified by age at diagnosis (with the cut point at 60 years), and the results were adjusted for smoking. Compared with the risk in clerical workers, no increased risk of cancer of the buccal cavity and pharynx was reported for bus, taxicab, and truck drivers; deliverymen and routemen; locomotive engineers and firemen; mechanics and repairmen; or mine operatives and laborers. Conclusion The three cohort mortality studies that assessed the relationship between cancer of the oral cavity and oropharynx and fuels (Jarvholm et al. 1997; Lagorio et al. 1994; Ritz 1999) had limited statistical power and therefore were mostly uninformative. The case-control studies failed to report any consistent relationships between occupational or other self-reported potential exposures to fuels and cancer of the oral cavity and oropharynx (Huebner et al. 1992; Zheng et al. 1996).

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to fuels and cancers of the oral cavity and oropharynx. All available studies of exposure to combustion products and cancer of the oral cavity and oropharynx were of the case-control design, and all were adjusted for cigarette-smoking and other confounders. Results of several studies suggest an association between cancers of the oral cavity and oropharynx and exposure to combustion products. Pintos et al. (1998) demonstrated an association between wood-stove use and cancers of the upper aerodigestive tract, and there were supportive findings from Dietz et al. (1995) that were based on exposure from fossil-fuel stove use in Germany, from Gustavsson et al. (1998) on PAH exposure in Sweden, and from Zheng et al. (1992, 1996) on kerosene-stove use in China. The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between exposure to combustion products and cancers of the oral cavity and oropharynx. CANCERS OF THE NASAL CAVITY AND NASOPHARYNX Cancers of the nasopharynx (ICD-9 147) or of the nasal cavity and paranasal sinuses (ICD-9 160), which previously have been grouped with oral cancers as “head and neck cancers” were considered as a separate group by the committee. The tissues of the nasal cavity and nasopharynx are subject to exposures that may be somewhat different from those of the tissues of the oral cavity. Nasopharyngeal carcinoma (NPC) is the most frequent malignant tumor of the nasopharynx. As for other cancers of the head and neck, the most important risk factor for cancers of the nasal cavity and nasopharynx is smoking (ACS 2003b, 2003c, 2003d). Others include diets high in salt-cured fish and meats and infection with the Epstein-Barr virus. Cancers of the nasal cavities and sinuses have been found to be associated with occupational exposures, such as to dusts from wood, textiles, leather, and metals; glues; formaldehyde; solvents used in furniture and shoe production; mustard gas; isopropyl alcohol; and radium. In 2000, there were 1.4 new cases of cancers of the nasal cavity and nasopharynx per 100,000 in the US (1.9 among men and 0.9 among women) and 0.4 deaths per 100,000 (0.5 among men and 0.2 among women) (Ries et al. 2004). NPC is rare in most parts of the world, with incidences generally less than 1 per 100,000 persons per year (Muir et al. 1987). The highest incidence is observed among southern Chinese (30–50 per 100,000 person-years); it might be attributable to the consumption of salted fish and preserved foods early in life. Several studies of NPC focused on Chinese populations because of the large number of available cases. Fuels Table 4.3 presents the most relevant findings reviewed by the committee in drawing its conclusion on the possibility of an association between exposure to fuels and cancers of the nasal cavity and nasopharynx.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Case-Control Studies Increased risk of nasopharyngeal cancer posed by 20 occupational exposures was assessed in a case-control study (Armstrong et al. 2000). During a 2-year period, 530 subjects with histologically confirmed NPC were identified from four hospitals in Malaysia and 282 cases underwent interviews that included occupational history and work exposure. Each case was matched by sex and age to a general population control without a history of cancer of the head, neck, or respiratory system. Exposure to motor fuel or oil, assigned according to type of job, was associated with a greater risk of NPC in a crude analysis (OR 1.79, 95% CI 1.16–2.82). However, after adjustment for smoking, passive smoke exposure, and diet, the association was largely reduced, and the CI suggested no effect (OR 1.33, 95% CI 0.81–2.20). A case-control study conducted by Teschke (1997) had only four cases, and no increased risk of sinonasal cancer was observed. Combustion Products Table 4.4 presents the most relevant findings reviewed by the committee in drawing its conclusion on the possibility of an association between exposure to combustion products and cancers of the nasal cavity and nasopharynx. Case-Control Studies A case-control study of NPC was conducted in rural Zangwu County in the middle 1980s (Zheng et al. 1994). Beginning in 1986, 88 cases of NPC were recruited with 176 controls matched on neighborhood, sex, and age. Subjects were interviewed to determine their use of wood fuels in the year before diagnosis. Use of wood fuels was associated with an increased risk of NPC in unadjusted models (OR 3.7, p=0.02), models adjusted for a sociodemographic confounder score (OR 6.4, p=0.003), and models adjusted for the confounder score, childhood consumption of salted fish, and consumption of herbal tea in the year before diagnosis (OR 5.4, 95% CI 1.5–19.8). There was some evidence that the risk of NPC was increased by household factors that can affect fume concentrations; specifically, the observed wood-fuel association increased in households with lower ventilation (for example, households that had no windows or no windows in the kitchen). A hospital-based case-control study was conducted in Guangzhou City, China, in March 1983-August 1985 (Yu et al. 1990). Because Chinese living in the area have a high risk of NPC because of dietary factors, the researchers