IJC International Journal of Cancer
Contact with ruminants is associated with esophageal squamous cell carcinoma risk Dariush Nasrollahzadeh1,2, Weimin Ye1, Ramin Shakeri2, Masoud Sotoudeh2, Shahin Merat2, Farin Kamangar3, Christian C. Abnet4, Farhad Islami2,5, Paolo Boffetta5, Sanford M. Dawsey4, Paul Brennan6 and Reza Malekzadeh2 1
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran 3 Department of Public Health Analysis, School of Community Health and Policy, Morgan State University, Baltimore, MD 4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 5 Institute for Translational Epidemiology and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY 6 International Agency for Research on Cancer, Genetic Epidemiology Group, Lyon, France 2
The etiology of esophageal squamous cell carcinoma (ESCC) in the high risk area of northern Iran is only partially known. We aimed to investigate prolonged animal contact as a risk factor for ESCC in this population. From 2003 to 2007, we administered a validated questionnaire to 300 ESCC cases and 571 randomly selected controls matched for neighborhood of residence, age (62 years) and sex. Questions on lifelong exposure to equines, ruminants, canines, and poultry, including duration and level of contact, were asked in a face-to-face interviews. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. A total of 94.7% of cases and 68.7% of controls reported lifelong history of contact with ruminants. After controlling for potential confounders, contact with ruminants was associated with an eightfold increase (95% CI: 3.92–14.86) in risk of ESCC, and increments in duration of contact raised the risk estimates in a dose-dependent manner. Contact with equines and poultry did not significantly change associated OR for ESCC risk and contact with ruminants. OR (95% CI) for contact with canines was 1.99 (1.35–2.93) which after exclusion of contact with ruminants was not significant (OR for contact only with canine: 3.18, 95% CI: 0.73–13.17). These results add to the evidence that contact with ruminants may increase the risk of ESCC.
Short Report
Esophageal cancer has a very unusual geographical distribution, with the areas of highest incidence occurring across central Asia and from eastern to southern Africa.1 At the edge of the so-called Central Asian Esophageal Cancer Belt, the esophageal cancer incidence can vary 10 times more than a distance of a few hundred kilometers.2 The etiology of esophageal squamous cell carcinoma (ESCC) in this endemic area is poorly understood. In contrast to low-risk populations,3 smoking tobacco and heavy alcohol consumption are not Key words: esophageal neoplasm, risk factors, ruminants, animal contact, relative risk Part of this work has been presented as a poster in UEGW 2012, Amsterdam Grant sponsor: Digestive Disease Research Center of Tehran University of Medical Sciences; Grant number: 82–603; Grant sponsor: National Cancer Institute at the National Institutes of Health. Grant sponsor: KID scholarship from Karolinska Institute (Supporting D.N.) DOI: 10.1002/ijc.29109 History: Received 8 Mar 2014; Accepted 10 July 2014; Online 1 Aug 2014 Correspondence to: Reza Malekzadeh, Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 14117, Iran, Tel.: [1982188019008], Fax: 1[982188012992], E-mail: [email protected]
C 2014 UICC Int. J. Cancer: 136, 1468–1474 (2015) V
dominant risk factors.4 In Golestan Province, Iran, at the western end of this endemic area, several environmental risk factors have been identified, including drinking hot tea,5 poor oral health,6 tobacco and opium consumption,7 low socioeconomic status8 and unexplained high exposure to polycyclic aromatic hydrocarbons9 but it remains unclear whether these risk factors explain the observed high incidence of ESCC in this area. Although studies have shown a significant decline in ESCC incidence in Golestan,10 a recent population-based cancer registry has documented that eastern Golestan Province still has age standardized rates of esophageal cancer of 70.7 in men and 42.6 in women.11 Contact with animals has been suggested as a potential risk factor for ESCC based on ecologic observations,12 veterinarybased studies and occupational cohort studies. The geographical distribution of the Central Asian Esophageal Cancer Belt is well-matched to a historically nomadic lifestyle which included close contacts with equines, ruminants, canines, and poultry. This type of life style is disappearing as socioeconomic status has improved during the last decades. Further suggestive observations are reports of high incidence of esophageal malignancies among animals in endemic areas, including autopsied chickens in Linxian, China13 and cattle in Kenya.14 Studies of occupational exposure among butchers15 and workers in poultry16 or ruminant17 abattoirs or processing plants have shown inconsistent results of increased risk of mortality due to
1469
Nasrollahzadeh et al.
