FEMS MicrobiologyImmunology 64 (1990) 235-242
235
Published by Elsevier FEMSIM 00124
Diet and nasopharyngeal carcinoma Mimi C. Yu Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, CA 90033-0800 U.S.A.
Received28 June 1990 Accepted12 July 1990 Key words: Salted fish; Preserved foods; Nasopharyngeal cancer; Chinese 1, SUMMARY
2. RESULTS AND DISCUSSION
Nasopharyngeal carcinoma (NPC) is a disease with a remarkable racial and geographical distribution. It is very rare (incidence of less than 1 per 100000 person-years) in most parts of the world and only a handful of populations are known to deviate from this low-risk profile, which include people of southern China, Eskimos and other natives of the Arctic region, natives of southeast Asia, and mainly Arab populations of north Africa and Kuwait. There is now convincing evidence implicating dietary factors as the primary cause of NPC among Chinese. A series of case-control studies conducted in various Chinese populations with distinct risks of NPC, ranging from the very high-risk Cantonese to the relatively low-risk Northern Chinese, have suggested that ingestion of salted fish and other kinds of preserved foods by the Chinese constitutes the most important cause of NPC development among these people. Preliminary data on Malays in southeast Asia, Eskimos in Alaska, and Arabs of north Africa also suggest that ingestion of preserved foods by these population groups may be responsible for their raised incidence of NPC.
Regardless of race and geography, the commonest form of nasopharyngeal cancers are those that arise from the epithelial cells lining the nasopharynx. These carcinomas (commonly referred to as NPCs) constitute 75-95% of nasopharyngeal cancers in low-risk populations and virtually all nasopharyngeal cancers in highrisk populations [1-3].
Correspondence to: M.C. Yu, Department of PreventiveMedicine, Universityof Southern California School of Medicine, 1441 EastlakeAvenue,Los Angeles,CA 90033-0800, U.S.A.
2.1. International patterns
NPC is a rare malignancy in most parts of the world where the age-standardized incidence rate for either sex is generally less than 1 per 100000 persons per year [4]. Table 1 lists the handful of populations that are known to deviate from this low-risk pattern together with their age-standardized (world population) incidence rates of nasopharyngeal cancer for men and women separately. Overall incidence of NPC is elevated in China, with substantial variation between regions. In general, incidence increases as one travels from north to south China. Whereas rates in Chinese men in the northernmost provinces are about 23/100000 person-years, those residing in the southernmost province of Guangdong exhibit rates of 25-40/100000 person-years [4-6]. High rates approaching those observed in southern China are seen in Eskimos and other natives of the Artic
0920-8534/90/$03.50 © 1990 Federation of European MicrobiologicalSocieties
236 Table 1 Populations at increased risk for nasopharyngeal cancer Age-standardized (world) incidencea Male Female 30.0 12.9 8.1 3.2 4.4 2.0 1.7 0.9 12.3 8.5
Population
Chinese (Hong Kong) Chinese (Tapei) Chinese (Shanghai) Chinese(Tianjin) Eskimos (Greenland) Eskimos. Indians, Aleuts (Alaska) Malays (Malaysia) Malays (Singapore) Filipinos(Rizal) Kadazans (Sabah) Kuwaitis (Kuwait) Non-Kuwaitis(Kuwait) Israeli Jewsborn in Africa/Asia
13.5 2.3 4.0
Reference
4 52 4 4 7
15.9 2.1 2.9
3.7 0.7 1.5 2.6 8.7 1.3 1.4
8 10 4 4 11 4 4
3.3
0.7
4
4.7
among Filipinos [4]. In Sabah, Malaysia, rates similar to those observed among the Eskimos have been reported for the native Kadazans [11]. Although mortality or incidence data are lacking for the other indigenous people of southeast Asia, raised relative frequencies of NPC in biopsy series have been reported among natives of ,'F,~ail;and, Indonesia, Sarawak, and Viet~tam [12]. Intermediate rates of N P C are observed among the people of Kuwait, both local-born Arabs and immigrants from neighboring Arab countries [4]. Based on reviews of hospita~ ~,:ries, it is believed that rates of N P C are also ~aised in the m a ~ , y Arab populations of Algeria, Tunisia, Morocco, and Sudan [12-14]. The intermeO~ate rates of NPC among Israeli Jews born in Africa or Asia, many of whom were from north Africa, tend to support this view [4].
