Instituto de Epidemiología y Salud Comunitaria Manuel Amunárriz, Apdo. 17-10-7410, Quito, Ecuador. E-mail: sandyura{at}ecuanex.net.ec
Abstract
Background Since 1972, oil companies have extracted more than 2 billion barrels of crude oil from the Ecuadorian Amazon, releasing billions of gallons of untreated wastes and oil directly into the environment. This study aimed to determine if there was any difference in overall and specific cancer incidence rates between populations living in proximity to oil fields and those who live in areas free from oil exploitation.
Methods Cancer cases from the provinces of Sucumbios, Orellana, Napo and Pastaza during the period 19851998 were included in the study. The exposed population was defined as those living in a county (n = 4) where oil exploitation had been ongoing for a minimum of 20 years up to the date of the study. Non-exposed counties were identified as those (n = 11) without oil development activities. Relative risks (RR) along with 95% CI were calculated for men and women as ratios of the age-adjusted incidence rates in the exposed versus non-exposed group.
Results The RR of all cancer sites combined was significantly elevated in both men and women in exposed counties. Significantly elevated RR were observed for cancers of the stomach, rectum, skin melanoma, soft tissue and kidney in men and for cancers of the cervix and lymph nodes in women. An increase in haematopoietic cancers was also observed in the population under 10 years in the exposed counties in both males and females.
Conclusion Study results are compatible with a relationship between cancer incidence and living in proximity to oil fields. An environmental monitoring and cancer surveillance system in the area is recommended.
Keywords Crude oil, cancer, Amazon, Ecuador
Accepted 20 November 2001
The Amazon basin of Ecuador, known as the Oriente, consists of more than 40 million hectares of tropical rainforest lying at the headwaters of the Amazon river network. The region contains one of the most diverse collections of plant and animal life in the world.1
In 1967, a Texaco-Gulf consortium discovered a rich field of oil beneath the rainforest, leading to an oil boom that has permanently reshaped the region. Since then, foreign companies together with Ecuadors national oil company have extracted more than 2 billion barrels of crude oil from the Ecuadorian Amazon. During this process, millions of gallons of untreated toxic wastes, gas and oil have been released into the environment.2 Indigenous federations, peasants movements and environmental groups in Ecuador have organized in opposition to unregulated oil development, charging that contamination has caused widespread damage to both people and to the environment.35
Oil development activities include several contaminating processes. In the Amazon basin of Ecuador, exploration for crude oil has involved thousands of miles of trail-clearing and hundreds of seismic detonations that have caused erosion of land and dispersion of wildlife. Each exploratory well that is drilled produces an average of 4000 m3 of drilling wastes (drilling muds, petroleum, natural gas and formation water) from deep below the earths surface. These wastes are deposited into open, unlined pits called separation ponds, from which they are either directly discharged into the environment or leach out as the pits degrade or overflow from rainwater.2,3
If commercial quantities of oil are detected, the production stage starts. Beneath the earths surface oil is mixed with gas and liquid substances. It is not possible to separate the oil from these other components during extraction, this is instead done at a later stage in a central facility. At each facility, over 4.3 million gallons of liquid wastes are generated every day and discharged without treatment into pits. Roughly 53 million cubic feet of waste gas from the separation process is burned daily. The gas is burned without temperature or emissions control, and contaminants from the gas flares pollute the air. Additional potential contamination of the air is generated at pits and oil spills by hydrocarbons coming from standing oil slicks.2
Routine maintenance activities at over 300 producing wells discharge an estimated 5 million gallons of untreated toxic wastes into the environment every year. Leaks from wells and spills from tanks have been common.6 According to a study conducted by the government in 1989, spills from flow lines alone were dumping an estimated 20 000 gallons of oil every 2 weeks.7
Overall, more than 30 billion gallons of toxic wastes and crude oil had been discharged into the land and waterways of the Oriente up until 1993.3 This compares to the 10.8 million gallons spilled in the Exxon Valdez disaster in 1989. For instance, in 1989 at least 294 000 gallons and in 1992, about 275 000 gallons of crude oil caused the Napo river (1 km wide) to run black for 1 week.8