What’s new? People across a particular part of Central Asia have an elevated risk of esophageal cancer, but no one has yet discovered quite why. This study asks how contact with animals influences risk. The authors gave a questionnaire to people in northern Iran with and without esophageal squamous cell cancer, inquiring about their contact with various animals, including horses, dogs, poultry, and ruminants, such as sheep and cattle. It turned out that contact with ruminants was associated with an 8fold increase in risk of esophageal squamous cell carcinoma, and the longer the exposure over a lifetime, the greater the risk.
Material and Methods Details of the study have been reported earlier.7 Briefly, case subjects were recruited from December 2003 to June 2007 at the only specialized clinic for esophageal cancer diagnosis and treatment in eastern Golestan. Included cases were histopathologically confirmed ESCC patients who underwent esophagogastroscopy and agreed to participate in the study. Reports of the local cancer registry showed that approximately 70% of all incident cases during the study period were referred to this clinic (unpublished data). Local physicians and health workers in catchment area were asked to refer those who were suspicious for malignancies to this clinic. Additionally controls were matched geographically which would have same referral pattern in case of development of upper gastrointestinal malignancies as recruited cases. Two population-based control subjects, individually matched to the cases by age (62 years), sex, and urban neighborhood or village, were selected using the annually-updated family health census. Seventy-seven percent of the enrolled controls were the first selected neighbors, and 11 and 3% were the second and third choices. Absence of the eligible controls at the time of invitation was almost always the reason for not participating in the study. In total, we recruited 300 cases and 571 matched controls. After obtaining written informed consent, a structured questionnaire was administrated face to face by a nurse and a physician. The questionnaire included questions on lifelong history of exposure to four groups of animals: equines (horses, mules, donkeys and camels), ruminants (sheep, goats, and cattle), dogs and poultry. A detailed history was obtained including the starting and stopping ages and the level of contact with each animal group. Also any changes in types of animals or the levels of contact were recorded. Animal contact was graded into four levels. Occasional contact with animals (less than once every 2 weeks) that were kept within 200 meters of resiC 2014 UICC Int. J. Cancer: 136, 1468–1474 (2015) V
dence or work place was graded as level one. The second level was defined as contact with animals kept in the neighborhood or workplace at least once every 2 weeks but less than daily. Daily contact with animals (e.g., when animals were kept in the residence or work place) was considered the third level. The fourth level was used for daily close contact with animals, for example, those who were responsible for jobs such as feeding, cleaning or slaughtering animals on daily basis. Statistical analysis
For each animal group (equines, ruminants, canines, and poultry) total duration was categorized into tertiles based on levels among the exposed controls. Whenever subjects were exposed to more than one animal type, duration of contact with animals was divided by the number of animal types. Conditional logistic regression models were used to calculate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). Case and control subjects were matched for age, sex, and place of residence (urban/rural) by design. Results were further adjusted for potential confounders including education (as a proxy for socioeconomic status), ethnicity (Turkmen vs. non-Turkmen), opium and tobacco use (4 categories), fruit and vegetable use, alcohol consumption, source of drinking water (piped water vs. otherwise), use of animal waste as fuel, and family history of cancer. Two-sided p-values 0.05 were considered as statistically significant. All statistical analyses were performed using STATA, version 12.0 (StataCorp, College Station, TX). The study was approved by the ethical committee of the Digestive Disease Research Institute of Tehran University of Medical Sciences, Iran; the Institutional Review Board of the National Cancer Institute, USA; the Institutional Review Board of the International Agency for Research on Cancer, France.