" Per 100000 person-years. 2.2. Racial~ ethnic variation High risk to. NPC among Chinese is mainly
region [7,8]. Intermediate rates of NPC (25/100000 person-years) are observed among Malays in Singapore [9] and Malaysia [10], and 80°E J/
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237
[5] (Fig. 1). Several distinct racial-ethnic groups reside in this high-risk region and these groups possess different rates of NPC. Highest rates are observed among the Tankas, a sub-ethnic group of the Cantonese who inhabit the Pearl River Delta Basin in central Guangdong. One distinguishing feature of the Tankas from the other Cantonese is t~mt they are seafaring people (either fishermen or sea transporters) who five on houseboats parked along the banks of the many branches of the Pearl River. The rates of NPC among the Tankas are 2 times those in the land-dwelling Cantonese [15,16]. In turn, the land-dwelling Cantonese (who comprise 98-99~ of Cantonese) have a 2-fold rate of NPC relative to the Hakka and Chiu Chan dialect groups who reside in northeast Guangdong [6,16]. The people of Fujian Province are culturally similar to the Chiu Chan people in Guangdong Province, and so are their rates of NPC [17]. It is interesting to note that the Hakkas (who rarely intermarry with other dialect groups) originated from northern China more than 500 years ago [18], but their rates resemble tbek Chiu Chau neighbors instead of their low-risk ancestors in the north. Even after migration to southeast Asia, the Cantonese continue to exhibit a 2-fold risk of NPC relative to the Hakkas, Chiu Chaus, and
Fujianese [10,19]. Two distinct racial groups inhabit the Autonomous Region of Ouangxi. While the Zhuang people in western Ouangxi possess one-fifth the NPC rate in Cantonese, the Han (the predominant race in China) people of eastern Guangxi who are ethnically close to the Cantonese in Guangdong show similar rates. Hunan Province borders both Guangxi and Guangdong to the north, and not surprisingly, areas that border Guangdong and Guangxi have high NPC rates. In addition, the Tujia and Miao tribes (minority races in China) who inhabit the mountainous region of western Hunan are found to possess NPC rates approaching those in the Cantonese [17]. In summary, the geographic variation of NPC incidence within southern China closely parallels the distribution of racial-ethnic groups inhabiting the region. The relatively high NPC rates observed among the Hakkas who originated from low-risk northern China argues against genetic predisposi-
tion as a major cause of the varying risk patterns among these population groups. On the other hand, these ethnic groups are distinct in their customs and food habits, and it is possible that environmental factors inherent in their traditional cultures are responsible for their varying susceptibitity to NPC.
2.3. Chinese salted fish The higher rates of NPC among the boat-dwellmg Tankas as compared to the land-dwelling Cantonese was first noted by Ho of Hong Kong, who further observed that these boat people had tittle exposure to domestic inhalants as they 'five all their fives in open boats and cook their food in the open air...." [20]. Ho then turned his attention to dietary factors, especially the traditional foods of southern China. He observed that salted fish is dominant in the diet of the boat people, being the principle source of supplementary food in a diet consisting mainly of rice. Often spending long periods at sea, southern Chinese fishermen salt most of their catch as a means of preservation. These fishermen and their fan, lies prefer to consume salted instead of fresh fish since the latter can command a much higher price. In 1971, Ho suggested that Chinese salted fish, ' a common and favourite item of food among most (Cantonese) in and outside China' be investigated as a 'possible etiological factor' for NPC [1]. Seven case-control studies conducted among various Chinese populations with distinct risks of NPC have investigated this possible exposure-disease association (Table 2). Four were conducted in populations that are predominantly Cantonese (Chinese in California, Hong Kong, and Guangzhou). While the 2 earlier studies among Cantonese [21,22] examined exposure at a single time point, the latter 2 studies conducted in this ethnic group [23,24] investigated exposure during multiple time periods throughout the subjects' lifetime. All 4 studies demonstrated a significant and positive association between salted fish intake and NPC risk. Moreover, in the two studies that investigated exposure at various time points, both found childhood exposu~-e, especially during infancy (at weaning), to be more strongly related to risk than adulthood exposure [23,24]. It is worthy
238 Table 2 Case-control studies of NPC which examined exposure to Chinese salted fish Chinese population studied
Years of diagnosis of cases
Numberof cases/controls
California, U.S.A.
1971-74
74/109
Hong Kong Selangnr, Malaysia
1973-74 1973-80
108/103 100/100
Period of exposureto salted fish Current During weaning During childhood During adolescence
Hong Kong
1981-83
250/250
During weaning At age 10 3 yr before
Gaangzhoa, China
1983-85
306/306
During weaning At age 10 3 yr before
Yufin, China
1984-86
128/174
Tianjin, China
1985-86
100/300
During weaning At age 10 At age 10 3 yr before
Estimate of risk relative )o no/rare consumption 1/wk, 2.1 2 +/wk, 3.1 Ever, 2.6 Weekly, 3.1 Daily, 17.4 Weekly, 1.3 Daily, 3.5 Ever, 7.5 Weekly/daily, 37.7 Weekly, 3.2 Dally, 7.5 Ever, 2.1 Weekly, 1.1 Dally, 2.4 Weekly, 1.4 Daily, 1.8 Ever, 2.6 Weekly *, 1.5 Weekly/dally, 6.7 Monthly/weekly a 1.2
Reference
21 22 25
23
24
26 27
a No subject reported daily consumption.