In 1994, the Ecuadorian environmental and human rights organization Centro de Derechos Económicos y Sociales (Centre for Economic and Social Rights), released a report documenting dangerous levels of toxic contamination.9 Concentrations of polynuclear aromatic hydrocarbons (PAH) were found in drinking, bathing and fishing waters. These were 10 to 10 000 times greater than the US Environmental Protection Agency guidelines. In 1999, the Instituto de Epidemiología y Salud Comunitaria Manuel Amunárriz (IESCMA), a local non-governmental organization concerned with health, undertook water analysis for total petroleum hydrocarbons (TPH) in communities in the proximity of oil fields and communities far away from them. Water analyses showed high exposure to oil-derived chemicals among the residents of the exposed communities.10 In some streams hydrocarbon concentrations reached 144 and 288 times the limit permitted by European Community regulations.11 The same year, a report from the Ministry of Environment supported these results when concentrations of TPH over 300 times the limit permitted were found in the streams of one of the communities of the previous study.12
Although several studies have focused on residents exposed to major oil spillages,1315 epidemiological studies of communities exposed to oil pollutants near oil fields are scarce.10 Few studies have been conducted in petroleum exploration and producing workers. In one of two case-control studies, an excess risk for testicular cancer was observed among petroleum and natural gas extraction workers.16 No such excess was found in the other study.17 In a case-control study of cancer at many sites, an association was observed between exposure to crude oil and rectal and lung cancer, however the association was based on small numbers.18 A study carried out in producing and pipeline workers in the US did not find significant differences for any major cause of death.19 Sathiakumar et al.20 conducted an epidemiological study in oil and gas field workers in the US which showed a positive association between work and acute myelogenous leukaemia. A study from China has also reported increased incidences of leukaemia in oil-field workers.21 A recent update of a study of crude oil production workers showed a lower mortality risk for these employees compared with the general US population (perhaps a reflection of the healthy worker effect). An increased mortality from acute myelogenous leukaemia was found in those people who were first employed before 1940 and who were employed in the production of crude oil for more than 30 years.22
In a recent study in the Amazon basin of Ecuador, an excess of cancers was observed among males in a village located in an oil producing area.23 The objective of this study was to determine if there was any difference in overall and specific cancer incidence rates between populations living in the proximity of oil fields and those who live in areas free from oil exploitation in the Amazon basin of Ecuador.
Population and Methods
Area of study
The study was carried out in the provinces of Sucumbios, Orellana, Napo and Pastaza, situated in the eastern part of Ecuador (Figure 1). Each province is divided into counties (cantones). The study area has a total population of approximately 280 000 indigenous people and peasants.24 The indigenous people live in small communities scattered along the rivers, making their living by hunting, fishing and subsistence agriculture. The peasants arrived in the area in the 1970s following the paths opened by oil companies. They make their living mainly by agriculture and cattle-raising. In oil producing areas approximately 2% of the working population is employed by the oil industry.25 Physical infrastructure in the region is poor. Few villages and small towns (1015 000 citizens) have electricity and piped drinking water and the majority of the inhabitants live without these facilities. Many of the roads in oil producing counties are paved by crude oil to reduce the amount of dust otherwise produced in this tropical climate. In each province there is a provincial hospital and the counties have health centres. The hospitals have no histopathological services and no access to radio- or chemotherapy treatment. Two mission hospitals with efficiently functioning infrastructure are located in the counties Mera and Archidonathese are not oil producing areas. Oil producing areas have no better medical facilities than those areas where no such industry is present. Qualified personnel in the oil industry are contracted from the capital or abroad and flown out in the case of health problems. Only recently have some oil companies included health expenditure in their contracts with residents. Two counties, Sachas and Shushufindi, are producing and processing palm oil. There are no other major industries in the region apart from oil.