Results The study included 300 incident case patients and 571 matched control subjects, from whom animal contact history was available for 287 (96%) cases and 542 (95%) controls. Of the 42 subjects (13 cases, 29 controls) with a missing history of animal contact, 18 case-control pairs were missing, due to lack of information on cases in 13 pairs and lack of exposure data on controls in five pairs. For the rest of the subjects with missing data, at least one control for each matched-pair existed. A total of 19 subjects (8 cases and 11 controls) reported having contact with more than one animal type without further specification; there
Short Report
esophageal cancer. Shared environmental resources were suggested as a link between animal and human ESCC in the ecologic observations and exposure to animal viruses were proposed as potential causes for cancer development in the occupational studies. In 2003, we initiated a population-based case-control study to assess the role of previously suggested risk factors and other potential risk factors of ESCC in Golestan Province. In this article, we present the results of our evaluation of lifetime contact with animals as a risk factor for ESCC in this region.
1470
Animal contact and esophageal cancer risk
Table 1. Characteristics of esophageal squamous cell carcinoma cases and matched controls Characteristic
Controls (n 5 531)
Cases (n 5 281)
Age years; mean (SD)
64.4 (10.4)
64.5 (11.1)
Males
257 (48.4)
139 (49.5)
Females
274 (51.6)
142 (50.5)
Urban
141 (26.5)
72 (25.6)
Rural
390 (73.4)
209 (74.4)
Turkmen
288 (54.2)
164 (58.4)
Non-Turkmen
243 (45.8)
117 (41.6)
Illiterate
438 (82.5)
257 (91.5)
Primary school/ higher
93 (17.5)
24 (8.5)
No
518 (97.6)
275 (97.9)
Yes
13 (2.4)
6 (2.1)
p value
Sex (%)
Residence area (%) 0.77
Ethnicity (%) 0.26
Education (%) 0.001
Alcohol ever use (%) 0.78
Tobacco and opium, ever use (%) Neither
369 (69.5)
157 (56.1)
Tobacco only
62 (11.7)
39 (13.9)
Opium only
34 (6.4)
28 (10.0)
Tobacco and opium
66 (12.4)
56 (20.0)
0.001
Fruit and vegetable consumption (%) median
238 (44.8)
133 (47.3)
> median
293 (55.2)
148 (52.7)
0.49
Use of animal waste fuel life time1 No
494 (93.2)
265 (94.6)
Yes
36 (6.8)
15 (54)
0.42
Short Report
Access to piped water source Yes
481 (90.6)
206 (73.3)
No
50 (9.4)
75 (26.7)
0.0001
Family history of cancer No
439 (82.7)
193 (68.7)
Yes
92 (17.3)
88 (31.3)
Cool
362 (68.2)
117 (41.7)
Warm
149 (28.0)
103 (36.6)
Hot
18 (3.4)
61 (21.7)
Missing
2 (0.4)
0
< 0.0001
Tea drinking habit < 0.0001
was no association with risk of ESCC among this group (OR: 1.87, 95% CI: 0.62–5.69) and they were excluded when association with a particular type of animal was investigated. Table 1 summarizes the demographic characteristics
of participants and the distribution of potential confounders. Among demographic variables and potential confounders ESCC subjects in study area were less educated, consumed more tobacco/opium, had less access to piped water, more likely to have a relative with history of cancer and consuming hot tea (Table 1). No substantial difference was observed in these variables between subjects with available and missing history of exposure to animals. Table 2 shows association of exposure to the four groups of animals in ESCC cases and matched controls and the corresponding crude and adjusted ORs (95% CI). An equal proportion of cases and controls resided in rural areas (73 and 74%), and proportions of exposure to equines and poultry were essentially identical among cases and controls. However, exposure to the ruminants and canines was significantly greater among ESCC cases than among controls: 94.7% of cases and only 68.7% of controls were exposed to ruminants, and 70.8% of cases and 52.7% of controls were exposed to canines (both p-values
Contact with ruminants is associated with esophageal squamous cell carcinoma risk Dariush Nasrollahzadeh1,2, Weimin Ye1, Ramin Shakeri2, Masoud Sotoudeh2, Shahin Merat2, Farin Kamangar3, Christian C. Abnet4, Farhad Islami2,5, Paolo Boffetta5, Sanford M. Dawsey4, Paul Brennan6 and Reza Malekzadeh2 1
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran 3 Department of Public Health Analysis, School of Community Health and Policy, Morgan State University, Baltimore, MD 4 Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 5 Institute for Translational Epidemiology and Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, NY 6 International Agency for Research on Cancer, Genetic Epidemiology Group, Lyon, France 2