to note that the apparent disparity in the magnitude of relative risks observed among the Cantonese in Guangzhou compared to those in Hong Kong was an artifact which is related to the effect of exposure misclassification on the observable relative risk. An exposition was given in [24]. Two case-control studies which examined salted fish intake in non-Cantonese populations of southern China have also found a significant association between NPC risk and ingestion of this traditional food, with early age at exposure being an important co-determinant of risk. Armstrong et al. [25] studies 100 cases of NPC in Malaysian Chinese of whom approximately one-third were Cantonese, another one-third were Hakka, and the remaining were Chiu Chau/Fujianese. Ingestion of salted fish was associated with NPC risk in all 3 ethnic groups, and risk was higher for exposure during childhood than adolescence. Recent exposure was not related to NPC risk. Yu et al. [26] investigated salted fish intake in Yulin (in eastern Guangxi) where consumption level is relatively
low and again found the earliest exposure (at weaning) to exhibit the strongest association with risk. Finally, a recent case-control study in Tianjin, a coastal city in northern China where NPC is relatively rare, confirmed the salted fish-NPC association previously observed in southern Chinese populations [27]. This latest study clearly showed that risk increased with earlier age at first exposure. It also suggested that risk was influenced by the method of cooking; steaming the fish seemed to carry a higher NPC risk than frying, grilling or boiling it. In sunmlary, all case-control studies to date have produced remarkably consistent findings in support of intake of Chinese salted fish as a cause of NPC. Data derived from Cantonese populations indicate that most cases of NPC occurring in people of this ethnic group are related to early ingestion of this food. Data from whole animal expefinents have further strengthened the hypothesi~ that Chinese salted fish is a human nasopharyngeal carcinogen.
239
Huang et al. [28] successfully induced cancers of the nasal cavity in Wistar rats fed cooked Chinese salted fish, which otherwise rarely occurs in this animal species. Yu et al. [29] confLrmed those findings in a larger study which demonstrated a dose-response relationship between level of intake and rate of tumour occurrence. Furthermore, the amounts of salted fish (in terms of % total diet) fed to the rats in Yu et al. [29] were within the range of potential human (Cantonese) consumption, and the tumour (nasal cavity) rate observed in those rats was in general agreement with the rate of NPC occurrence in Cantonese. Low-levels (sub-parts per million) of several volatile nitrosamines, including N-nitrosodimethylamlne, N-nitrosodiethylamine, N-nitrosodi-npropylamine, N-nitrosodi-n-butylamine and Nnitrosomorpholine, have been detected in samples of Chinese salted fish [30,31]. Most of these volatile nitrosamines can induce nasal and paranasal cavity turnouts in animals [32-35]. In addition to these preformed nitrosaraines, Tannenbanm et al. [31] have detected bacterial mutagens in Chinese salted fish that had been exposed to a nitrosating agent under simulated gastric conditions. At present, it is not clear whether the volatile nitrosamines or bacterial mutagens present in Chinese salted fish are the carcinogens for NPC; the food may contain other types of carcinogenic substances which have not been identified. Recently, samples of Chinese salted fish were found to contain substance(s) capable of activating the Epstein-Barr virus (EBV) in latently infected Raji cells [36]. It is known that NPC patients of all races and geographical locales show significantly higher antibody titres to various EBV-associated antigens compared to controls [37-42] and that EBV DNA is present in epithelial cells of NPC tumour tissues irrespective of their degrees of differentiation [40,43-45]. If confirmed, this finding would add support to a causal interpretation of the well established EBV-NPC association.
2. 4. Other dietary factors There is some preliminary evidence that early exposure to other types of salted fish may explain at least some of the raised rates of NPC in the
native peoples of southeast Asia and the arctic region. In a small case-control study (13 cases, 50 controls) of NPC among Malays in Selangor, Malaysia, Armstrong and Armstrong [46] found 5 (38%) cases vs. 4 (8%) controls to be daily eaters of salted fish during childhood. In Alaska, interviews on 13 NPC patient-control pairs revealed more cases than controls to be frequent users of salted fi~h during childhood (case yes/control no vs. control yes/case no = 4 vs. 1) [8]. Besides salted fish, early exposure to other fermented food products has been shown to be related to NPC risk. In Yulin, exposure before age 2 years to chung choi (a kind of salted root), salted duck eggs, salted mustard green, dried fish, and fermented soy bean paste were independent risk factors for NPC [26]. In Guangzhou, exposure before age 10 years to fermented fish sauce, moldy bean curd, salted shrimp paste, and 'chart pai mui' and 'gar ink gee' (2 kinds of preserved plum) were independently related to NPC risk [24]. In Tianjin, exposure to salted shrimp paste at age 10 years was related to NPC risk independent of salted fish intake [27]. In Taiwan, exposure before age 20 years to fermented bean products and smoked meat increased risk of NPC independently [47]. While childhood exposure levels to most of these foods were low in the case series studied, chung choi was a weaning food for 60~ of cases in Yulin, salted shrimp paste was consumed at age 10 by 48~ of cases in Tianjin, and 63~ of cases in Taiwan consumed fermented bean products before age 20 years. Thus, preserved foods other than salted fish may account for a substantial proportion of NPC cases in certain non-Cantonese populations. Poirier et al. [48] analyzed samples of salted mustard green (described by the authors as green mustard leaves fermented in brine), chung choi (described by the authors as radish roots and stem fermented in brine) and fermented soy bean paste for volatile nitrosamines and detected one or more volatile nitrosamines in all 3 foods. N-nitroso-dimethylamine was detected in salted mustard green and chung choi, N-nitrosopiperidine in salted mustard green, and N-nitrosopyrrolidine in salted mustard green, chung choi, and fermented soy bean paste. As in the case of salted fish, it is not