evaluated diet in detail and controlled for its influence in their analyses. There were 306 histologically confirmed incident cases of cancer of the nasal cavity and nasopharynx in subjects who were all less than 50 years old, and 306 controls were selected from the index cases’ neighborhoods of residence and matched on age, sex, and neighborhood. Exposure was based on self-reporting of occupation and exposure to specific risk factors. Subjects were interviewed in a standardized fashion that included inquiries about lifetime occupational history; exposure to dust, smoke, and chemical fumes; use of specific cooking fuels; and exposure to smoke from incense or mosquito coils. When associations were found for a self-reported occupational exposure, an occupational-medicine specialist reviewed the occupational information (job title and activity in job and industry) blindly to determine exposure status independently of case status. Exposure to smoke in a job held for at least 6 months (ever vs never) was found to be associated with an increased risk of NPC (RR adjusted for dietary risk factors in childhood based on self-reported exposure ever 2.4; 1–9 years of

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 exposure 1.6; 10 years or more of exposure 7.6). No confidence intervals were reported, but the authors stated that the results for “ever” exposed or exposed for 10 years or more had a “2-sided p value for the adjusted RR of less than 0.05”. Those results were attenuated when exposure was based on the specialist’s assessment (RR with 1–9 years of exposure 1.6, 95% 1.1–2.5; RR with 10 years or more of exposure 2.7, 95% CI 1.4–5.5). There was no association with domestic exposure to cooking fire, burning incense, or antimosquito coils. Two case-control studies that collected occupational and environmental risk-factor information for NPC were conducted in Malaysia and included subjects of Chinese origin. The first was a hospital-based study (Armstrong and Armstrong 1983) of 117 histologically confirmed cases diagnosed in 1973–1980 and treated at the only radiotherapy center for NPC in Malaysia. In addition, the researchers interviewed 200 population controls (matched on neighborhood, sex, and ethnicity) to determine risk-factor information, including exposure to smoke and dust in the workplace. Exposure to both smoke and dust was associated with an increased risk of NPC among Chinese participants (RR for smoke exposure 6.0, p=0.006; RR for dust exposure 4.0, p<0.001). There was some evidence of an increased risk for Malays and Indians associated with smoke exposure, but the number of exposed cases was too small (four) to reach any conclusions. Smoke exposure was generated from the burning of wood, paper, grass, and oil and tar from in such occupations as rubber-tapping (wood-smoke exposure) and street-hawking. Some of the jobs seemed to involve more than one type of exposure; from the description of the analyses, the estimates do not seem to have been adjusted for multiple exposure or for risk factors other than age and sex. The same researchers conducted a second case-control study on histologically confirmed cases of squamous-cell NPC which is described above (Armstrong et al. 2000). There were 119 prevalent cases (diagnosed before 1990) and 163 incident cases (diagnosed in 1990–1992). Exposures to inhalants were coded in a JEM approach by one of the authors blinded to case-control status. Cases and controls did not differ with respect to exposure amount or to median number of hours exposed to engine exhaust after adjustment for smoking and diet. No increased risk of NPC was associated with exposure to engine exhaust. In addition to those largely Asian studies of wood-burning and other cooking fuels, the committee considered a large pooled reanalysis of cancers of nasal cavities and paranasal sinuses (ICD-9 160). Leclerc et al. (1997) assembled data from 12 previous studies in seven countries that included occupational-exposure information—the same set of 12 studies as reviewed in Demers et al. (1995) and in Luce et al. (2002). The dates of cancer diagnosis spanned 1968–1990. The inclusion criteria for the selected studies were histologic confirmation of cases; age, sex, and smoking information available on both cases and controls; and occupational histories of cases and controls obtained by interviews or questionnaires given to subjects or survivors (proxies). In 10 of the 12 studies, there were a total of 680 male cases of sinonasal cancer (330 squamous-cell carcinomas, 169 adenocarcinomas, 156 cases of other histologic types, and 25 cases of unknown histology) and 250 female cases of sinonasal cancer (102 squamous-cell carcinomas, 26 adenocarcinomas, 104 cases of other histologic types, and 18 cases of unknown histology). For the pooled analysis, subjects’ self-reported occupational information was recoded with the one-or two-digit International Standard Classification of Occupations. The researchers state that they controlled only for study and age category because they found that “introduction of cigarette smoking into the models, in addition to age and study, had no appreciable effect” on the risk of squamous-cell carcinoma. Among men, employment as a motor-vehicle driver was associated with an increased risk of adenocarcinoma (OR adjusted for study and age 2.50, 95% CI 1.03–