The etiology of esophageal squamous cell carcinoma (ESCC) in the high risk area of northern Iran is only partially known. We aimed to investigate prolonged animal contact as a risk factor for ESCC in this population. From 2003 to 2007, we administered a validated questionnaire to 300 ESCC cases and 571 randomly selected controls matched for neighborhood of residence, age (62 years) and sex. Questions on lifelong exposure to equines, ruminants, canines, and poultry, including duration and level of contact, were asked in a face-to-face interviews. Conditional logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs) adjusted for potential confounders. A total of 94.7% of cases and 68.7% of controls reported lifelong history of contact with ruminants. After controlling for potential confounders, contact with ruminants was associated with an eightfold increase (95% CI: 3.92–14.86) in risk of ESCC, and increments in duration of contact raised the risk estimates in a dose-dependent manner. Contact with equines and poultry did not significantly change associated OR for ESCC risk and contact with ruminants. OR (95% CI) for contact with canines was 1.99 (1.35–2.93) which after exclusion of contact with ruminants was not significant (OR for contact only with canine: 3.18, 95% CI: 0.73–13.17). These results add to the evidence that contact with ruminants may increase the risk of ESCC.
Short Report
Esophageal cancer has a very unusual geographical distribution, with the areas of highest incidence occurring across central Asia and from eastern to southern Africa.1 At the edge of the so-called Central Asian Esophageal Cancer Belt, the esophageal cancer incidence can vary 10 times more than a distance of a few hundred kilometers.2 The etiology of esophageal squamous cell carcinoma (ESCC) in this endemic area is poorly understood. In contrast to low-risk populations,3 smoking tobacco and heavy alcohol consumption are not Key words: esophageal neoplasm, risk factors, ruminants, animal contact, relative risk Part of this work has been presented as a poster in UEGW 2012, Amsterdam Grant sponsor: Digestive Disease Research Center of Tehran University of Medical Sciences; Grant number: 82–603; Grant sponsor: National Cancer Institute at the National Institutes of Health. Grant sponsor: KID scholarship from Karolinska Institute (Supporting D.N.) DOI: 10.1002/ijc.29109 History: Received 8 Mar 2014; Accepted 10 July 2014; Online 1 Aug 2014 Correspondence to: Reza Malekzadeh, Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran 14117, Iran, Tel.: [1982188019008], Fax: 1[982188012992], E-mail: [email protected]
C 2014 UICC Int. J. Cancer: 136, 1468–1474 (2015) V
dominant risk factors.4 In Golestan Province, Iran, at the western end of this endemic area, several environmental risk factors have been identified, including drinking hot tea,5 poor oral health,6 tobacco and opium consumption,7 low socioeconomic status8 and unexplained high exposure to polycyclic aromatic hydrocarbons9 but it remains unclear whether these risk factors explain the observed high incidence of ESCC in this area. Although studies have shown a significant decline in ESCC incidence in Golestan,10 a recent population-based cancer registry has documented that eastern Golestan Province still has age standardized rates of esophageal cancer of 70.7 in men and 42.6 in women.11 Contact with animals has been suggested as a potential risk factor for ESCC based on ecologic observations,12 veterinarybased studies and occupational cohort studies. The geographical distribution of the Central Asian Esophageal Cancer Belt is well-matched to a historically nomadic lifestyle which included close contacts with equines, ruminants, canines, and poultry. This type of life style is disappearing as socioeconomic status has improved during the last decades. Further suggestive observations are reports of high incidence of esophageal malignancies among animals in endemic areas, including autopsied chickens in Linxian, China13 and cattle in Kenya.14 Studies of occupational exposure among butchers15 and workers in poultry16 or ruminant17 abattoirs or processing plants have shown inconsistent results of increased risk of mortality due to
1469
Nasrollahzadeh et al.