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Population data
Population data from the counties of the four provinces by gender and 5-year age strata for the year 1992 were used. These were projections of the National Institute of Statistics and Census based on the 1990 National Census.27
Exposure status
The study was ecologic and the exposure status defined at a county level. The exposed population was defined as those living in a county where oil exploitation had been ongoing for a minimum of 20 years to the date of the study. The non-exposed were identified as those counties without oil development activities (excluding seismic studies during the late 1990s with no exploitation activities). Four counties (Lago Agrio, Shushufindi, Orellana and Sachas) (118 264 people; 55.0% males) were defined as exposed and 11 as non-exposed (Cascales, Pto El Carmen, La Bonita, Lumbaqui, Aguarico, Tena, Archidona, El Chaco, Baeza, Puyo, Mera) (155 710 people; 52.4% males).
Statistical analysis
Incidence rates for overall and specific sites were calculated and age-adjusted to the world standard population.28 Relative risks (RR) along with 95% CI were calculated for men and women as ratios of the age-adjusted incidence rates in the exposed versus non-exposed group.
Results
In all, 473 cancer cases (39.1% in males) were identified in exposed counties and 512 (40.2% in males) in non-exposed counties. An increased incidence for all sites combined by age was observed in both men and women (Figure 2). The RR of all cancer sites combined was significantly elevated in both men (RR = 1.40; 95% CI: 1.151.71) and women (RR = 1.63; 95% CI: 1.391.91) in exposed counties (Table 1
). Significantly elevated RR were observed for cancers of the stomach (RR = 2.51; 95% CI: 1.602.94), rectum (RR = 10.40; 95% CI: 1.1612.98), skin melanoma (RR = 10.15; 95% CI: 2.9146.97), soft tissue (RR = 15.59; 95% CI: 1.74139.30) and kidney (RR = 9.2; 95% CI: 1.0382.20) in men and for cancers of the cervix (RR = 4.01; 95% CI: 2.975.41) and lymph nodes (RR = 4.74; 95% CI: 1.8911.88) in women. Four cases of larynx cancer were found in males in exposed counties but none in the non-exposed countries (Table 1
).
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Discussion
This study compared cancer incidence in counties with oil development and those without such activities in the Amazon basin of Ecuador (19851998). The results showed considerable geographical differences in the incidence of several cancers. Epidemiological studies have reported the same types of cancer being associated with occupational or residential exposure to oil pollutants.20,21,2933
Crude oil is a complex mixture of many chemical compounds, mostly hydrocarbons. The petroleum hydrocarbons of most toxicological interest are volatile organic compounds (benzene, xylene and toluene) and PAH.34 Studies on mice have reported skin tumours after application to the skin of crude oil.3537 However, a review concluded that there is limited evidence for carcinogenicity of crude oil in experimental animals. The same review concluded that there was inadequate evidence for carcinogenicity of crude oil in humans.34
Benzene is a well known cause of leukaemia,38,39 and perhaps other haematological neoplasms and disorders.40,41 No adequate data on the incidence of cancer after human exposure to the other volatile organic chemicals exist.42 A population-based case-control study carried out in Montreal showed limited evidence of increased risk for the following associations: oesophagus-toluene, colon-xylene, rectum-toluene, rectum-xylene and rectum-styrene.43 An ecological study performed to examine the relation between the incidence of leukaemia and the occurrence of volatile organic chemical (VOC) contamination of drinking water supplies suggested that drinking water contaminated with VOC might increase the incidence of leukaemia among exposed females.44 Different epidemiological studies have reported direct evidence of the carcinogenic effects of PAH in occupationally exposed subjects. Strong evidence of the carcinogenic effects of PAH on the skin, bladder and scrotum has been found.29,30,4446 Workers in several industries with significant PAH exposure have also been shown to be at risk of lung cancer.2931,45
There have been few studies of residents near oil fields or petrochemical industries. In the US, an ecological study found an association in both sexes between residential exposure to petroleum and chemical air emissions and cancer of the buccal cavity and pharynx. In males, increased age-adjusted incidence rates for cancers of the stomach, lung, prostate and kidney and urinary organs were also associated with petroleum and chemical plant air emission exposures.47 A study in the same country found high rates of cancer of the lung, nasal cavity and sinuses, and skin among the resident male population.48 Other studies in the US have suggested high rates of lung cancer and an elevated risk of brain cancer among people living near petrochemical plants.49,50 Studies from the US have also reported negative results.51 Studies conducted in Taiwan have reported an excess rate for liver and lung cancer52,53 and an excess of cancer (bone, brain, and bladder) deaths in young adults associated with residence near petrochemical industries.54
The increase in haematopoietic cancers found among children under 10 years old is troubling. Childhood leukaemia and other childhood cancers have been geographically associated with industrial atmospheric effluent, for example with petroleum derived volatiles in the UK.32,33 By contrast, a study from Wales did not find an association between incidence of leukaemia and lymphomas in children and young people in the area around the BP Chemical site at Baglan Bay, South Wales.55 A recent report around all industrial complexes that include major oil refineries in the UK found no evidence of association between residence near oil refineries and leukaemia or non-Hodgkins lymphoma.56
The findings of this study are consistent with earlier reports from the area evidencing severe contamination of water sources and an apparent excess of cancer morbidity and mortality in males in a village located in an oil producing area.23 The type of cancers found in that village, ampulla of Vater, stomach, larynx, liver and melanoma in males, lymphoma and cervix in women and leukaemia in children, are similar to those found in this study.