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 6.10) but not of squamous-cell carcinoma (OR 1.13, 95% CI 0.78–1.63). Duration of exposure did not change the point estimates for squamous-cell carcinoma, and only shorter exposure duration was linked to the increased risk of adenocarcinomas (OR<10 years 3.29, no CI; OR ≥10 years 0.80, no CI given). Also among men, employment as a cook was associated with an increased risk of squamous-cell carcinoma only in the shorter-duration group (OR adjusted 1.99, 95% CI 1.04–3.83; OR<10 years 2.72; OR≥10 years 1.25). Among women, however, employment as a cook was associated with a suggestion of a decreased risk of squamous-cell carcinoma (based on only three exposed cases; OR ever employed vs never employed 0.51, 95% CI 0.15–1.77; OR<10 years 0.27; OR≥10 years 0.69). A population-based case-control study of incident nasal cavity and sinus cancer was conducted in British Columbia, Canada (Teschke et al. 1997). There were 48 cases identified in 1990–1992, and 159 population controls were frequency matched to cases on sex and age. Exposure was ascertained in interviews that included occupational history and items on individual exposures. Occupation-disease associations were estimated in models adjusted for age, sex, and tobacco use. There was no association with any particular occupation. The incidence of pharyngeal, sinonasal, and oropharyngeal or hypopharyngeal cancer was assessed in a population-based case-control study from the Washington state cancer registry (Vaughan 1989). There were 231 cases aged 20–74 years diagnosed in 1979–1983 (sinonasal cancer) or 1980–1983 (pharyngeal cancer) and 552 population controls frequency matched to cases on age and sex (also de facto matched on telephone prefix because they were recruited with random-digit dialing). Histories for all jobs held at least 6 months were taken in interviews with subjects or their proxies. People were classified into 31 industrial and 59 occupational groups, and duration of employment was calculated on the basis of the start and end dates of employment. Models for oropharyngeal, hypopharyngeal, or sinonasal cancer were adjusted for age, sex, tobacco use, and alcohol consumption. Models for NPC were adjusted for age, sex, and race. Employment as a motor vehicle operator or other transportation worker was not associated with sinonasal cancer or pharyngeal cancer. Conclusion Little information is available on exposure to fuels and cancers of the nasal cavity and nasopharynx. The two studies reviewed by the committee did not report convincingly positive findings (Armstrong et al. 2000; Teschke et al. 1997). The committee concludes, from its assessment of the epidemiologic literature, that there is inadequate/insufficient evidence to determine whether an association exists between exposure to fuels and cancers of the nasal cavity and nasopharynx. Overall, the results of studies of the relationship between combustion products and cancers of the nasal cavity and nasopharynx are inconsistent, and indirect methods were used to assess exposure. However, positive associations were reported by studies conducted in China (Yu et al. 1990; Zheng et al. 1994) between combustion products (particularly wood smoke) and cancer of the nasopharynx. Those findings are supported by the work of Leclerc et al. (1997) and Armstrong and Armstrong (1983). The committee believes that the evidence is strong enough to suggest an association between combustion products and cancers of the nasal cavity and nasopharynx.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 The committee concludes, from its assessment of the epidemiologic literature, that there is limited/suggestive evidence of an association between exposure to combustion products and cancers of the nasal cavity and nasopharynx. ESOPHAGEAL CANCER This review focuses on esophageal cancer (ICD-9 150). Risk factors for that cancer are increasing age, sex, ethnicity, dietary habits, chronic reflux esophagitis, alcohol and tobacco use, and work exposure (ACS 2004q, 2004w). In the United States in 2000, there were 4.7 new cases of esophageal cancer per 100,000 people (7.9 among men and 2.1 among women) and 4.4 deaths per 100,000 (7.7 among men and 1.8 among women) (Ries et al. 2004). Fuels Table 4.5 presents the most relevant findings reviewed by the committee in drawing its conclusion on the possibility of an association between exposure to fuels and esophageal cancer. Cohort Studies A cohort of 3,814 male uranium-processing workers in Ohio in 1951–1989 was used to assess the potential relationship between esophageal and stomach cancers and kerosene exposure (Ritz 1999). Kerosene exposure based on a detailed industrial hygiene assessment (light or medium exposure) was associated with an increased risk of esophageal and stomach cancers; those cancers were analyzed together. Light kerosene exposure for 2 years or more with a 15-year lag before disease onset was associated with an RR of 3.46 (95% CI 1.22–9.80); medium kerosene exposure of the same duration and lag were also associated with an increased risk of esophageal and stomach cancer (RR 7.71, 95% CI 2.04–29.1). Mortality was assessed in a cohort of 15,032 men with 5 years or more of work in 1964–1973 at Imperial Oil Limited refinery in Canada (Hanis et al. 1979). No specific industrial-hygiene assessment was available. There was an additional 11-year update that included 34,597 workers, including those hired in 1964–1983 (Lewis et al. 2000b; Schnatter et al. 1992). In followup through 1973, potential daily exposure to petroleum was associated with a greater risk of combined esophageal and stomach cancers (RR 3.25, p<0.05); the increase was greater with increasing years of employment (Hanis et al. 1979). However, the risk was not consistently observed in later followup studies of the cohort (Lewis et al. 2000b; Schnatter et al. 1992). In a nationwide survey of gasoline-station attendants in Italy, the SMR for esophageal cancer was 2.34 (90% CI 0.80–5.35) (Lagorio et al. 1994). In small stations, where there were higher sales per employee, the risk of esophageal cancer was greater (SMR 3.42, 90% CI 1.17–7.82). Workers in small stations with higher sales of super-premium gasoline may have experienced higher exposure. Combustion Products Table 4.6 presents the most relevant findings reviewed by the committee in drawing its conclusion on the possibility of an association between exposure to combustion products and esophageal cancer.