This is the first multi-jurisdiction ecological study that examined the associations between secular trends of NPC risk and salted fish consumption per capita. We also adjusted for the potentially confounding effects of two most important lifestyle factors, namely tobacco and vegetable consumption, using per capita estimates. We included 7 regions in 3 continents to include both endemic and low-risk areas, to analyse the pattern with a more global perspective.
We observed a decline in both ASIR and ASMR of NPC in Hong Kong over the past three decades. Higher NPC ASMR was observed in males than females in most of the jurisdictions included, consistent with previous studies [11, 30, 31], which may be due to a combination of differential risk factor exposures such as greater tobacco consumption in males and genetic factors. The rather consistent; more than 3-fold risk in males compared with females needs further investigation. Our results showed markedly decreasing trends in salted fish intake and tobacco consumption, but an increasing trend in vegetable consumption in Hong Kong over the past several decades. All of these environmental risk factors were individually highly correlated with ASMR and ASIR. The decrease in salted fish consumption may represent a change in dietary culture with westernisation of dietary patterns among Hong Kong citizens from a traditional Cantonese diet and from increased awareness of the carcinogenicity of salted fish. Decrease in intake of salted fish should lower the risk of an individual getting NPC if the relationship is causal .
There were no substantial changes in the proportion of Cantonese residing in Hong Kong, thus any changes noted should not be confounded by migration effect. Additional file 1: Tables S1-S3 show the population structure in Hong Kong from 1961–2006. Nevertheless, in the multivariable model, the relations between salted fish consumption and NPC ASIR and ASMR were attenuated and became mostly insignificant. In contrast, the negative association between vegetable consumption and NPC ASIR remained statistically significant after adjustment and was robust across varying estimates of cumulative exposure windows prior to NPC outcomes. Consistent with findings from previous case-control studies [18, 32], dietary intake of fruits and vegetables may have a protective effect against NPC due to its antioxidant contents, potentially interfering with the actions of nitrosamines . World Cancer Research Fund (WCRF) panel suggested fruit and vegetable consumption have limited to suggestive levels of evidence for protection against NPC , which is consistent with the result found in this study. Although positive association was observed for cigarette consumption and NPC ASIR in males, previous literature suggested that for lung cancer, of which smoking is known as one of the major risk factor, the lag year for the disease from exposure to cancer onset was 25–30 years , it is expected that the lag for NPC should not be shorter if not similar to lung cancer. As our study is ecological, further analytical studies, such as case control studies with genetic, viral and other biomarkers are warranted to examine the link between salted fish and NPC in Hong Kong, taking into account smoking, vegetable consumption and other potential confounders.
Despite the parallel secular trends of salted fish consumption and NPC rates in Hong Kong, the same pattern was not observed in all other jurisdictions. For instance, in China, salted fish consumption increased over the years and there was no sign in apparent increase of ASMR in both males and females. Similarly, there are jurisdictions where NPC ASIR/ASMR had markedly decreased, but with no accompanying drop in salted fish consumption. Caution needs to be taken in interpretation, since the salted fish consumed in other countries might not be the Cantonese-styled salted fish, which is categorised as a group I carcinogen by IARC. The effect of salted fish on NPC development might only have a notable impact among Hong Kong Chinese but not in other populations, due to the higher underlying disease rates of NPC in Hong Kong, or could be due to genetic differences e.g. nitrosamine metabolism . Indeed, the vast majority of previous case-control studies on salted fish consumption and NPC were only conducted in Chinese [1, 4, 5, 37]. It remains uncertain whether the same carcinogenesis mechanism could apply to different Chinese sub-group or non-Chinese populations.
Our findings highlight the importance of examining the relations between key risk factor exposures and NPC on multiple jurisdictions rather than focusing on a single locality and a single exposure in an ecological study. Furthermore, since NPC includes a spectrum of squamous, and keratinising versus non-keratinising subtypes which are linked to differential risk factors, this may also be an important reason underlying the varying patterns of ecological associations found across different jurisdictions. Thus an ecological study investigates the links between risk and protective factors and different subtypes would be of interest, especially when the pathogenesis processes for various NPC subtypes appear to be distinct. Therefore it is important to first elucidate the secular trend of salted fish consumption and NPC incidence/mortality rates between multiple areas. The findings from this study have encouraged us to further examine the time trend of different NPC subtypes across regions, and so far our literature review has shown that a more thorough review and deeper understanding is needed of different NPC histological classification between China and the West, but such data are often scarce. Also, the differences between Chinese and WHO classifications need to be further examined and resolved. We believe this would warrant a separate paper for a detailed discussion.
There are several limitations in our study. First of all we could not be certain that the capture of NPC incidence and mortality was 100% complete and accurate in each jurisdiction, but most data were derived from cancer registries where completeness of data; especially that of mortality, is good with high accuracy. Variations of diagnostic criteria could exist but this effect is minimised by using International Classification of Disease (ICD 8–10) since NPC is a rare and uncommon cancer. Secondly, per capita consumption was calculated by taking the difference between export, import, production and re-export of salted fish. Consequently, there was a possibility of over or underestimating the actual amount of salted fish being consumed. Nevertheless, data obtained from Hong Kong Trade and Statistics and from the FAO were largely consistent. Even though we tried to obtain all the salted fish related data as precisely as possible, the data we used might include other dried fish products rather than just Cantonese style salted fish, details of which could not be obtained from other jurisdictions. Moreover, the uncertainty of latency period between the consumption patterns and ASIR/ASMR is well acknowledged, for that we included the sensitivity analysis by using year of cumulative consumption for regression and result were shown to be robust. Furthermore, vegetable consumption in Hong Kong was not available from Agriculture, Fisheries and Conservation Department HKSAR prior to 1991, thus multivariable analysis was done only between 1991–2008 but not from 1978–2008.
Finally, the limitations of ecological studies due to the ecological fallacy are well recognised, and unknown, unmeasured or immeasurable confounding factors may be present. We tried to take account of important and known factors by accounting for tobacco consumption, vegetable consumption and migration effects, which is the first example of its kind in NPC epidemiological studies. In future studies, age-specific rather than age-standardised mortality and incidence rates could be more informative to investigate disease risk across different ages and in different populations. Because NPC is endemic mainly in Southern China, ecological analysis focusing on the endemic regions of China would yield more important information than a national study. Data specifically in Southern China on salted fish, vegetable and cigarette consumptions, together with NPC incidence and mortality rates (with subtypes) would be highly valuable if such data are available in the near future and more in depth analysis is warranted.