Gastric cancer: an epidemiological review.

Environmental Geochemistry and Health, Vol. 12, pages 201-214

Gastric cancer: an epidemiological review Stephen A. Matthews 1 Department of Geography, University of California, Los Angeles, CA 90024-1524, USA

Abstract An attempt is made to synthesize the epidemiological literature and identify salient factors from the multitude of potential antecedents of gastric cancer, factors which to a greater or lesser degree create nonrandom variations in the distribution of the disease. Implicit in this approach is the notion that observation of spatial variations in the incidence of gastric cancer may lead to hypotheses relating to the biological, personal and physical environmental factors. An extensive bibliography accompanies the text.

Introduction Gastric cancer is a disease which has frustrated physicians for decades. The results of its treatment in most countries are very poor indeed, with approximately only 5-10% of patients surviving five years after a positive diagnosis. The causes are unknown, although vast amounts of time and money have been spent investigating the numerous hypotheses and theories based on environmental and endogenous factors which have been proposed as to its aetiology. Investigators over the past thirty years have pointed to social class, occupation, blood group and ethnicity; also to smoking, diet, nitrates, soil, water, geology and climate.

Pathology Pathologists now recognise that gastric cancer is not histologically homogenous. Lauren (1965) proposed two major histological types of gastric cancer. He classified these as (1) intestinal adenocarinoma - characterised by large cells with a definite glandular pattern, and (2) diffuse carcinoma - in which the cells are poorly differentiated and rarely form glandular structures. In the two decades since Lauren's paper, research has revealed different aetiologies and epidemiologies for intestinal and diffuse gastric cancers. A series of papers in the early 1970s, Munoz, Correa and Cuello (1968), Correa (1970), Hirayama (1971), Munoz and Asvall (1971), Correa, Sasano and Stemmermann (1973) and Bjelke (1974), h i g h l i g h t e d the salient d i f f e r e n c e s . The undifferentiated (diffuse) type is more predominant in women than in men. It is also found more frequent in younger age groups than the intestinal type, and is more predominant in certain occupations and geographical areas. Of significance is the finding that while diffuse type gastric cancer tends to occur with similar frequency in both high and low risk areas, the intestinal type is more common in areas of high gastric cancer. Although this is the case, 1 Formerly of the Department of Town Planning, University of Wales, College of Cardiff, PO Box 906, Cardiff CF1 3YN, Wales.

further confirmation is desirable on the prevalence of intestinal and diffuse cancers from both high and low risk areas, especially where considerable intra-country variation exists (for example, by ethnic and socioeconomic groups). In the literature intestinal gastric cancer, with its widely varying spatial and temporal frequency, is thought of as the 'epidemic type', being more closely governed by environmental factors, whilst the diffuse is associated more with familial and 'genetic' factors (see Day, i981; Correa, 1982; and Grabiec and Owen, 1985). It has been suggested that the pathogenesis of gastric cancer involves distinct stages. The intestinal type of the disease is associated with a number of precursor lesions and Correa et al. (1975) postulated a histopathological sequence in which the first step was gastric atrophy, followed by atrophic gastritis, then intestinal metaplasia with increasing degrees of dysplasia and finally neoplasia (see Figure 1.) Chronic atrophic gastritis and intestinal metaplasia are characterised by a low serum pepsinogen (PG I). A low PG I correlates well with the degree of severity of gastritis, pernicious anaemia, achlorhydria (Levine and Beer, 1984), and the risk of subsequent gastric cancer. Gastric atrophy is accompanied by deceased acid secretion and eventually achlorhydria, and this has two results. The absence of gastric acid permits the establishment of a resident bacterial flora and under these conditions nitrate is reduced to nitrite and N-nitroso compounds are formed. Both pernicious anemia and Polya partial gastrectomy are accompanied by gastric achlorhydria and carry an increased risk of gastric cancer. Differences in gastric cancer mortality between population groups seem to arise from factors which operate over long periods of time (see Burr et al., 1987). In Colombia Correa et al. (1975) found a high prevalence of intestinal metaplasia of the gastric mucosa, which predisposes to gastric cancer, occurs in adults who spent their first ten years of life in an area of high risk of gastric cancer. The likelihood of acquiring atrophic gastritis is probably also determined over many years. In later life adult life neoplastic changes occur in some cases of severe gastric gastritis. Indeed, it has been estimated by Siurala el al. (1968) that 19 years intervene between the onset of

202

Gastric cancer: an epidemiological review

Figure 1 A postulated histological sequence of gastric carcinogenesis (based on Correa et al., 1975).