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Gustavsson P, Jakobsson R, Nyberg F, Pershagen G, Jarup L, Scheele P. 2000. Occupational exposure and lung cancer risk: A population-based case-referent study in Sweden. American Journal of Epidemiology 152(1):32–40. Gustavsson P, Plato N, Lidstrom EB, Hogstedt C. 1990. Lung cancer and exposure to diesel exhaust among bus garage workers. Scandinavian Journal of Work, Environment & Health 16(5):348–354. Hanis NM, Stavraky KM, Fowler JL. 1979. Cancer mortality in oil refinery workers. Journal of Occupational Medicine 21(3):167–174. Hanis NM, Holmes TM, Shallenberger G, Jones KE. 1982. Epidemiologic study of refinery and chemical plant workers. Journal of Occupational Medicine 24(3):203–212. Hannuksela-Svahn A, Pukkala E, Karvonen J. 1999. Basal cell skin carcinoma and other nonmelanoma skin cancers in Finland from 1956 through 1995. Archives of Dermatology 135(7):781–786. Hansen ES. 1993. A follow-up study on the mortality of truck drivers. American Journal of Industrial Medicine 23(5):811–821. Hansen J. 2000. Elevated risk for male breast cancer after occupational exposure to gasoline and vehicular combustion products. American Journal of Industrial Medicine 37(4):349–352. Hansen J, Raaschou-Nielsen O, Olsen JH. 1998. Increased risk of lung cancer among different types of professional drivers in Denmark. Occupational and Environmental Medicine 55(2):115–118. Hartge P, Cahill JI, West D, Hauck M, Austin D, Silverman D, Hoover R. 1984. Design and methods in a multi-center case-control interview study. American Journal of Public Health 74(1):52–56. Hayes RB, Thomas T, Silverman DT, Vineis P, Blot WJ, Mason TJ, Pickle LW, Correa P, Fontham ETH, Schoenberg JB. 1989. Lung cancer in motor exhaust-related occupations. American Journal of Industrial Medicine 16(6):685–695. He XZ, Chen W, Liu ZY, Chapman RS. 1991. An epidemiological study of lung cancer in Xuan Wei County, China: Current progress. Case-control study on lung cancer and cooking fuel. Environmental Health Perspectives 94:9–13. Heineman EF, Olsen JH, Pottern LM, Gomez M, Raffn E, Blair A. 1992. Occupational risk factors for multiple myeloma among Danish men. Cancer Causes & Control 3(6):555–568. Hoar SK, Hoover R. 1985. Truck driving and bladder cancer mortality in rural New England. Journal of the National Cancer Institute 74(4):771–774. Hoek G, Brunekreef B, Goldbohm S, Fischer P, Van den Brandt PA. 2002. Association between mortality and indicators of traffic-related air pollution in the Netherlands: A cohort study. Lancet 360(9341):1203–1209. Hours M, Dananche B, Fevotte J, Bergeret A, Ayzac L, Cardis E, Etard JF, Fallen C, Roy P, Fabry J. 1994. Bladder cancer and occupational exposures. Scandinavian Journal of Work, Environment & Health 20(5):322–330. Howe GR, Burch JD, Miller AB, Cook GM, Esteve J, Morrison B, Gordon P, Chambers LW, Fodor G, Winsor GM. 1980. Tobacco use, occupation, coffee, various nutrients, and bladder cancer. Journal of the National Cancer Institute 64(4):701–713. Howe GR, Fraser D, Lindsay J, Presnal B, Yu SZ. 1983. Cancer mortality (1965–77) in relation to diesel fume and coal exposure in a cohort of retired railway workers. Journal of the National Cancer Institute 70(6):1015–1019. Hu J, Mao Y, White K. 2002. Renal cell carcinoma and occupational exposure to chemicals in Canada. Occupational Medicine 52(3):157–164. Huang C, Zhang X, Qiao Z, Guan L, Peng S, Liu J, Xie R, Zheng L. 1992. A case-control study of dietary factors in patients with lung cancer. Biomedical & Environmental Sciences 5(3):257–265. Huebner WW, Chen VW, Friedlander BR, Wu XC, Jorgensen G, Bhojani FA, Friedmann CH, Schmidt BA, Sales EA, Joy JA, Correa CN. 2000. Incidence of lymphohaematopoietic malignancies in a petrochemical industry cohort: 1983–94 follow up. Occupational & Environmental Medicine 57(9):605–614.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Huebner WW, Schoenberg JB, Kelsey JL, Wilcox HB, McLaughlin JK, Greenberg RS, Preston-Martin S, Austin DF, Stemhagen A, Blot WJ, Winn DM, Fraumeni J, Jr. 1992. Oral and pharyngeal cancer and occupation: A case-control study. Epidemiology 3(4):300–309. IARC (International Agency for Research on Cancer). 1984a. Polynuclear Aromatic Compounds, Part 2, Carbon Blacks, Mineral Oils and some Nitroarenes. 33. Lyon, France: IARC. IARC. 1984b. Polynuclear Aromatic Compounds, Part 3, Industrial Exposures in Aluminum Production, Coal Gasification, Coke Production, and Iron and Steel Founding. 34. Lyon, France: IARC. IARC. 1985. Polynuclear aromatic Compounds, Part 4, Bitumens, Coal-Tars and Derived Products, Shale-oils and Soots. 35. Lyon, France: IARC. Ido M, Nagata C, Kawakami N, Shimizu H, Yoshida Y, Nomura T, Mizoguchi H. 1996. A case-control study of myelodysplastic syndromes among Japanese men and women. Leukemia Research 20(9):727–731. IOM (Institute of Medicine). 2003. Gulf War and Health, Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. Iscovich J, Castelletto R, Esteve J, Munoz N, Colanzi R, Coronel A, Deamezola I, Tassi V, Arslan A. 1987. Tobacco smoking, occupational exposure and bladder cancer in Argentina. International Journal of Cancer 40(6):734–740. Iyer V, Harris RE, Wynder EL. 1990. Diesel exhaust exposure and bladder cancer risk. European Journal of Epidemiology 6(1):49–54. Jarvholm B, Silverman D. 2003. Lung cancer in heavy equipment operators and truck drivers with diesel exhaust exposure in the construction industry. Occupational and Environmental Medicine 60(7):516–520. Jarvholm B, Mellblom B, Norrman R, Nilsson R, Nordlinder R. 1997. Cancer incidence of workers in the Swedish petroleum industry. Occupational and Environmental Medicine 54(9):686–691. Jedrychowski W, Becher H, Wahrendorf J, Basa-Cierpialek Z. 1990. A case-control study of lung cancer with special reference to the effect of air pollution in Poland. Journal of Epidemiology and Community Health 44(2):114–120. Jemal A, Murray T, Samuels A, Ghafoor A, Ward E, Thun MJ. 2003. Cancer statistics, 2003. CA: A Cancer Journal for Clinicians 53(1):5–26. Jensen OM, Knudsen JB, McLaughlin JK, Sorensen BL. 1988. The Copenhagen case-control study of renal pelvis and ureter cancer: Role of smoking and occupational exposures. International Journal of Cancer 41(4):557–561. Jensen OM, Wahrendorf J, Knudsen JB, Sorensen BL. 1987. The Copenhagen case-referent study on bladder cancer. Risks among drivers, painters and certain other occupations. Scandinavian Journal of Work, Environment & Health 13(2):129–134. Jockel KH, Ahrens