240
clear yet whether any of the volatile nitrosamines detected in these fermented foods are directly involved in the carcinogenic process. The Arabs of north Africa, who are believed to possess raised rates of NPC, are known to consume a number of preserved foods on a regular basis. Poirier et al. [48] examined 10 preserved foods common in the Tunisian diet and found 3 of them (dried mutton preserved in olive oil, turnips fermented in brine, and 'Touklia' stewing base) to contain volatile nitrosamines. Although analytical data are lacking, it is possible that ingestion of preserved foods in the local diet is related to the increased ri,~k of NPC among Arabs of north Africa. In an uncontrolled study of very young (under age 25 years) NPC patients in Hong Kong, Anderson et al. [49] reported that 'all families felt that vegetables and fruit were bad for babies, and the children had been fed accordingly'. These observations were later confirmed in case-control studies. In both Hung Kong and Guangzhou [23,24], cases ingested significantlyless fresh vegetables and fruit than controls, especially during childhood. Whereas in Hong Kong [23] the protective effect of fresh vegetables and fruit was no longer significant after adjustment for salted fish intake, in Guangzhou such an effect was not explained by the differing consumption pattern of salted fish and other preserved foods between cases and controls [24]. In Tianjin [27], although general consumption of 'fresh fruit' or 'fresh vegetables' was not associated with a reduction in NPC risk, a significant protective effect with carrot imake at age 10 years was evident and garlic, the only other fresh vegetable item on the questionnaire, also showed declining risks with increasing frequency of consvmption although the effect was not statistically significant. Fruit and vegetables are rich in an array of chemical compounds which have been suggested to be protective against cancer [50]. It is interesting to note that African NPC patients showed significantly lower levels of serum carotene compared to controls [51]. The hypothesis that substance(s) present in certain fresh vegetables and fruit exert a modifying and beneficial effect on risk of NPC deserves further investigation.
2.5. Future research (1) Although a number of potentially carcinogenic substances have been identified in Chinese salted fish, it is presently unclear whether any of them are involved as nasopharyngeal carcinogens. Laboratory work to systematically search for the compound(s) contained in Chinese salted fish and other NPC-associated foods which give rise to NPC in humans should receive a high priority. (2) Although Chinese men are more than 2 times as likely to develop NPC as Chinese women, men have not been shown to consume Chinese salted fish or other NPC-associated foods more frequently than women. Future epidemiologic studies in this population should incorporate portion size measurements such that the question of whether the sex difference is due to constitutional factors or explicable on the basis of exposure level can be addressed. (3) It is presently unknown whether diet plays a role in the etiology of NPC in non-Chinese populations. There is some suggestion that the elevated rates in Malays, Alaskan Natives, and Northern Africans may be diet related, but data from analytical studies that have examined this hypothesis are lacking.
ACKNOWLEDGEMENTS This work was supported by Public Health Service Grant R01-CA40468 from the United States National Cancer Institute.
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242 Y., de The, G. and Bartsch, H. (1988). Epstcin-Barr virus activation in Raji cells by extracts of preserved food from high risk areas for nasopharyngeal carcinoma. Carcinogenesis 9, 1455-1457. [37] Henle, W., Henle, G., and Ho, H.-C. (1970) Antibodies to Epstein-Barr virus in nasopharyngeal carcinoma, other head and neck neoplasms, and control groups. J. Natl. Cancer Inst. 44, 225-231. [38] Sawaki, S., Hirayama, T. and Sugano, H. (1976) Studies on nasopharyngeal carcinoma in Japan. Gann 18, 63-74. [39] Henderson, B.E., Louie, E.W., Jing, J.S., and Alena, B. (1977) Epstcin-Barr virus and nasopharyngeal carcinoma: is there an etiologic relationship? J. Natl. Cancer Inst. 59, 1393-1395. [40] Lanier, A.P., Borukamm, G.W., Henle, W., Henle, G., Bender, T., Talbot, M.L. and Dohan, P.H. (1981) Association of Epstein-Barr virus with nasopharyngeal carcinoma in Alaskan native patients: serum antibodies and tissue EBNA and DNA. Int. J. Cancer 28, 301-305. [41] Zeng, Y. (1985) Sero-epidemiological studies on nasopharyngeal carcinoma in China. Adv. Cancer Res. 44, 121-138. [42] Bogger-Goren, S., Gotlieb-Stematsky, T., Raehima, M., Barkowsky, E. and Schlomo-David, J. (1987) Nasopharyngeal carcinoma in Israel: epidemiology and Epstein-Barr virus-related serology. Eur. J. Cancer Clin. Oncol. 23, 1277-1281. [43] zur Hausen, H., Scbolte-Holthausen, H., Klein, G., Henle~ W., Henle, G., Clifford, P. and Santesson, L. (1970) EBV DNA in biopsies of Burkitt tumoars and anaplastic carcinomas of the nasopharynx. Nature (Lond.) 228, 1056-1058. [44] Wolf, H., zur Hausen, H., Klein, G., Becker, V., Henle, G. and Henle, W. (1975) Attempts to detect virus-specific DNA sequences in human tumors, III. Epstein-Barr viral DNA in non-lympboid nasopharyngeal carcinoma cells. Med. Micrubiol. Immunol. 161, 15-21.
