Fish consumption is inversely associated with male lung cancer mortality in countries with high levels of cigarette smoking or animal fat consumption

Jianjun Zhang, Elisabeth HM Temme and Hugo Kesteloot

Department of Epidemiology, School of Public Health, Catholic University of Leuven, Leuven, Belgium.

Reprint request to: Prof. Hugo Kesteloot, Department of Epidemiology, Kapucijnenvoer 33, B-3000 Leuven, Belgium. E-mail: hugo.kesteloot{at}med.kuleuven.ac.be


    Abstract
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background A striking difference in fish consumption and lung cancer mortality (LCM) exists among populations worldwide. This study investigated the relation between fish consumption and LCM at the population level.

Methods Sex-specific LCM data, mostly around 1993 and fish consumption data for 10 periods 1961–1994 in 36 countries were obtained from WHO and FAO, respectively.

Results A significant inverse correlation exists between log fish consumption and LCM rate in 9 out of the 10 time periods (r = –0.34 to r = –0.46, P = 0.044 to P = 0.005). After adjusting for smoking and other confounders, log fish consumption (% of total energy [% E]) was inversely and significantly associated with LCM rate (per 100 000 per year) in all 10 time periods (ß = –26.3 to ß = –36.7; P = 0.0039 to P < 0.0001). The stratified analysis showed that this inverse relation was significant only in countries with above median level of smoking (>2437 cigarettes/adult/year) or animal fat minus fish fat consumption (22.4% E). An increase in fish consumption by 1% E was calculated to reduce mean male LCM rate of the populations examined in the age class of 45–74 years by 8.4%. In women, no significant relation between fish consumption and LCM could be established.

Conclusions Fish consumption is associated with a reduced risk from LCM, but this possible protective effect is clear-cut only in men and in countries with high levels of cigarette smoking or animal fat consumption.

Keywords Animal fat, cigarette smoking, fish consumption, lung cancer mortality

Accepted 7 February 2000


    Introduction
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Although the prevalence of smoking is declining in many industrialized countries,1 lung cancer is still a leading cause of cancer death.2 Cigarette smoking is the predominant cause of lung cancer but this alone cannot completely explain the striking difference in lung cancer mortality (LCM) among populations worldwide.2 This suggests that other factors, especially of dietary origin, may be involved in the aetiology of lung cancer. In the past two decades, several epidemiological studies have explored the relation of dietary fat, cholesterol, vegetable and fruit intake to lung cancer risk.3–8 To date, however, few investigations examined the association between fish intake and the risk of lung cancer, and the findings obtained are rather inconsistent with inverse, null and positive relations reported.9–11 The purpose of the present study, using LCM data from the latest available 3 years and fish consumption data during 10 periods from 36 countries, is to clarify the relation between fish consumption and LCM at the population level. The importance of different time intervals between fish exposure and LCM will also be evaluated. To our knowledge, this is the first ecological study to address this issue which has important public health implications.


    Materials and Methods
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Data sources
A total of 36 countries (areas) have been recruited in the present study (including 6 American, 24 European and 6 Western Pacific countries) based on availability of relatively reliable data on LCM (International Classification of Diseases, 8th Revision, A 51; 9th Revision, 101), fish consumption and other confounding factors. The sex-specific LCM rates (per 100 000 per year) in the age classes of 45–54 years, 55–64 years and 65–74 years for the latest available 3 years, mostly around 1993, were obtained from the World Health Statistics Annual, World Health Organization (WHO).2 The corresponding period available for Belgium was 1987–1989, the most remote period among all the countries considered. The LCM rate was averaged over 3 years and standardized to 45–74 years according to the European Standard Population.2

The data of fish, animal fat, vegetable and fruit consumption were derived from the Food Balance Sheets, Food and Agriculture Organization (FAO) for 10 periods (1961–1963, 1964–1966, 1969–1971, 1974–1976, 1979–1981, 1982–1984, 1984–1986, 1987–1989, 1989–1991 and 1992–1994).12 The dietary and mortality data were obtained from the same 36 countries, with missing dietary data for Singapore for the last three periods. Animal fat includes fish fat in the FAO data set. To better adjust for the confounding effect of animal fat on the relation between fish consumption and LCM, a new variable, animal fat minus fish fat (AFFF), was created. Fish, AFFF, vegetable and fruit consumption were expressed as per cent of total energy (% E), because % E is more appropriate than absolute units for FAO's food consumption data.13 Cigarette consumption data (n/adult/year) in 1970–1972, 1980–1982 and 1990–1992 were obtained from WHO.1 The Czech Republic and Hong Kong have missing data in these three periods. Cigarette consumption data from these two countries (areas) in 1970 and 1985 were used instead.14