W, Jahn I, Pohlabeln H, Bolm-Audorff U. 1998. Occupational risk factors for lung cancer: A case-control study in West Germany. International Journal of Epidemiology 27(4):549–560. Jockel KH, Ahrens W, Wichmann HE, Becher H, Bolm-Audorff U, Jahn I, Molik B, Greiser E, Timm J. 1992. Occupational and environmental hazards associated with lung cancer. International Journal of Epidemiology 21(2):202–213. Kadamani S, Asal NR, Nelson RY. 1989. Occupational hydrocarbon exposure and risk of renal cell carcinoma. American Journal of Industrial Medicine 15(2):131–141. Kaplan I. 1959. Relationship of noxious gases to carcinoma of the lung in railroad workers. JAMA 171:2039–2043. Katsouyanni K, Trichopoulos D, Kalandidi A, Tomos P, Riboli E. 1991. A case-control study of air pollution and tobacco smoking in lung cancer among women in Athens. Preventive Medicine 20(2):271–278. Kauppinen T, Partanen T, Degerth R, Ojajarvi A. 1995. Pancreatic cancer and occupational exposures. Epidemiology 6(5):498–502.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Kleinerman RA, Wang Z, Wang L, Metayer C, Zhang S, Brenner AV, Zhang S, Xia Y, Shang B, Lubin JH. 2002. Lung cancer and indoor exposure to coal and biomass in rural China. Journal of Occupational and Environmental Medicine 44(4):338–344. Kneller RW, Gao YT, McLaughlin JK, Gao RN, Blot WJ, Liu MH, Sheng JP, Fraumeni JF Jr. 1990. Occupational risk factors for gastric cancer in Shanghai, China. American Journal of Industrial Medicine 18(1):69–78. Ko YC, Lee CH, Chen MJ, Huang CC, Chang WY, Lin HJ, Wang HZ, Chang PY. 1997. Risk factors for primary lung cancer among non-smoking women in Taiwan. International Journal of Epidemiology 26(1):24–31. Kogevinas M, ‘t Mannetje A, Cordier S, Ranft U, Gonzalez C, Vineis P, Chang-Claude J, Lynge E, Wahrendorf J, Tzonou A, Jockel K, Serra C, Porru S, Hours M, Greiser E, Boffetta P. 2003. Occupation and bladder cancer among men in Western Europe. Cancer Causes & Control 14(10):907–914. Koo LC, Lee N, Ho JH. 1983. Do cooking fuels pose a risk for lung cancer? A case-control study of women in Hong Kong. Ecology of Disease 2(4):255–265. Krewski D, Burnett RT, Goldberg MS, Hoover BK, Siemiatycki J, Jerrett M, Abrahamowicz M, White WH. 2003. Overview of the reanalysis of the Harvard Six Cities Study and American Cancer Society Study of Particulate Air Pollution and Mortality. Journal of Toxicology and Environmental Health—Part A 66(16–19):1507–1551. Krewski D, Snyder R, Beatty P, Granville G, Meek B, Sonawane B. 2000. Assessing the health risks of benzene: A report on the Benzene State-of-the-Science Workshop. Journal of Toxicology and Environmental Health—Part A 61(5–6):307–338. Krstev S, Baris D, Stewart P, Dosemeci M, Swanson G, Greenberg R, Schoenberg J, Schwartz A, Liff J, Hayes RB. 1998. Occupational risk factors and prostate cancer in U.S. blacks and whites. American Journal of Industrial Medicine 34(5):421–430. Kubasiewicz M, Starzynski Z. 1989. Case-referent study on skin cancer and its relation to occupational exposure to polycyclic aromatic hydrocarbons: I. Study design. Polish Journal of Occupational Medicine 2(3):221–228. Kubasiewicz M, Starzynski Z, Szymczak W. 1991. Case-referent study on skin cancer and its relation to occupational exposure to polycyclic aromatic hydrocarbons. II. Study results. Polish Journal of Occupational Medicine and Environmental Health 4(2):141–147. Kunze E, Chang-Claude J, Frentzel-Beyme R. 1992. Life style and occupational risk factors for bladder cancer in Germany: A case-control study. Cancer 69(7):1776–1790. Lagorio S, Forastiere F, Iavarone I, Rapiti E, Vanacore N, Perucci CA, Carere A. 1994. Mortality of filling station attendants. Scandinavian Journal of Work, Environment & Health 20(5):331–338. Lagorio S, Forastiere F, Iavarone I, Vanacore N, Fuselli S, Carere A. 1993. Exposure assessment in a historical cohort of filling station attendants. International Journal of Epidemiology 22(Suppl 2):S51–S56. Lan Q, Chapman RS, Schreinemachers DM, Tian L, He X. 2002. Household stove improvement and risk of lung cancer in Xuanwei, China. Journal of the National Cancer Institute 94(11):826–835. Lan Q, Chen W, Chen H, He XZ. 1993. Risk factors for lung cancer in non-smokers in Xuanwei County of China. Biomedical and Environmental Sciences 6(2):112–118. Lan Q, Feng Z, Tian D, He X, Rothman N, Tian L, Lu X, Terry MB, Mumford JL. 2001. p53 gene expression in relation to indoor exposure to unvented coal smoke in Xuan Wei, China. Journal of Occupational and Environmental Medicine 43(3):226–30. Larkin EK, Smith TJ, Stayner L, Rosner B, Speizer FE, Garshick E. 2000. Diesel exhaust exposure and lung cancer: Adjustment for the effect of smoking in a retrospective cohort study. American Journal of Industrial Medicine 38(4):399–409.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Leclerc A, Luce D, Demers PA, Boffetta P, Kogevinas M, Belli S, Bolm-Audorff U, Brinton LA, Colin D, Comba P, Gerin M, Hardell L, Hayes RB, Magnani C, Merler E, Morcet JF, Preston-Martin S, Vaughan TL, Zheng W. 1997. Sinonasal cancer and occupation. Results from the reanalysis of twelve case-control studies. American Journal of Industrial Medicine 31(2):153–165. Lee WJ, Baris D, Jarvholm B, Silverman DT, Bergdahl IA, Blair A. 2003. Multiple myeloma and diesel and other occupational exposures in Swedish construction workers. International Journal of Cancer 107(1):134–138. Lei YX, Cai WC, Chen YZ, Du YX. 1996. Some lifestyle factors in human lung cancer: A case-control study of 792 lung cancer cases. Lung Cancer 14(Suppl 1):S121–S136. Lerchen ML, Wiggins CL, Samet JM. 1987. Lung cancer and occupation in New Mexico. Journal of the National Cancer Institute 79(4):639–45. Lewis RJ, Gamble JF, Jorgensen G. 2000a. Mortality among three refinery/petrochemical plant cohorts. I. 1970 to 1982 active/terminated workers. Journal of Occupational and Environmental Medicine 42(7):721–729. Lewis RJ, Schnatter AR, Drummond I, Murray N, Thompson FS, Katz AM, Jorgensen G, Nicolich MJ, Dahlman D, Theriault G. 2003. Mortality and cancer morbidity in a cohort of Canadian petroleum workers. Occupational and