NORMAL GASTRIC MUCOSA virus infection ? malnutrition ? high salt intake ? GASTRIC ATROPHY

................... >

GASTRIC ACHLORHYDRIA

action of bacterial flora

ATROPHIC GASTRITIS

1

< ..................................................

NO and

N-NITROSO COMPOUNDS

INTESTINAL METAPLASIA

CARCINOMA < ...............................................

atrophic gastritis and gastric cancer, and Svendsen et al. (1986) find that severe atrophic gastritis is associated prospectively with a 4-6 fold increase in the risk of gastric cancer. Howson, Hiyama and Wynder (1986) in their search for an explanation for the international decline in the incidence of gastric cancer, review the work of Muroz and AsvaU (1971) for Norway, and suggest that it was, in large part, due to the decreasing rate of intestinal type cancer. More recently, Hirayama (1975), Antonioli and Goldman (1982) and Hanai, Fujimoto and Taniguchi (1982) confirm similar findings in the USA and Japan. Correa et al. (1973) estimated the age- specific incidence rate of stomach cancer by histological type among Japanese migrants to Hawaii, and among the Japanese remaining in the home country. They were able to show that the incidence rate curve of the diffuse type has a more gradual slope than that of the intestinal type, that is, the rate for the diffuse type increases more slowly with age. According to Haenszel and Correa (1975) the intestinal-diffuse distinction apparent in inter-population contrasts has not been well demonstrated in studies of time trends or by case-control studies of suspected salient factors conducted on a single population. It is clear that epidemiological studies attempting to understand gastric cancer should distinguish, whenever possible, b e t w e e n the intestinal and the diffuse classification. However, it remains a fundamental weakness of much research into the epidemiology of gastric cancer that it has not been able to differentiate between these two histological types. More recently, it has been suggested that although it is important to be able to differentiate histological type, it is equally important to be able to differentiate gastric cancer from cancer of the lower oesophagus and pancreas (errors in cancer registration or death certificates by site needs to be considered).

Trends and Patterns International trends

One of the more striking trends in cancer mortality internationally has been the marked decline in deaths from gastric cancer over time. Its decreasing incidence provides an intriguing epidemiological problem, for the reasons are not apparent. Numerous theories have been proposed for a decline that is quite remarkable in an age when the incidence of some cancers (for example, lung cancer) has been increasing. Howson et al. (1986) describe the decline in gastric cancer as an 'unplanned triumph'. Mortality and incidence rates have been falling in the USA since the Second World War, and similarly in other countries (see Haenszel, 1958; Wynder et al., 1963; Munoz and Asvall 1971; H i r a y a m a 1975; W a t e r h o u s e et al., 1976; Clemmesen, 1977; Devesa and Silverman, 1978; Segi et al., 1981; and Miller, 1982). Significantly, and as one would expect, the rates of decline have shown a wide degree of inter-country variation. For example, for the period 1950-80, the four Scandinavian countries, Switzerland and the USA witnessed a decline of between 65-74% in their gastric cancer mortality rates. In England and Wales, the decline was approximately 51%, while in Japan, Italy and Eastern Europe it was only 43-44%. Using adapted figures from Alderson (1981), Howson et al. (1986) also illustrate the wide inter- country variation in the magnitude of the decline. For those countries with the highest rates of gastric cancer (Japan, Chile and Finland) the decline was both steeper and later in occurrence than that of countries with lower gastric cancer mortality rates. Papers by Wynder et al. (1963), Nobrega et al. (1983) and Sandier and Holland (1987) dismiss the suggestion that this decline is due to refinements in the diagnosis and classification of stomach cancers rather than being a true decline in the incidence of gastric cancer (misdiagnosis of gastric cancer when really it was cancer of the pancreas,

S. A. Matthews

Table 1 Age-sex distribution of gastric cancer England and Wales 1970-72 (per 100,000). Age

Male

40455055606570-74

6 13 25 50 89 137 188

Mean age at death 64.5 95% of cases between age 41-85 proportion by sex 58.1%

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Table 2 Regional studies of gastric cancer. Country

Author(s) and date

Australia Belgium Canada Chile China

Learmonth and Grau Verhasselt Phillips and Owchar Armijo and Coulson Day Armstrong

(1969) (1981) ,(1955) (1975) (1975) (1980)

Xu

(1981)