Statistical analysis
The normality of the distribution of the data used was tested prior to the analysis. Because of the skewed distribution of fish consumption in the 10 time periods considered, the data were transformed by natural logarithm, resulting in a normal distribution. The Pearson correlation analysis was made between fish consumption and LCM rate. Multiple linear regression analysis was performed with LCM rate as a dependent variable and fish, AFFF, vegetable, fruit and cigarette consumption as independent variables. All independent variables were retained in the regression equations irrespective of their significance levels. In the multivariate models, AFFF, vegetable and fruit consumption data were obtained from the same period as the fish consumption. Mean cigarette consumption of 1970–1972, 1980– 1982 and 1990–1992 was calculated and then introduced into the multivariate models. For the Czech Republic and Hong Kong, the mean cigarette consumption of 1970 and 1985 was used for substitution. To explore whether the relation between fish consumption and LCM varies with the amount of cigarette and AFFF consumption among all the countries selected, the interaction terms between fish and cigarette consumption and between fish and AFFF consumption were examined in multiple regression models which only include the interaction term and its constituting variables. Based on the findings of the interaction analysis, stratified analyses were performed between countries with low and high levels of cigarette smoking and with low and high levels of AFFF consumption in the same manner as in the analysis with all countries included. The only difference is that vegetable and fruit consumption was excluded from the models, as only 18 observations were available in each group. Countries with low and high levels of smoking were defined as the countries with cigarette consumption < and > the median (2437 cigarettes/adult/year) of mean cigarette consumption of 1970–1972, 1980–1982 and 1990–1992, while countries with low and high levels of AFFF consumption as the countries with AFFF < and > the median (22.4 % E) of mean AFFF of the 10 periods considered. The classification of countries by using the mean consumption over a prolonged period of time is more relevant in view of the dynamic nature of the exposures which can change during the period of observation. The number of countries was 36 in the analysis including all countries and 18 in the stratified analysis. Because of missing data of fish, AFFF, vegetable and fruit consumption in Singapore in the last three periods, the number of countries examined in these periods was one less than that in other periods. Significance level was P < 0.05 (two-tailed). All analyses were performed with the statistical package SAS (SAS Institute, Inc., Cary, North Carolina) for 10 periods and for both sexes. Because no significant relation between fish consumption and LCM rate in women was detected in any of the analyses performed, only the results for men are presented.


    Results
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Data on fish, AFFF, vegetable, fruit and cigarette consumption and LCM obtained from 36 countries are shown in Table 1Go. LCM rates in men and women did not correlate significantly (r = 0.24, P = 0.16). The Pearson correlation coefficients between log fish consumption and LCM rate in men are presented in Table 2Go. Log fish consumption inversely and significantly correlated with LCM rate in 9 out of the 10 periods (r = –0.34 to r = –0.46, P = 0.044 to P = 0.005). Table 3Go shows the partial regression coefficients (ß) of LCM rates in men versus log fish consumption, adjusted for confounders. A significant inverse relation exists between log fish consumption (%E) and LCM rate (per 100 000 per year) in all 10 periods (ß = –26.3 to ß = –36.7; P = 0.0039 to P < 0.0001), which is independent of cigarette, AFFF, vegetable and fruit consumption. The association between log fish consumption and LCM became more significant in all 10 periods examined after adjusting for confounders. Relating the mean log fish consumption of the 10 periods to LCM gave similar results (ß = –34.8, P = 0.0002) (Table 3Go). When the consumption of vegetables and fruit was expressed in g/1000 kcal/day instead of % E in the analyses, the results obtained remained essentially unchanged. The Pearson correlation coefficients and partial regression coefficients of log fish consumption versus LCM rates did not significantly correlate with the time intervals between fish consumption and LCM (P > 0.07) (Tables 2 and 3GoGo).