Environmental Medicine 60(12):918–928. Lewis RJ, Schnatter AR, Katz AM, Thompson FS, Murray N, Jorgensen G, Theriault G. 2000b. Updated mortality among diverse operating segments of a petroleum company. Occupational and Environmental Medicine 57(9):595–604. Lewis-Michl EL, Melius JM, Kallenbach LR, Ju CL, Talbot TO, Orr MF, Lauridsen PE. 1996. Breast cancer risk and residence near industry or traffic in Nassau and Suffolk Counties, Long Island, New York. Archives of Environmental Health 51(4):255–265. Lindquist R, Nilsson B, Eklund G, Gahrton G. 1991. Acute leukemia in professional drivers exposed to gasoline and diesel. European Journal of Haematology 47(2):98–103. Linet MS, Harlow SD, McLaughlin JK. 1987. A case-control study of multiple myeloma in whites: Chronic antigenic stimulation, occupation, and drug use. Cancer Research 47(11):2978–2981. Linet MS, Malker HS, Chow WH, McLaughlin JK, Weiner JA, Stone BJ, Ericsson JL, Fraumeni JF Jr. 1995. Occupational risks for cutaneous melanoma among men in Sweden. Journal of Occupational and Environmental Medicine 37(9):1127–1135. Linet MS, Malker HS, McLaughlin JK, Weiner JA, Blot WJ, Ericsson JL, Fraumeni JF Jr. 1993. Non-Hodgkin’s lymphoma and occupation in Sweden: A registry based analysis. British Journal of Industrial Medicine 50(1):79–84. Linet MS, McLaughlin JK, Malker HS, Chow WH, Weiner JA, Stone BJ, Ericsson JL, Fraumeni JF Jr. 1994. Occupation and hematopoietic and lymphoproliferative malignancies among women: A linked registry study. Journal of Occupational Medicine 36(11):1187–1198. Liu Q, Sasco AJ, Riboli E, Hu MX. 1993. Indoor air pollution and lung cancer in Guangzhou, People’s Republic of China. American Journal of Epidemiology 137(2):145–154. Luce D, Leclerc A, Begin D, Demers PA, Gerin M, Orlowski E, Kogevinas M, Belli S, Bugel I, Bolm-Audorff U, Brinton LA, Comba P, Hardell L, Hayes RB, Magnani C, Merler E, Preston-Martin S, Vaughan TL, Zheng W, Boffetta P. 2002. Sinonasal cancer and occupational exposures: A pooled analysis of 12 case-control studies. Cancer Causes & Control 13(2):147–157. Luo RX, Wu B, Yi YN, Huang ZW, Lin RT. 1996. Indoor burning coal air pollution and lung cancer-a case-control study in Fuzhou, China. Lung Cancer 14(Suppl 1):S113–S119. Magnani C, Pannett B, Winter PD, Coggon D. 1988. Application of a job-exposure matrix to national mortality statistics for lung cancer. British Journal of Industrial Medicine 45(1):70–72. Maier H, Tisch M. 1997. Epidemiology of laryngeal cancer: Results of the Heidelberg case-control study. Acta Oto-laryngologica. Supplementum 527:160–164. Mandel JS, McLaughlin JK, Schlehofer B, Mellemgaard A, Helmert U, Lindblad P, McCredie M, Adami HO. 1995. International renal-cell cancer study. IV. Occupation. International Journal of Cancer 61(5):601–605.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Mao Y, Hu J, Ugnat AM, White K. 2000. Non-Hodgkin’s lymphoma and occupational exposure to chemicals in Canada. Canadian Cancer Registries Epidemiology Research Group. Annals of Oncology 11(Suppl 1):69–73. Marsh GM, Stone RA, Esmen NA, Gula MJ, Gause CK, Petersen NJ, Meaney FJ, Rodney S, Prybylski D. 1998. A case-control study of lung cancer mortality in four rural Arizona smelter towns. Archives of Environmental Health 53(1):15–28. Matos EL, Vilensky M, Mirabelli D, Boffetta P. 2000. Occupational exposures and lung cancer in Buenos Aires, Argentina. Journal of Occupational and Environmental Medicine 42(6):653–659. McCredie M, Stewart JH. 1993. Risk factors for kidney cancer in New South Wales. IV. Occupation. British Journal of Industrial Medicine 50(4):349–354. McLaughlin JK, Blot WJ, Mehl ES, Stewart PA, Venable FS, Fraumeni JF Jr. 1985. Petroleum-related employment and renal cell cancer. Journal of Occupational Medicine 27(9):672–674. McLaughlin JK, Malker HS, Stone BJ, Weiner JA, Malker BK, Ericsson JL, Blot WJ, Fraumeni JF Jr. 1987. Occupational risks for renal cancer in Sweden. British Journal of Industrial Medicine 44(2):119–123. McLaughlin JK, Mandel JS, Blot WJ, Schuman LM, Mehl ES, Fraumeni JF Jr. 1984. A population-based case-control study of renal cell carcinoma. Journal of the National Cancer Institute 72(2):275–284. Mellemgaard A, Engholm G, McLaughlin JK, Olsen JH. 1994. Occupational risk factors for renal-cell carcinoma in Denmark. Scandinavian Journal of Work, Environment & Health 20(3):160–165. Menvielle G, Luce D, Fevotte J, Bugel I, Salomon C, Goldberg P, Billon-Galland MA, Goldberg M. 2003. Occupational exposures and lung cancer in New Caledonia. Occupational and Environmental Medicine 60(8):584–589. Merletti F, Boffetta P, Ferro G, Pisani P, Terracini B. 1991. Occupation and cancer of the oral cavity or oropharynx in Turin, Italy. Scandinavian Journal of Work, Environment and Health 17(4):248–254. Metayer C, Wang Z, Kleinerman RA, Wang L, Brenner AV, Cui H, Cao J, Lubin JH. 2002. Cooking oil fumes and risk of lung cancer in women in rural Gansu, China. Lung Cancer 35(2):111–117. Michelozzi P, Fusco D, Forastiere F, Ancona C, Dell’Orco V, Perucci CA. 1998. Small area study of mortality among people living near multiple sources of air pollution. Occupational and Environmental Medicine 55(9):611–615. Mommsen S, Aagard J. 1984. Occupational exposures as risk indicator of male bladder carcinoma in a predominantly rural area. Acta Radiologica—Oncology 23(2–3):147–152. Mommsen S, Aagaard J, Sell A. 1982. An epidemiological case-control study of bladder cancer in males from a predominantly rural district. European Journal of Cancer and Clinical Oncology 18(11):1205–1210. Mommsen S, Aagaard J, Sell A. 1983. An epidemiological study of bladder cancer in a predominantly rural district. Scandinavian Journal of Urology and Nephrology 17(3):307–312. Monarrez-Espino J, Stang A, Bromen K, Merzenich H, Anastassiou G, Jockel KH. 2002. Occupation as a risk factor for uveal melanoma in Germany. Scandinavian Journal of Work, Environment & Health 28(4):270–277. Morris PD, Koepsell TD, Daling JR, Taylor JW, Lyon JL, Swanson GM, Child M, Weiss NS. 1986. Toxic substance exposure and multiple myeloma: A case control-study. Journal of the National Cancer Institute 76(6):987–994. Muir C, Waterhouse J, Mack T, Powell J, Whelan S. 1987. Cancer Incidence in Five Continents, Vol. 5. IARC Scientific Publication. 