Because they reflect group rather than individual characteristics and exposures, ecologic studies must be interpreted cautiously. The use of aggregated data instead of the joint distributions of exposure, outcome, and covariates at the individual level, may lead to severe bias in ecologic analyses.57 Using narrow exposure data and small units of analysis (parishes) could have minimized the effect of this bias but this could not be carried out due to the lack of data. Overall, it is difficult to measure the impact of the ecologic bias in the study.
Because of geographical and socioeconomic difficulties in accessing adequate health care, it is likely that many cases of cancer were never referred to Quito from the study area. Health services are poor in both exposed and unexposed counties, but factors such as diagnostic skills and transport facilities might influence referral patterns. It is also possible that on a county level there are differences in racial composition and lifestyle patterns between exposed and unexposed populations that might confound risk estimates. However, no information was available on the distribution of these potentially important confounders.
Several limitations in the data and methods also need to be considered. Population data relied on county census estimated from the 1990 National Census. Errors in population estimates, including differential migration patterns, might bias estimates of risk. It is possible that exposed counties have had a more rapidly increasing population compared to non-exposed, providing a relatively greater underestimate of population denominators for these counties. However, population projections from the National Institute of Statistics and Census give no evidence that this is the case.27 Cancer rates were based on county of residence at time of diagnosis without information as to length of time at current residence. Because the latency period for cancer can be long, an assessment of migration into and out of counties as well as residence time in the county would have been useful, but no data were available.
Furthermore, the study design did not allow for measurement of relevant exposure over time. Although there is documented contamination of water sources used by the population in exposed areas, the relevant exposure period for cancers may extend one or two decades further back. However, in the four counties defined as exposed there is a commonly known history of heavy oil development activities since the early 1970s.2,4,6
One possibility that may explain any excess risk near an industrial source is that it reflects occupational rather than environmental factors. Individual occupational data were not available. Two exposed counties also have palm oil industries where pesticide use is common. The impact of this exposure on the results presented could not be measured.
The results suggest a relationship between cancer incidence and living in proximity to oil fields, although this ecologic study cannot lead to causal inference. However, the possibility of a causal relationship is supported by several criteria. First, the strength of the association between the outcome and the exposure. Second, there has been considerable attention devoted to the biological mechanism by which some of the components of crude oil (benzene, PAH) could increase cancer risk.5862 Third, consistency with other investigations is apparent after reviewing the body of literature that associates oil pollutants and cancer. Fourth, by using surrogate data that are representative of several decades of oil pollution exposure, a plausible time sequence from exposure to development of disease can be inferred.
Further research is necessary to determine if the observed associations do reflect an underlying causal relationship. A next step could be epidemiological studies at the individual level. Meanwhile, an environmental monitoring system to assess, control and assist in elimination of sources of pollution in the area, and a surveillance system to gain knowledge of the evolution of cancer incidence and distribution in the area, are urgently recommended.
KEY MESSAGES
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Acknowledgments
We are grateful to Dr Pepe Yepez from the National Tumour Registry of Ecuador for providing the cancer data and Dr Ben Armstrong for valuable comments on an earlier draft. This study was supported by a grant from Medicus Mundi Gipuzkoa, Capuchinos-Navarra and Fundación para los Indios del Ecuador.