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Table 1 Fish, animal fat minus fish fat (AFFF), vegetable (VEG) and fruit consumption, mean of 10 periods 1961–1994, Food and Agriculture Organization, and cigarette consumption (CC), mean of 1970–1972, 1980–1982 and 1990–1992 (Lopez, 1997) and lung cancer mortality rate, age-standardized to 45–74 years, mean of the latest available 3 years, mostly around 1993, World Health Organization
 

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Table 2 Pearson correlation coefficienta between log fish consumption (% E)b in 10 periods and lung cancer mortality rate (per 100 000 per year), age-standardized to 45–74 years, mean of the latest available 3 years in men
 

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Table 3 Multiple regression analysis of lung cancer mortality rate (per 100 000 per year), age-standardized to 45–74 years, mean of the latest available 3 years, versus log fish consumption (% E)a in 10 periods in all countries in menb (n = 36)c
 
A significant negative interaction between log fish and cigarette consumption on LCM was detected in 9 out of the 10 periods (P = 0.03 to P = 0.006) except for 1979–1981. This significant negative interaction was also found between log fish and AFFF consumption in 7 out of 10 periods (P = 0.041 to P = 0.002; P > 0.05 for 1961–1963, 1969–1971 and 1979–1981). The results of the stratified analysis according to cigarette and AFFF consumption levels are shown in Tables 2, 4, and 5GoGoGo. A significant inverse correlation between log fish consumption and LCM rate was observed in all 10 periods but only in countries with a high level of cigarette smoking (r = –0.62 to r = –0.75, P = 0.006 to P = 0.0004) or in countries with a high level of AFFF consumption (r = –0.62 to r = –0.70, P = 0.006 to P = 0.001) (Table 2Go). This characteristic of the relation between log fish consumption and LCM was confirmed in the multivariate analysis.


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Table 4 Multiple regression analysis of lung cancer mortality rate (per 100 000 per year), age-standardized to 45–74 years, mean of the latest available 3 years, versus log fish consumption (% E)a in 10 time periods in countries with low and high levels of CCb in menc
 

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Table 5 Multiple regression analysis of lung cancer mortality rate (per 100 000 per year), age-standardized to 45–74 years, mean of the latest available 3 years, versus log fish consumption (% E)a in 10 time periods in countries with low and high levels of AFFFb consumption in menc
 

    Discussion
 Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The present study shows that fish consumption is inversely and significantly associated with LCM in men in 10 periods covering a span of about 30 years. This significant association is independent of cigarette, AFFF, vegetable and fruit consumption. From Tables 1 and 3GoGo it can be calculated that an increase of 1% E of mean fish consumption of 10 periods among all populations examined would result in a reduction of mean male LCM at ages 45–74 years by 8.4% (–34.8/2.72/152.8, where 2.72 is the base of the natural logarithm used for converting log ß [–34.8] into ß). The possible protective effect of fish consumption on lung cancer risk is clear-cut only in men and in countries with high levels of cigarette smoking or animal fat consumption. The time interval between fish consumption and LCM has little influence on the strength of this inverse relation.

To date, most studies concerning diet and lung cancer have concentrated on the relation of dietary intake of fat, cholesterol, vegetable, fruit and vitamin A to lung cancer risk.3–8,15–19 Epidemiological evidence on the relation between fish consumption and lung cancer risk is scarce. The findings obtained so far, mostly from a case-control approach, are rather controversial. The possible protective effect of fish consumption on LCM observed here is consistent with the results of case-control studies from Hong Kong10 and Australia.20 The beneficial influence of fish intake on lung cancer risk was also detected in a Norwegian cohort of 13 785 men and 2928 women followed up for 11.5 years17 and in a case-control study in Kerala, India,11 although the results from these studies did not attain statistical significance. No significant relation between fish consumption and LCM was found in a multiethnic case-control study in Hawaii.3 The relative risk of lung cancer increased with the ascending quartiles of fish intake (P for trend < 0.01) in a Chinese mining community.21 However, caution should be given to this finding because fish intake, both in cases and controls, was very low in the latter study (<1/month).21