[45] Raab-Tranb, N., Fiyrm, K., Pearson, G., Huang, A., Lanier, P., Lanier, A. and Pagano, J. (1987) The differentiated form of nasopharyngeal carcinoma contains Epstcin-Barr virus DNA. Int. J. Cancer 39, 25-29. [46] Armstrong, R.W. and Armstrong, MJ. (1983) Environmental risk factors and nasopharyngeal carcinoma in Selangor, Malaysia: a cross-ethnic perspective. Ecol. Dis. 2, 185-198. [47] Chen, C.-J., Wang, Y.-F., Shieh, T., Chen, J.-Y. and Lin, M.-Y. (1988) Multifactorial etiology of nasopharyngeal carcinoma. Epstsin-Barr virus, familial tendency and environmental cofactors. In Head and Neck Oncology Research (Wolf, G.T. and Carey, T.E., Eds.), pp. 469-476. Kugier Publications, Amsterdam, Berkeley. [48] puirier, S., Ohshima, H., de The, (3., Hubert, A., Bourgade, M.C. and Bart.~h, H. (1987) Volatile nitrosamine levels in common foods from Tunisia, south China and Greenland, high-risk areas for nasopharyngeal carcinoma (NPC). Int. J. Cancer 39, 293-296. [49] Anderson, E.N., Anderson, M.L. and Ho, H.C. (1978) Environmental backgrounds of young Chinese nasopharyngeal carcinoma patients. IARC Sci. Publ. 20, 231-239. [50] Wattenberg, L.W. (1978) Inhibitors of chemical carcinogenesis. Adv. Cancer Res. 26, 197-226. [51] Clifford, P. (1972) Carcinogens in the nose and throat: nasopharyngeal carcinoma in Kenya. Proc. Roy. Soc. Med. 65, 682-686. [52] Chen, C.-J., Chen, J.-Y., Hsu, M.-M., Shieh, T., Tu, S.-M. and Yang, C.-S. (1988) Epidemiological characteristics and early detection of nasopharyngeal carcinoma in Taiwan. In Head and Neck Oncology Research (Wolf, G.T. and Carey, T.E., Eds.), pp. 503-513. Kugler publications, Amsterdam, Berkeley.
235
Published by Elsevier FEMSIM 00124
Diet and nasopharyngeal carcinoma Mimi C. Yu Department of Preventive Medicine, University of Southern California School of Medicine, Los Angeles, CA 90033-0800 U.S.A.
Received28 June 1990 Accepted12 July 1990 Key words: Salted fish; Preserved foods; Nasopharyngeal cancer; Chinese 1, SUMMARY
2. RESULTS AND DISCUSSION
Nasopharyngeal carcinoma (NPC) is a disease with a remarkable racial and geographical distribution. It is very rare (incidence of less than 1 per 100000 person-years) in most parts of the world and only a handful of populations are known to deviate from this low-risk profile, which include people of southern China, Eskimos and other natives of the Arctic region, natives of southeast Asia, and mainly Arab populations of north Africa and Kuwait. There is now convincing evidence implicating dietary factors as the primary cause of NPC among Chinese. A series of case-control studies conducted in various Chinese populations with distinct risks of NPC, ranging from the very high-risk Cantonese to the relatively low-risk Northern Chinese, have suggested that ingestion of salted fish and other kinds of preserved foods by the Chinese constitutes the most important cause of NPC development among these people. Preliminary data on Malays in southeast Asia, Eskimos in Alaska, and Arabs of north Africa also suggest that ingestion of preserved foods by these population groups may be responsible for their raised incidence of NPC.
Regardless of race and geography, the commonest form of nasopharyngeal cancers are those that arise from the epithelial cells lining the nasopharynx. These carcinomas (commonly referred to as NPCs) constitute 75-95% of nasopharyngeal cancers in low-risk populations and virtually all nasopharyngeal cancers in highrisk populations [1-3].
Correspondence to: M.C. Yu, Department of PreventiveMedicine, Universityof Southern California School of Medicine, 1441 EastlakeAvenue,Los Angeles,CA 90033-0800, U.S.A.