References
1 Myers N. The Primary Source: Tropical Forests and Our Future. New York: Norton Press, 1984.
2 Kimerling J. Amazon Crude. New York: Brickfront Graphics Inc, 1991.
3 Jochnick C, Normand R, Zaidi S. Rights violations in the Ecuadorian Amazon: the human consequences of oil development. Health Human Rights 1994;1:82100.
4 Garzón P. Impacto socioambiental de la actividad petrolera: estudio de caso de las comunidades San Carlos y La Primavera. In: Varea A, Ortiz P (eds). Marea Negra en la Amazonía: Conflictos Socioambientales Vinculados a la Actividad Petrolera en el Ecuador. Quito: Abya-Yala, 1995, pp. 26594.
5 Kimerling J. Oil Development in Ecuador and Peru: Law, Politics and the Environment. Draft paper presented at Amazonia 2000: Development, environment and geopolitics. London: Institute of Latin American Studies, University of London, 1998.
6 Almeida A. Reseña sobre la historia ecológica de la Amazonía ecuatoriana. In: Martínez E (ed.). Ecuador Post Petrolero. Quito: Acción Ecológica, 2000.
7 Dirección General de Medio Ambiente. Estudio de Impacto Ambiental 42. Quito: Dirección General de Medio Ambiente, 1989.
8 Rainforest Action Network News. http://www.ran.org/ran/ran_campaigns/amazonia/texaco_ecuador.html, 1998.
9 Centro de Derechos Económicos y Sociales. Violaciones de Derechos en la Amazonía Ecuatoriana. Quito: Abya-Yala, 1994.
10 San Sebastian M, Armstrong B, Stephens C. La salud de mujeres que viven cerca de pozos y estaciones de petróleo en la Amazonía ecuatoriana. Rev Panam Salud Pública 2001;9:37584.[Medline]
11 Zehner R, Villacreces LA. Estudio de la Calidad de Aguas de Río en la Zona de Amortiguamiento del Parque Nacional Yasuní. Primera Fase: Monitoreo de AguasScreening Octubre de 1997. Coca, Ecuador: Laboratorio de Aguas y Suelos P. Miguel Gamboa-Fepp, 1998.
12 Ministerio de Medio Ambiente. Informe de Inspección Ambiental al Área de las Comunidades Flor de Manduro y Centro Manduro Ubicadas en el Bloque Siete Operado por la Compañía Oryx. Quito: Ministerio de Medio Ambiente, 1999.
13 Campbell D, Cox D, Crum J et al. Initial effects of the grounding of the tanker Braer on health in Shetland. Br Med J 1993;307:125155.[ISI][Medline]
14 Palinkas LA, Petterson JS, Russell J et al. Community patterns of psychiatric disorders after the Exxon Valdez oil spill. Am J Psychiatry 1993;150:151723.[Abstract]
15 Lyons RA, Temple MF, Evans D et al. Acute health effects of the Sea Empress oil spill. J Epidemiol Community Health 1999;53:30610.[Abstract]
16 Mills PK, Newell GR, Johnson DE. Testicular cancer associated with employment in agriculture and oil and natural gas extraction. Lancet 1984; i:20710.
17 Sewell CM, Castle SP, Hull HF et al. Testicular cancer and employment in agriculture and oil and natural gas extraction. Lancet 1986;i:553.
18 Siemiatycki J, Dewar R, Nadon L et al. Associations between several sites of cancer and twelve petroleum-derived liquids. Results from a case-referent study in Montreal. Scand J Work Environ Health 1987; 13:493504.[ISI][Medline]
19 Divine BJ, Barron V. Texaco mortality study III. A cohort study of producing and pipeline workers. Am J Ind Med 1987;11:189202.[ISI][Medline]
20 Sathiakumar N, Delzell E, Cole P et al. A case-control study of leukemia among petroleum workers. J Occup Environ Med 1995;37:126977.[ISI][Medline]
21 Yang C, Zhang X. Incidence survey of leukemia in China. Chin Med Sci J 1991;6:6570.[Medline]
22 Divine BJ, Hartman CM. Update of a study of crude oil production workers 194694. Occup Environ Med 2000;57:41117.
23 San Sebastian M, Armstrong B, Stephens C. Environmental exposure and cancer incidence near oil fields in the Amazon basin of Ecuador. Occup Environ Med 2001;58:51722.