88. Lyon, France: IARC; as cited in Yu et al. 1990. Muscat JE, Wynder EL. 1995. Diesel exhaust, diesel fumes, and laryngeal cancer. Otolaryngology—Head and Neck Surgery 112(3):437–440. Muscat JE, Stellman SD, Richie JP Jr, Wynder EL. 1998. Lung cancer risk and workplace exposures in black men and women. Environmental Research 76(2):78–84. Nadon L, Siemiatycki J, Dewar R, Krewski D, Gerin M. 1995. Cancer risk due to occupational exposure to polycyclic aromatic hydrocarbons. American Journal of Industrial Medicine 28(3):303–324.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Nafstad P, Haheim LL, Oftedal B, Gram F, Holme I, Hjermann I, Leren P. 2003. Lung cancer and air pollution: A 27 year follow up of 16,209 Norwegian men. Thorax 58(12):1071–1076. Nagata C, Shimizu H, Hirashima K, Kakishita E, Fujimura K, Niho Y, Karasawa M, Oguma S, Yoshida Y, Mizoguchi H. 1999. Hair dye use and occupational exposure to organic solvents as risk factors for myelodysplastic syndrome. Leukemia Research 23(1):57–62. Najem GR, Louria DB, Seebode JJ, Thind IS, Prusakowski JM, Ambrose RB, Fernicola AR. 1982. Life time occupation, smoking, caffeine, saccharine, hair dyes and bladder carcinogenesis. International Journal of Epidemiology 11(3):212–217. NCI (National Cancer Institute). 2002. What You Need to Know About Bladder Cancer; Information About Detection, Symptoms, Diagnosis, and Tretment of Bladder Cancer. [Online]. Available: http://www.lnci.nih.gov/cancerinfo/wyntk/bladder [accessed May 18, 2004]. NCI. 2004. What You Need to Know About Leukemia. [Online]. Available: http://www.nci.nih.gov/cancertopics/wyntk/leukemia [accessed August, 2004]. Nelemans PJ, Scholte R, Groenendal H, Kiemeney LA, Rampen FH, Ruiter DJ, Verbeek AL. 1993. Melanoma and occupation: Results of a case-control study in The Netherlands. British Journal of Industrial Medicine 50(7):642–646. Nelson NA, Barker DM, Van Peenen PF, Blanchard AG. 1985. Determining exposure categories for a refinery retrospective cohort mortality study. American Industrial Hygiene Association Journal 46(11):653–657. Nelson NA, Van Peenen PF, Blanchard AG. 1987. Mortality in a recent oil refinery cohort. Journal of Occupational Medicine 29(7):610–612. Netterstrom B. 1988. Cancer incidence among urban bus drivers in Denmark. International Archives of Occupational and Environmental Health 61(3):217–221. Nisse C, Haguenoer JM, Grandbastien B, Preudhomme C, Fontaine B, Brillet JM, Lejeune R, Fenaux P. 2001. Occupational and environmental risk factors of the myelodysplastic syndromes in the North of France. British Journal of Haematology 112(4):927–935. Nisse C, Lorthois C, Dorp V, Eloy E, Haguenoer JM, Fenaux P. 1995. Exposure to occupational and environmental factors in myelodysplastic syndromes. Preliminary results of a case-control study. Leukemia 9(4):693–699. Notani PN, Shah P, Jayant K, Balakrishnan V. 1993. Occupation and cancers of the lung and bladder: A case-control study in Bombay. International Journal of Epidemiology 22(2):185–191. Nyberg F, Gustavsson P, Jarup L, Bellander T, Berglind N, Jakobsson R, Pershagen G. 2000. Urban air pollution and lung cancer in Stockholm. Epidemiology 11(5):487–495. Paradis G, Theriault G, Tremblay C. 1989. Mortality in a historical cohort of bus drivers. International Journal of Epidemiology 18(2):397–402. Parent ME, Hua Y, Siemiatycki J. 2000a. Occupational risk factors for renal cell carcinoma in Montreal. American Journal of Industrial Medicine 38(6):609–618. Parent ME, Siemiatycki J, Fritschi L. 2000b. Workplace exposures and oesophageal cancer. Occupational & Environmental Medicine 57(5):325–334. Partanen T, Heikkila P, Hernberg S, Kauppinen T, Moneta G, Ojajarvi A. 1991. Renal cell cancer and occupational exposure to chemical agents. Scandinavian Journal of Work, Environment & Health 17(4):231–239. Pesch B, Haerting J, Ranft U, Klimpel A, Oeschlagel B, Schill W. 2000a. Occupational risk factors for renal cell carcinoma: Agent-specific results from a case-control study in Germany. International Journal of Epidemiology 29(6):1014–1024. Pesch B, Haerting J, Ranft U, Klimpel A, Oelschlagel B, Schill W. 2000b. Occupational risk factors for urothelial carcinoma: Agent-specific results from a case-control study in Germany. International Journal of Epidemiology 29(2):238–247.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Petralia SA, Vena JE, Freudenheim JL, Dosemeci M, Michalek A, Goldberg MS, Erasure J, Graham S. 1999. Risk of premenopausal breast cancer in association with occupational exposure to polycyclic aromatic hydrocarbons and benzene. Scandinavian Journal of Work, Environment & Health 25(3):215–221. Pietri F, Clavel F, Auquier A, Flamant R. 1990. Occupational risk factors for cancer of the pancreas: A case-control study. British Journal of Industrial Medicine 47(6):425–428. Pintos J, Franco EL, Kowalski LP, Oliveira BV, Curado MP. 1998. Use of wood stoves and risk of cancers of the upper aero-digestive tract: A case-control study. International Journal of Epidemiology 27(6):936–940. Pion IA, Rigel DS, Garfinkel L, Silverman MK, Kopf AW. 1995. Occupation and the risk of malignant melanoma. Cancer 75(2 Suppl):637–644. Pollan M, Lopez-Abente G. 1995. Wood-related occupations and laryngeal cancer. Cancer Detection & Prevention 19(3):250–257. Poole C, Dreyer NA, Satterfield MH, Levin L, Rothman KJ. 1993. Kidney cancer and hydrocarbon exposures among petroleum refinery workers. Environmental Health Perspectives 101(Suppl 6):53–62. Pope CA 3rd, Burnett RT, Thun MJ, Calle EE, Krewski D, Ito K, Thurston GD. 2002. Lung cancer, cardiopulmonary mortality, and long-term exposure to fine particulate air pollution. Journal of the American Medical Association 287(9):1132–1141. Pope CA 3rd, Thun MJ, Namboodiri MM, Dockery DW, Evans JS, Speizer FE, Heath CW Jr. 1995. Particulate air pollution as a predictor of mortality in a prospective study of U.S. adults. American Journal of Respiratory and Critical Care Medicine 151(3 