2.1. International patterns
NPC is a rare malignancy in most parts of the world where the age-standardized incidence rate for either sex is generally less than 1 per 100000 persons per year [4]. Table 1 lists the handful of populations that are known to deviate from this low-risk pattern together with their age-standardized (world population) incidence rates of nasopharyngeal cancer for men and women separately. Overall incidence of NPC is elevated in China, with substantial variation between regions. In general, incidence increases as one travels from north to south China. Whereas rates in Chinese men in the northernmost provinces are about 23/100000 person-years, those residing in the southernmost province of Guangdong exhibit rates of 25-40/100000 person-years [4-6]. High rates approaching those observed in southern China are seen in Eskimos and other natives of the Artic
0920-8534/90/$03.50 © 1990 Federation of European MicrobiologicalSocieties
236 Table 1 Populations at increased risk for nasopharyngeal cancer Age-standardized (world) incidencea Male Female 30.0 12.9 8.1 3.2 4.4 2.0 1.7 0.9 12.3 8.5
Population
Chinese (Hong Kong) Chinese (Tapei) Chinese (Shanghai) Chinese(Tianjin) Eskimos (Greenland) Eskimos. Indians, Aleuts (Alaska) Malays (Malaysia) Malays (Singapore) Filipinos(Rizal) Kadazans (Sabah) Kuwaitis (Kuwait) Non-Kuwaitis(Kuwait) Israeli Jewsborn in Africa/Asia
13.5 2.3 4.0
Reference
4 52 4 4 7
15.9 2.1 2.9
3.7 0.7 1.5 2.6 8.7 1.3 1.4
8 10 4 4 11 4 4
3.3
0.7
4
4.7
among Filipinos [4]. In Sabah, Malaysia, rates similar to those observed among the Eskimos have been reported for the native Kadazans [11]. Although mortality or incidence data are lacking for the other indigenous people of southeast Asia, raised relative frequencies of NPC in biopsy series have been reported among natives of ,'F,~ail;and, Indonesia, Sarawak, and Viet~tam [12]. Intermediate rates of N P C are observed among the people of Kuwait, both local-born Arabs and immigrants from neighboring Arab countries [4]. Based on reviews of hospita~ ~,:ries, it is believed that rates of N P C are also ~aised in the m a ~ , y Arab populations of Algeria, Tunisia, Morocco, and Sudan [12-14]. The intermeO~ate rates of NPC among Israeli Jews born in Africa or Asia, many of whom were from north Africa, tend to support this view [4].
" Per 100000 person-years. 2.2. Racial~ ethnic variation High risk to. NPC among Chinese is mainly
region [7,8]. Intermediate rates of NPC (25/100000 person-years) are observed among Malays in Singapore [9] and Malaysia [10], and 80°E J/
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I I (,~r Hainan Is. I 90°E IO0°E 1 lO°E 120°E Fig. l, Map of China showinghigh-risk provincesfor NPC.
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237
[5] (Fig. 1). Several distinct racial-ethnic groups reside in this high-risk region and these groups possess different rates of NPC. Highest rates are observed among the Tankas, a sub-ethnic group of the Cantonese who inhabit the Pearl River Delta Basin in central Guangdong. One distinguishing feature of the Tankas from the other Cantonese is t~mt they are seafaring people (either fishermen or sea transporters) who five on houseboats parked along the banks of the many branches of the Pearl River. The rates of NPC among the Tankas are 2 times those in the land-dwelling Cantonese [15,16]. In turn, the land-dwelling Cantonese (who comprise 98-99~ of Cantonese) have a 2-fold rate of NPC relative to the Hakka and Chiu Chan dialect groups who reside in northeast Guangdong [6,16]. The people of Fujian Province are culturally similar to the Chiu Chan people in Guangdong Province, and so are their rates of NPC [17]. It is interesting to note that the Hakkas (who rarely intermarry with other dialect groups) originated from northern China more than 500 years ago [18], but their rates resemble tbek Chiu Chau neighbors instead of their low-risk ancestors in the north. Even after migration to southeast Asia, the Cantonese continue to exhibit a 2-fold risk of NPC relative to the Hakkas, Chiu Chaus, and
Fujianese [10,19]. Two distinct racial groups inhabit the Autonomous Region of Ouangxi. While the Zhuang people in western Ouangxi possess one-fifth the NPC rate in Cantonese, the Han (the predominant race in China) people of eastern Guangxi who are ethnically close to the Cantonese in Guangdong show similar rates. Hunan Province borders both Guangxi and Guangdong to the north, and not surprisingly, areas that border Guangdong and Guangxi have high NPC rates. In addition, the Tujia and Miao tribes (minority races in China) who inhabit the mountainous region of western Hunan are found to possess NPC rates approaching those in the Cantonese [17]. In summary, the geographic variation of NPC incidence within southern China closely parallels the distribution of racial-ethnic groups inhabiting the region. The relatively high NPC rates observed among the Hakkas who originated from low-risk northern China argues against genetic predisposi-
tion as a major cause of the varying risk patterns among these population groups. On the other hand, these ethnic groups are distinct in their customs and food habits, and it is possible that environmental factors inherent in their traditional cultures are responsible for their varying susceptibitity to NPC.
2.3. Chinese salted fish The higher rates of NPC among the boat-dwellmg Tankas as compared to the land-dwelling Cantonese was first noted by Ho of Hong Kong, who further observed that these boat people had tittle exposure to domestic inhalants as they 'five all their fives in open boats and cook their food in the open air...." [20]. Ho then turned his attention to dietary factors, especially the traditional foods of southern China. He observed that salted fish is dominant in the diet of the boat people, being the principle source of supplementary food in a diet consisting mainly of rice. Often spending long periods at sea, southern Chinese fishermen salt most of their catch as a means of preservation. These fishermen and their fan, lies prefer to consume salted instead of fresh fish since the latter can command a much higher price. In 1971, Ho suggested that Chinese salted fish, ' a common and favourite item of food among most (Cantonese) in and outside China' be investigated as a 'possible etiological factor' for NPC [1]. Seven case-control studies conducted among various Chinese populations with distinct risks of NPC have investigated this possible exposure-disease association (Table 2). Four were conducted in populations that are predominantly Cantonese (Chinese in California, Hong Kong, and Guangzhou). While the 2 earlier studies among Cantonese [21,22] examined exposure at a single time point, the latter 2 studies conducted in this ethnic group [23,24] investigated exposure during multiple time periods throughout the subjects' lifetime. All 4 studies demonstrated a significant and positive association between salted fish intake and NPC risk. Moreover, in the two studies that investigated exposure at various time points, both found childhood exposu~-e, especially during infancy (at weaning), to be more strongly related to risk than adulthood exposure [23,24]. It is worthy
238 Table 2 Case-control studies of NPC which examined exposure to Chinese salted fish Chinese population studied
Years of diagnosis of cases
Numberof cases/controls
California, U.S.A.