What’s new? People across a particular part of Central Asia have an elevated risk of esophageal cancer, but no one has yet discovered quite why. This study asks how contact with animals influences risk. The authors gave a questionnaire to people in northern Iran with and without esophageal squamous cell cancer, inquiring about their contact with various animals, including horses, dogs, poultry, and ruminants, such as sheep and cattle. It turned out that contact with ruminants was associated with an 8fold increase in risk of esophageal squamous cell carcinoma, and the longer the exposure over a lifetime, the greater the risk.
Material and Methods Details of the study have been reported earlier.7 Briefly, case subjects were recruited from December 2003 to June 2007 at the only specialized clinic for esophageal cancer diagnosis and treatment in eastern Golestan. Included cases were histopathologically confirmed ESCC patients who underwent esophagogastroscopy and agreed to participate in the study. Reports of the local cancer registry showed that approximately 70% of all incident cases during the study period were referred to this clinic (unpublished data). Local physicians and health workers in catchment area were asked to refer those who were suspicious for malignancies to this clinic. Additionally controls were matched geographically which would have same referral pattern in case of development of upper gastrointestinal malignancies as recruited cases. Two population-based control subjects, individually matched to the cases by age (62 years), sex, and urban neighborhood or village, were selected using the annually-updated family health census. Seventy-seven percent of the enrolled controls were the first selected neighbors, and 11 and 3% were the second and third choices. Absence of the eligible controls at the time of invitation was almost always the reason for not participating in the study. In total, we recruited 300 cases and 571 matched controls. After obtaining written informed consent, a structured questionnaire was administrated face to face by a nurse and a physician. The questionnaire included questions on lifelong history of exposure to four groups of animals: equines (horses, mules, donkeys and camels), ruminants (sheep, goats, and cattle), dogs and poultry. A detailed history was obtained including the starting and stopping ages and the level of contact with each animal group. Also any changes in types of animals or the levels of contact were recorded. Animal contact was graded into four levels. Occasional contact with animals (less than once every 2 weeks) that were kept within 200 meters of resiC 2014 UICC Int. J. Cancer: 136, 1468–1474 (2015) V
dence or work place was graded as level one. The second level was defined as contact with animals kept in the neighborhood or workplace at least once every 2 weeks but less than daily. Daily contact with animals (e.g., when animals were kept in the residence or work place) was considered the third level. The fourth level was used for daily close contact with animals, for example, those who were responsible for jobs such as feeding, cleaning or slaughtering animals on daily basis. Statistical analysis
For each animal group (equines, ruminants, canines, and poultry) total duration was categorized into tertiles based on levels among the exposed controls. Whenever subjects were exposed to more than one animal type, duration of contact with animals was divided by the number of animal types. Conditional logistic regression models were used to calculate unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs). Case and control subjects were matched for age, sex, and place of residence (urban/rural) by design. Results were further adjusted for potential confounders including education (as a proxy for socioeconomic status), ethnicity (Turkmen vs. non-Turkmen), opium and tobacco use (4 categories), fruit and vegetable use, alcohol consumption, source of drinking water (piped water vs. otherwise), use of animal waste as fuel, and family history of cancer. Two-sided p-values 0.05 were considered as statistically significant. All statistical analyses were performed using STATA, version 12.0 (StataCorp, College Station, TX). The study was approved by the ethical committee of the Digestive Disease Research Institute of Tehran University of Medical Sciences, Iran; the Institutional Review Board of the National Cancer Institute, USA; the Institutional Review Board of the International Agency for Research on Cancer, France.