Pt 1):669–674. Porru S, Aulenti V, Donato F, Boffetta P, Fazioli R, Cosciani Cunico S, Alessio L. 1996. Bladder cancer and occupation: A case-control study in northern Italy. Occupational and Environmental Medicine 53(1):6–10. Pottern LM, Heineman EF, Olsen JH, Raffn E, Blair A. 1992. Multiple myeloma among Danish women: Employment history and workplace exposures. Cancer Causes & Control 3(5):427–432. Pukkala E, Soderholm AL, Lindqvist C. 1994. Cancers of the lip and oropharynx in different social and occupational groups in Finland. European Journal of Cancer. Part B, Oral Oncology 30B(3):209–215. Raabe GK, Collingwood KW, Wong O. 1998. An updated mortality study of workers at a petroleum refinery in Beaumont, Texas. American Journal of Industrial Medicine 33(1):61–81. Rafnsson V, Gunaarsdottir H. 1991. Mortality among professional drivers. Scandinavian Journal of Work, Environment & Health 17(5):312–317. Rebelakos A, Trichopoulos D, Tzonou A, Zavitsanos X, Velonakis E, Trichopoulos A. 1985. Tobacco smoking, coffee drinking, and occupation as risk factors for bladder cancer in Greece. Journal of the National Cancer Institute 75(3):455–461. Ries, LAG, Eisner, MP, Kosary, CL Hankey BF, Miller, BA, Clegg, L, Mariotto, A, Fay, MP, Feuer, EJ, Edwards, BK, eds. 2003. SEER Cancer Statistics Review, 1975–2000. [Online]. Available: http://seer.cancer.gov/csr/1975_2000/ [accessed February 2, 2004]. Ries, LAG, Eisner, MP, Kosary, CL, Hankey BF, Miller, BA, Clegg, L, Mariotto, A, Feuer, EJ, Edwards, BK, eds. 2004. SEER Cancer Statistics Review, 1975–2001. [Online]. Available: http://seer.cancer.gov/csr/1975_2001/ [accessed July 15, 2004]. Rigolin GM, Cuneo A, Roberti MG, Bardi A, Bigoni R, Piva N, Minotto C, Agostini P, De Angeli C, Del Senno L, Spanedda R, Castoldi G. 1998. Exposure to myelotoxic agents and myelodysplasia: Case-control study and correlation with clinicobiological findings. British Journal of Haematology 103(1):189–197. Risch HA, Burch JD, Miller AB, Hill GB, Steele R, Howe GR. 1988. Occupational factors and the incidence of cancer of the bladder in Canada. British Journal of Industrial Medicine 45(6):361–367.

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Gulf War and Health: Fuels, Combustion Products, and Propellants - Volume 3 Ritchie G, Still K, Rossi J 3rd, Bekkedal M, Bobb A, Arfsten D. 2003. Biological and health effects of exposure to kerosene-based jet fuels and performance additives. Journal of Toxicology and Environmental Health B Critical Review 6(4):357–451. Ritz B. 1999. Cancer mortality among workers exposed to chemicals during uranium processing. Journal of Occupational and Environmental Medicine. 41(7):556–566. Rosamilia K, Wong O, Raabe GK. 1999. A case-control study of lung cancer among refinery workers. Journal of Occupational and Environmental Medicine 41(12):1091–1103. Saverin R, Braunlich A, Dahmann D, Enderlein G, Heuchert G. 1999. Diesel exhaust and lung cancer mortality in potash mining. American Journal of Industrial Medicine 36(4):415–422. Schairer C, Hartge P, Hoover RN, Silverman DT. 1988. American Journal of Epidemiology 128(5):1027–1037. Schlehofer B, Heuer C, Blettner M, Niehoff D, Wahrendorf J. 1995. Occupation, smoking and demographic factors, and renal cell carcinoma in Germany. International Journal of Epidemiology 24(1):51–57. Schnatter AR, Armstrong TW, Nicolich MJ, Thompson FS, Katz AM, Huebner WW, Pearlman ED. 1996. Lymphohaematopoietic malignancies and quantitative estimates of exposure to benzene in Canadian petroleum distribution workers. Occupational and Environmental Medicine 53(11):773–781. Schnatter AR, Katz AM, Nicolich MJ, Theriault G. 1993. A retrospective mortality study among Canadian petroleum marketing and distribution workers. Environmental Health Perspectives 101(Suppl 6):85–99. Schnatter AR, Theriault G, Katz AM, Thompson FS, Donaleski D, Murray N. 1992. A retrospective mortality study within operating segments of a petroleum company. American Journal of Industrial Medicine 22(2):209–229. Schoenberg JB, Stemhagen A, Mogielnicki AP, Altman R, Abe T, Mason TJ. 1984. Case-control study of bladder cancer in New Jersey. I. Occupational exposures in white males. Journal of the National Cancer Institute 72(5):973–981. Schumacher MC, Slattery ML, West DW. 1989. Occupation and bladder cancer in Utah. American Journal of Industrial Medicine 16(1):89–102. Seidler A, Heiskel H, Bickeboller R, Elsner G. 1998. Association between diesel exposure at work and prostate cancer. Scandinavian Journal of Work, Environment & Health 24(6):486–494. Shallenberger LG, Acquavella JF, Donaleski D. 1992. An updated mortality study of workers in three major United States refineries and chemical plants. British Journal of Industrial Medicine 49(5):345–354. Sharpe CR, Rochon JE, Adam JM, Suissa S. 1989. Case-control study of hydrocarbon exposures in patients with renal cell carcinoma. Canadian Medical Association Journal 140(11):1309–1318. Shen XB, Wang GX, Huang YZ, Xiang LS, Wang XH. 1996. Analysis and estimates of attributable risk factors for lung cancer in Nanjing, China. Lung Cancer 14(Suppl 1):S107–S112. Shen XB, Wang GX, Zhou BS. 1998. Relation of exposure to environmental tobacco smoke and pulmonary adenocarcinoma in non-smoking women: A case control study in Nanjing. Oncology Reports. 5(5):1221–1223. Siemiatycki J, Dewar R, Nadon L, Gerin M. 1994. Occupational risk factors for bladder cancer: Results from a case-control study in Montreal, Quebec, Canada. American Journal of Epidemiology 140(12):1061–1080. Siemiatycki J, Dewar R, Nadon L, Gerin M, Richardson L, Wacholder S. 1987a. Associations between several sites of cancer and twelve petroleum-derived liquids. Results from a case-referent study in Montreal. Scandinavian Journal of Work, Environment & Health 13(6):493–504. Siemiatycki J, Gerin M, Stewart P, Nadon L, Dewar R, Richardson L. 1988. Associations between several sites of cancer and ten types of exhaust and combustion products. Results from a case-referent study in Montreal. Scandinavian Journal of Work, Environment & Health 14(2):79–90.

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