1971-74
74/109
Hong Kong Selangnr, Malaysia
1973-74 1973-80
108/103 100/100
Period of exposureto salted fish Current During weaning During childhood During adolescence
Hong Kong
1981-83
250/250
During weaning At age 10 3 yr before
Gaangzhoa, China
1983-85
306/306
During weaning At age 10 3 yr before
Yufin, China
1984-86
128/174
Tianjin, China
1985-86
100/300
During weaning At age 10 At age 10 3 yr before
Estimate of risk relative )o no/rare consumption 1/wk, 2.1 2 +/wk, 3.1 Ever, 2.6 Weekly, 3.1 Daily, 17.4 Weekly, 1.3 Daily, 3.5 Ever, 7.5 Weekly/daily, 37.7 Weekly, 3.2 Dally, 7.5 Ever, 2.1 Weekly, 1.1 Dally, 2.4 Weekly, 1.4 Daily, 1.8 Ever, 2.6 Weekly *, 1.5 Weekly/dally, 6.7 Monthly/weekly a 1.2
Reference
21 22 25
23
24
26 27
a No subject reported daily consumption.
to note that the apparent disparity in the magnitude of relative risks observed among the Cantonese in Guangzhou compared to those in Hong Kong was an artifact which is related to the effect of exposure misclassification on the observable relative risk. An exposition was given in [24]. Two case-control studies which examined salted fish intake in non-Cantonese populations of southern China have also found a significant association between NPC risk and ingestion of this traditional food, with early age at exposure being an important co-determinant of risk. Armstrong et al. [25] studies 100 cases of NPC in Malaysian Chinese of whom approximately one-third were Cantonese, another one-third were Hakka, and the remaining were Chiu Chau/Fujianese. Ingestion of salted fish was associated with NPC risk in all 3 ethnic groups, and risk was higher for exposure during childhood than adolescence. Recent exposure was not related to NPC risk. Yu et al. [26] investigated salted fish intake in Yulin (in eastern Guangxi) where consumption level is relatively
low and again found the earliest exposure (at weaning) to exhibit the strongest association with risk. Finally, a recent case-control study in Tianjin, a coastal city in northern China where NPC is relatively rare, confirmed the salted fish-NPC association previously observed in southern Chinese populations [27]. This latest study clearly showed that risk increased with earlier age at first exposure. It also suggested that risk was influenced by the method of cooking; steaming the fish seemed to carry a higher NPC risk than frying, grilling or boiling it. In sunmlary, all case-control studies to date have produced remarkably consistent findings in support of intake of Chinese salted fish as a cause of NPC. Data derived from Cantonese populations indicate that most cases of NPC occurring in people of this ethnic group are related to early ingestion of this food. Data from whole animal expefinents have further strengthened the hypothesi~ that Chinese salted fish is a human nasopharyngeal carcinogen.
239
Huang et al. [28] successfully induced cancers of the nasal cavity in Wistar rats fed cooked Chinese salted fish, which otherwise rarely occurs in this animal species. Yu et al. [29] confLrmed those findings in a larger study which demonstrated a dose-response relationship between level of intake and rate of tumour occurrence. Furthermore, the amounts of salted fish (in terms of % total diet) fed to the rats in Yu et al. [29] were within the range of potential human (Cantonese) consumption, and the tumour (nasal cavity) rate observed in those rats was in general agreement with the rate of NPC occurrence in Cantonese. Low-levels (sub-parts per million) of several volatile nitrosamines, including N-nitrosodimethylamlne, N-nitrosodiethylamine, N-nitrosodi-npropylamine, N-nitrosodi-n-butylamine and Nnitrosomorpholine, have been detected in samples of Chinese salted fish [30,31]. Most of these volatile nitrosamines can induce nasal and paranasal cavity turnouts in animals [32-35]. In addition to these preformed nitrosaraines, Tannenbanm et al. [31] have detected bacterial mutagens in Chinese salted fish that had been exposed to a nitrosating agent under simulated gastric conditions. At present, it is not clear whether the volatile nitrosamines or bacterial mutagens present in Chinese salted fish are the carcinogens for NPC; the food may contain other types of carcinogenic substances which have not been identified. Recently, samples of Chinese salted fish were found to contain substance(s) capable of activating the Epstein-Barr virus (EBV) in latently infected Raji cells [36]. It is known that NPC patients of all races and geographical locales show significantly higher antibody titres to various EBV-associated antigens compared to controls [37-42] and that EBV DNA is present in epithelial cells of NPC tumour tissues irrespective of their degrees of differentiation [40,43-45]. If confirmed, this finding would add support to a causal interpretation of the well established EBV-NPC association.