Results The study included 300 incident case patients and 571 matched control subjects, from whom animal contact history was available for 287 (96%) cases and 542 (95%) controls. Of the 42 subjects (13 cases, 29 controls) with a missing history of animal contact, 18 case-control pairs were missing, due to lack of information on cases in 13 pairs and lack of exposure data on controls in five pairs. For the rest of the subjects with missing data, at least one control for each matched-pair existed. A total of 19 subjects (8 cases and 11 controls) reported having contact with more than one animal type without further specification; there
Short Report
esophageal cancer. Shared environmental resources were suggested as a link between animal and human ESCC in the ecologic observations and exposure to animal viruses were proposed as potential causes for cancer development in the occupational studies. In 2003, we initiated a population-based case-control study to assess the role of previously suggested risk factors and other potential risk factors of ESCC in Golestan Province. In this article, we present the results of our evaluation of lifetime contact with animals as a risk factor for ESCC in this region.
1470
Animal contact and esophageal cancer risk
Table 1. Characteristics of esophageal squamous cell carcinoma cases and matched controls Characteristic
Controls (n 5 531)
Cases (n 5 281)
Age years; mean (SD)
64.4 (10.4)
64.5 (11.1)
Males
257 (48.4)
139 (49.5)
Females
274 (51.6)
142 (50.5)
Urban
141 (26.5)
72 (25.6)
Rural
390 (73.4)
209 (74.4)
Turkmen
288 (54.2)
164 (58.4)
Non-Turkmen
243 (45.8)
117 (41.6)
Illiterate
438 (82.5)
257 (91.5)
Primary school/ higher
93 (17.5)
24 (8.5)
No
518 (97.6)
275 (97.9)
Yes
13 (2.4)
6 (2.1)
p value
Sex (%)
Residence area (%) 0.77
Ethnicity (%) 0.26
Education (%) 0.001
Alcohol ever use (%) 0.78
Tobacco and opium, ever use (%) Neither
369 (69.5)
157 (56.1)
Tobacco only
62 (11.7)
39 (13.9)
Opium only
34 (6.4)
28 (10.0)
Tobacco and opium
66 (12.4)
56 (20.0)
0.001
Fruit and vegetable consumption (%) median
238 (44.8)
133 (47.3)
> median
293 (55.2)
148 (52.7)
0.49
Use of animal waste fuel life time1 No
494 (93.2)
265 (94.6)
Yes
36 (6.8)
15 (54)
0.42
Short Report
Access to piped water source Yes
481 (90.6)
206 (73.3)
No
50 (9.4)
75 (26.7)
0.0001
Family history of cancer No
439 (82.7)
193 (68.7)
Yes
92 (17.3)
88 (31.3)
Cool
362 (68.2)
117 (41.7)
Warm
149 (28.0)
103 (36.6)
Hot
18 (3.4)
61 (21.7)
Missing
2 (0.4)
0
< 0.0001
Tea drinking habit < 0.0001
was no association with risk of ESCC among this group (OR: 1.87, 95% CI: 0.62–5.69) and they were excluded when association with a particular type of animal was investigated. Table 1 summarizes the demographic characteristics
of participants and the distribution of potential confounders. Among demographic variables and potential confounders ESCC subjects in study area were less educated, consumed more tobacco/opium, had less access to piped water, more likely to have a relative with history of cancer and consuming hot tea (Table 1). No substantial difference was observed in these variables between subjects with available and missing history of exposure to animals. Table 2 shows association of exposure to the four groups of animals in ESCC cases and matched controls and the corresponding crude and adjusted ORs (95% CI). An equal proportion of cases and controls resided in rural areas (73 and 74%), and proportions of exposure to equines and poultry were essentially identical among cases and controls. However, exposure to the ruminants and canines was significantly greater among ESCC cases than among controls: 94.7% of cases and only 68.7% of controls were exposed to ruminants, and 70.8% of cases and 52.7% of controls were exposed to canines (both p-values