The mechanisms by which fish consumption appears to protect against lung cancer remain unclear. N-3 polyunsaturated fatty acids, abundantly present in fish, have been shown to possess an anti-inflammatory effect.22–24 Fish intake was reported to protect cigarette smokers against chronic obstructive pulmonary disease25,26 and the deterioration of lung function.27 A case-control study in north-east China showed that prior chronic bronchitis and/or emphysema significantly contributed to the risk of lung cancer.28 However, whether this anti-inflammatory property of fish intake is partly responsible for its protective effect on lung cancer risk still needs to be elucidated. Some studies have found that the intake of animal fat, particularly, saturated fat, is associated with an increased risk of lung cancer.3,16,29 Previous findings have disclosed that animal fat interacts with cigarette smoking to promote the occurrence of lung cancer.30 It is likely that fish intake partially generates its beneficial influence on LCM by means of substituting for saturated fat intake.31 Therefore, it is reasonable to assume that the protective effect of fish consumption on lung cancer risk would be apparent only if its ‘challenge’, such as cigarette smoking and animal fat intake, are sufficiently strong and may explain why fish consumption confers its protective effect on LCM only in countries with high levels of cigarette smoking or AFFF consumption. Fish oil has been reported to inhibit rectal mucosal cell proliferation in subjects with sporadic adenomatous colorectal polyps32 and the growth of human breast carcinoma maintained in athymic nude mice.33

The observations of the present study aid clarification of some perplexing epidemiological phenomena. Hungary and Iceland are two countries with high levels of cigarette consumption and animal fat intake, but the LCM rate in Hungarian men is approximately 3.4 times that in Iceland. The major dietary difference between these two populations is that fish consumption is much higher in Iceland. Cigarette smoking in Japan is among the highest in the world, but its LCM rate is among the lowest. High fish consumption, coupled with a low animal fat intake, may offer a partial explanation for this paradoxical phenomenon (Table 1Go).

A significant relation between fish consumption and LCM was not found in women in the present study. The prevalence and amount of cigarette smoking is lower in women than in men in nearly all populations in the world.1,14 The actual smoking habits of women are of recent origin and their cigarette consumption is generally increasing.1,14 The time lag of lung cancer may thus explain the lack of a significant association in women.30

The findings of epidemiological studies should be universally applicable before a possible causal relationship can be considered. In the present study, all countries with relatively reliable data were included and no country was excluded as an outlier. The decision for inclusion was made before the results of the analysis were known. The relation between fish consumption and LCM was examined in 10 periods over a span of about 30 years. Linking LCM to different intervals of fish exposure, instead of a single one, is a relevant approach to reduce the possibility of obtaining a chance finding. Cigarette consumption (n/adult/year) was significantly and positively associated with male LCM (per 100 000 per year) in all periods (ß = 0.026 to ß = 0.034; P = 0.045 to P = 0.006) except for 1974–1976 (ß = 0.025, P = 0.053). This result suggests the reliability of the data used for the analysis.

Several limitations inherent in this study should be taken into account. The ecological approach covers exposure to disease on a population basis. Thus, our findings are subject to the ecological fallacy.34 The FAO data only reflect the overall pattern of food consumption of a whole population, without considering age and sex differences in dietary intake. The precision of diagnosis, the level of medical treatment and the completeness of death registration vary with the countries selected,2 which may weaken the reliability of the mortality data from WHO. These measurement errors contribute to regression dilution bias which tends to attenuate the true regression coefficients of fish consumption versus LCM.35 The data used in this study are far from optimal but are the best available for examining the relation between fish consumption and LCM in a large number of populations worldwide.

The present study suggests that fish intake protects against lung cancer, confirming findings from some case-control studies.10,20 The inverse significant relation between fish consumption and LCM was found only in countries with high levels of cigarette smoking or animal fat consumption. This observation has not been reported previously. A growing body of epidemiological evidence has shown that fish intake is also protective against cardiovascular disease,36–39 chronic respiratory disease,25,26 rheumatoid arthritis,40 ulcerative colitis41 and all-cause mortality.39,42 In view of the beneficial effect of fish intake on disease risk and the possibility of a dietary insufficiency of n-3 polyunsaturated fatty acids in the Western diet,43 it is inferred that increasing the amount of fish consumption could decrease the mortality of lung cancer and other related diseases, especially in populations with high levels of cigarette consumption and animal fat intake. More studies are needed to confirm these findings and to elucidate the mechanisms underlying the possible protective effect of fish intake on lung cancer risk.


    Acknowledgments
 
This study was supported by a grant from the Unilever Chair in Nutritional Epidemiology. The authors thank Roos Struyven for her editorial assistance.


    References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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