2. 4. Other dietary factors There is some preliminary evidence that early exposure to other types of salted fish may explain at least some of the raised rates of NPC in the
native peoples of southeast Asia and the arctic region. In a small case-control study (13 cases, 50 controls) of NPC among Malays in Selangor, Malaysia, Armstrong and Armstrong [46] found 5 (38%) cases vs. 4 (8%) controls to be daily eaters of salted fish during childhood. In Alaska, interviews on 13 NPC patient-control pairs revealed more cases than controls to be frequent users of salted fi~h during childhood (case yes/control no vs. control yes/case no = 4 vs. 1) [8]. Besides salted fish, early exposure to other fermented food products has been shown to be related to NPC risk. In Yulin, exposure before age 2 years to chung choi (a kind of salted root), salted duck eggs, salted mustard green, dried fish, and fermented soy bean paste were independent risk factors for NPC [26]. In Guangzhou, exposure before age 10 years to fermented fish sauce, moldy bean curd, salted shrimp paste, and 'chart pai mui' and 'gar ink gee' (2 kinds of preserved plum) were independently related to NPC risk [24]. In Tianjin, exposure to salted shrimp paste at age 10 years was related to NPC risk independent of salted fish intake [27]. In Taiwan, exposure before age 20 years to fermented bean products and smoked meat increased risk of NPC independently [47]. While childhood exposure levels to most of these foods were low in the case series studied, chung choi was a weaning food for 60~ of cases in Yulin, salted shrimp paste was consumed at age 10 by 48~ of cases in Tianjin, and 63~ of cases in Taiwan consumed fermented bean products before age 20 years. Thus, preserved foods other than salted fish may account for a substantial proportion of NPC cases in certain non-Cantonese populations. Poirier et al. [48] analyzed samples of salted mustard green (described by the authors as green mustard leaves fermented in brine), chung choi (described by the authors as radish roots and stem fermented in brine) and fermented soy bean paste for volatile nitrosamines and detected one or more volatile nitrosamines in all 3 foods. N-nitroso-dimethylamine was detected in salted mustard green and chung choi, N-nitrosopiperidine in salted mustard green, and N-nitrosopyrrolidine in salted mustard green, chung choi, and fermented soy bean paste. As in the case of salted fish, it is not
240
clear yet whether any of the volatile nitrosamines detected in these fermented foods are directly involved in the carcinogenic process. The Arabs of north Africa, who are believed to possess raised rates of NPC, are known to consume a number of preserved foods on a regular basis. Poirier et al. [48] examined 10 preserved foods common in the Tunisian diet and found 3 of them (dried mutton preserved in olive oil, turnips fermented in brine, and 'Touklia' stewing base) to contain volatile nitrosamines. Although analytical data are lacking, it is possible that ingestion of preserved foods in the local diet is related to the increased ri,~k of NPC among Arabs of north Africa. In an uncontrolled study of very young (under age 25 years) NPC patients in Hong Kong, Anderson et al. [49] reported that 'all families felt that vegetables and fruit were bad for babies, and the children had been fed accordingly'. These observations were later confirmed in case-control studies. In both Hung Kong and Guangzhou [23,24], cases ingested significantlyless fresh vegetables and fruit than controls, especially during childhood. Whereas in Hong Kong [23] the protective effect of fresh vegetables and fruit was no longer significant after adjustment for salted fish intake, in Guangzhou such an effect was not explained by the differing consumption pattern of salted fish and other preserved foods between cases and controls [24]. In Tianjin [27], although general consumption of 'fresh fruit' or 'fresh vegetables' was not associated with a reduction in NPC risk, a significant protective effect with carrot imake at age 10 years was evident and garlic, the only other fresh vegetable item on the questionnaire, also showed declining risks with increasing frequency of consvmption although the effect was not statistically significant. Fruit and vegetables are rich in an array of chemical compounds which have been suggested to be protective against cancer [50]. It is interesting to note that African NPC patients showed significantly lower levels of serum carotene compared to controls [51]. The hypothesis that substance(s) present in certain fresh vegetables and fruit exert a modifying and beneficial effect on risk of NPC deserves further investigation.
2.5. Future research (1) Although a number of potentially carcinogenic substances have been identified in Chinese salted fish, it is presently unclear whether any of them are involved as nasopharyngeal carcinogens. Laboratory work to systematically search for the compound(s) contained in Chinese salted fish and other NPC-associated foods which give rise to NPC in humans should receive a high priority. (2) Although Chinese men are more than 2 times as likely to develop NPC as Chinese women, men have not been shown to consume Chinese salted fish or other NPC-associated foods more frequently than women. Future epidemiologic studies in this population should incorporate portion size measurements such that the question of whether the sex difference is due to constitutional factors or explicable on the basis of exposure level can be addressed. (3) It is presently unknown whether diet plays a role in the etiology of NPC in non-Chinese populations. There is some suggestion that the elevated rates in Malays, Alaskan Natives, and Northern Africans may be diet related, but data from analytical studies that have examined this hypothesis are lacking.
ACKNOWLEDGEMENTS This work was supported by Public Health Service Grant R01-CA40468 from the United States National Cancer Institute.
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