24 Fundación José Peralta. Ecuador: su Realidad. Quito: Fundación de Investigación y Promoción Social José Peralta, 1999.
25 UNICEF. Situación de las Madres y los Niños en Zonas de Grandes Proyectos. Quito: United Nations Childrens Fund, 1992.
26 Sociedad de Lucha contra el Cáncer. Cáncer en Quito; Anuario 19951996. Quito: Sociedad de Lucha contra el Cáncer, 1998.
27 Instituto Nacional de Estadísticas y Censos del Ecuador. V Censo de Población y IV de Vivienda. Quito: INEC, 1990.
28 Smith PG. Comparison between registries: age-standardized rates. In: Parkin DM, Whelan SL, Ferlay J, Raymond L, Young J (eds). Cancer Incidence in Five Continents, Vol. VII. Lyon, France: International Agency for Research on Cancer, 1997.
29 Mastrangelo G, Fadda E, Marzia V. Polycyclic aromatic hydrocarbons and cancer in man. Environ Health Perspect 1996;104:116670.[ISI][Medline]
30 Boffetta P, Jourenkova N, Gustavsson P. Cancer risk from occupational and environmental exposure to polycyclic aromatic hydrocarbons. Cancer Causes Control 1997;8:44472.[CrossRef][ISI][Medline]
31 Nadon L, Siemiatycki J, Dewar R et al. Cancer risk due to occupational exposure to polycyclic aromatic hydrocarbons. Am J Ind Med 1995;28:30324.[ISI][Medline]
32 Knox EG, Gilman EA. Hazard proximities of childhood cancers in Great Britain from 195380. J Epidemiol Community Health 1997;51:15159.[Abstract]
33 Knox EG, Gilman EA. Migration patterns of children with cancer in Britain. J Epidemiol Community Health 1998;52:71626.[Abstract]
34 International Agency for Research on Cancer. Monographs on the evaluation of the carcinogenic risk of chemicals to man: occupational exposures to petroleum refining; crude oil and major petroleum fuels. Lyon, France: IARC, Vol. 45, 1989.
35 Grimmer G, Dettbarn G, Brune H et al. Quantification of the carcinogenic effect of polycyclic aromatic hydrocarbons in used engine oil by topical application onto the skin of mice. Int Arch Occup Environ Health 1982;50:95100.[ISI][Medline]
36 Clark CR, Walter MK, Ferguson PW et al. Comparative dermal carcinogenesis of shale and petroleum-derived distillates. Toxicol Ind Health 1988;4:1122.[ISI][Medline]
37 Wilson JS, Holland LM. Periodic response difference in mouse epidermis chronically exposed to crude-oils or BaP: males vs. females. Toxicology 1988;50:8394.[CrossRef][ISI][Medline]
38 Wong O. An industry wide mortality study of chemical workers occupationally exposed to benzene. I. General results. Br J Ind Med 1987;44:36581.[ISI][Medline]
39 Austin H, Delzell E, Cole P. Benzene and leukemia. A review of the literature and a risk assessment. Am J Epidemiol 1988;127:41939.[Abstract]
40 Hayes RB, Yin SN, Dosemeci M et al. Benzene and the dose-related incidence of hematologic neoplasms in China. J Natl Cancer Inst 1997; 89:106571.
41 Savitz DA, Andrews KW. Review of epidemiologic evidence on benzene and lymphatic and hematopoietic cancers. Am J Ind Med 1997;31:28795.[CrossRef][ISI][Medline]
42 Gerin M, Siemiatycki J, Desy M et al. Associations between several sites of cancer and occupational exposure to benzene, toluene, xylene, and styrene: results of a case-control study in Montreal. Am J Ind Med 1998;34:14456.[CrossRef][ISI][Medline]
43 Fagliano J, Berry M, Bove F et al. Drinking water contamination and the incidence of leukemia: an ecologic study. Am J Public Health 1990;80:120912.[Abstract]
44 Everall JD, Dowd PM. Influence of environmental factors excluding ultra violet radiation on the incidence of skin cancer. Bull Cancer 1978;65:24147.[ISI][Medline]
45 International Agency for Research on Cancer. Monographs on the evaluation of the carcinogenic risk of chemicals to man: polynuclear aromatic hydrocarbons. Lyon, France: IARC, 1983, Vol. 34.
46 Bonassi S, Merlo F, Pearce N et al. Bladder cancer and occupational exposure to polycyclic aromatic hydrocarbons. Int J Cancer 1989;44:64851.[ISI][Medline]
47 Kaldor J, Harris JA, Glazer E et al. Statistical association between cancer incidence and major-cause mortality, and estimated residential exposure to air emissions from petroleum and chemical plants. Environ Health Perspect 1984;54:31932.[ISI][Medline]
48 Blot WJ, Brinton LA, Fraumeni JF et al. Cancer mortality in U.S. counties with petroleum industries. Science 1977;198:5153.[ISI][Medline]
49 Gottlieb MS, Shear CL, Seale DB. Lung cancer mortality and residential proximity to industry. Environ Health Perspect 1982;45:15764.[ISI][Medline]
50 Olin RG, Ahlbom A, Lindberg-Navier I et al. Occupational factors associated with astrocytomas: a case-control study. Am J Ind Med 1987; 11:61525.[ISI][Medline]
51 Hearey CD, Ury H, Siegelaub A et al. Lack of association between cancer incidence and residence near petrochemical industry in the San Francisco Bay area. J Natl Cancer Inst 1980;64:129599.[ISI][Medline]
52 Yang CY, Chiu HF, Chiu JF et al. Cancer mortality and residence near petrochemical industries in Taiwan. J Toxicol Environ Health 1997; 50:26573.[CrossRef][ISI][Medline]
53 Yang CY, Cheng MF, Chiu JF et al. Female lung cancer and petrochemical air pollution in Taiwan. Arch Environ Health 1999;54:18085.[ISI][Medline]
54 Pan BJ, Hong YJ, Chang GC et al. Excess cancer mortality among children and adolescents in residential districts polluted by petrochemical manufacturing plants in Taiwan. J Toxicol Environ Health 1994;43:11729.[ISI][Medline]
55 Lyons RA, Monaghan SP, Heaven M et al. Incidence of leukaemia and lymphoma in young people in the vicinity of the petrochemical plant at Baglan Bay, South Wales, 1974 to 1991. Occup Environ Med 1995;52:22528.[Abstract]
56 Wilkinson P, Thakrar B, Walls P et al. Lymphohaematopoietic malignancy around all industrial complexes that include major oil refineries in Great Britain. Occup Environ Med 1999;56:57780.[Abstract]
57 Dos Santos Silva I. Cancer Epidemiology: Principles and Methods. Lyon, France: International Agency for Research on Cancer, 1999.
58 Smith MT, Robertson ML, Yager JW, Eastmond DA. Role of metabolism in benzene-induced myelotoxicity and leukemogenesis. Prog Clin Biol Res 1990;340B:12536.
59 Smith MT. The mechanism of benzene-induced leukemia: a hypothesis and speculations on the causes of leukemia. Environ Health Perspect 1996;104(Suppl.6):121925.[ISI][Medline]
60 Whysner J. Benzene-induced genotoxicity. J Toxicol Environ Health A 2000;61:34751.[CrossRef][ISI][Medline]
61 Burczynski ME, Penning TM. Genotoxic polycyclic aromatic hydrocarbon ortho-quinones generated by aldo-keto reductases induce CYP1A1 via nuclear translocation of the aryl hydrocarbon receptor. Cancer Res 2000;60:90815.
62 Dertinger SD, Lantum HB, Silverstone AE, Gasiewicz TA. Effect of 3-methoxy-4-nitroflavone on benzo[a]pyrene toxicity. Aryl hydrocarbon receptor-dependent and -independent mechanisms. Biochem Pharmacol 2000;60:18996.[CrossRef][ISI][Medline]