Columbia England & Wales

Cuello et al. (1976) Legon (1951) Ashley and Davies (1966) Howe (1970, 1979) Chilvers and Adelstein (1978) Gardner et al. (1983) Mesle (1984) Dungal (1961) Sigurjonsson (1966) Segi and Kurihara (1960) Kawashima (1966) Takehashi (1978) Tromp (1956) Kendrick (1980) Bradshaw et al. (1983) Haenszel (1958) Hoover et at. (1975) Kriebel and Jowett (1979) Baker (1980) Wynder et al. (1963) Gillis (1977) Segi et al. (1981) Parkin et al. (1984) Waterhouse (1985) Waterhouse et al. (1986)

Female

3 6 10 19 33 52 91 69.8 43-89 41.9%

for example (see Baker, 1980). Much has been made of the influence of dietary factors (for example, changing tastes and consumption patterns, new methods of food preservation and presentation). Wynder et al. (1963) suggest that the possibility that gastric cancer is, in part at least, related to diet has discouraged researchers from undertaking an epidemiological study because of the difficulties of obtaining reliable dietary information. Diet will be discussed in more detail below.

France Iceland Japan

Netherlands New Zealand South Africa United States

Age and sex trends

The rates for gastric cancer appear to go up with increasing age, a finding confn-med by both mortality and morbidity studies (Siurala et al., 1968; Villako et al., 1976, 1982). Hirayama (1971) plotted age-specific rates against a logarithmic scale, and reported a constant increase in the rate of cancer increase (for both men and women). Morris (1975) provided summary figures regarding the age-sex distribution of gastric cancer (see Table I). The age-specific sex ratio for gastric cancer has been examined in depth by Griffith (1968), Segi et al. (1972) and Sandier and Holland (1987). Griffith's work included data from twenty-four countries for the period 1958-1963. He observed a sex ratio pattern dominated by men, and indicating little geographical variation. He found that the ratio is close to unity at ages under thirty-five, reaches a peak of about 2:1 around the late fifties, and thereafter falls to approximately 1.3-1.5:1 among the oldest age groups. Doll (1967) observed no country in which the female gastric cancer rates was higher than that of males. Sandler and Holland (1987) analysed the US pattern in four time periods. Their findings for the late-1950s early-1960s comply with Griffith. However, for the period 1971-1977, the age- specific sex ratio is 1.2:1 for the under-thirties, 2:1 for the early-fifties peaking at 2.45:1 for the 60-64 age group, and falling to 2:1 for the 75-79 year olds and 1.8:1 for the over- eighties. In Wales the age-specific sex ratios varied widely in magnitude although the overall pattern was consistent (Welsh Office, 1988). For the years 1974-78 the sex ratio was close to unity upto the age of thirty-five. Thereafter, the ratio was approximately 2:1 for the 35-54 age groups, peaking at 2.4:1 for the 55-64 year olds, before falling to 2.2:1 in the 65-74 age group and 1.7:1 in the over

Yugoslavia The World

seventy-fives. For the years 1979- 1983 in Wales, the ratios are generally higher. For example, 2.4:1 (45-54 age group), 2.7:1 (55-64 age group), 2.5:1 (65-74 age group) and (1.9:1 for the over 75s). Howson et al. (1986) suggest that the shift in sex ratios with increasing age 'parallels the proportional increase in intestinal relative to diffuse type gastric cancer'. Thus further evidence is found suggesting that gastric cancer encompasses two disease entities, each with a different age at onset and a different set of risk factors (see also Haenszel and Correa, 1975). lntra-country variation

In the last twenty years or so there have been a number of important studies carried out at the level of the individual country (see Table 2). Such studies have frequently reported on the geographical variation of gastric cancer, particularly in terms of differences between urban and rural areas, low and high altitude, and latitude. In contrast to the marked intra-regional variations in gastric cancer, urban-rural variations are small and reveal few consistent patterns (see Table 3). This has led

204


Table 3 Papers reporting on urban-rural incidence of gastric cancer. Country

Author(s) and date

Urban areas highest incidence

Australia Denmark Finland

Norway United Kingdom

United States

Learmonth and Grau (1969) Clemmeson and Nielsen (1957) Saxen (1961) Observed for rates in men but not in women Petersen and Magnus (1961) Urban dominance falling over time Howe (1970) Gardner et al. (1983) Also reveal rural areas with high incidence levels. Haenszel (1958) Note link with migrant populations. The US has a low incidence of gastric cancer. International migrants tend to live in the larger cities pushing up incidence levels

Rural areas highest incidence

Chile Iceland Netherlands South Africa Sweden

Armijo and Coulson Sigurjonsson Tromp Bradshaw et al. Olinder (Cited by Haenszel, 1958)

(1975) (1966) (1956) (1983) (1953)

Migrant studies

Inconclusive

Japan

New Zealand

incidence in the Alpine regions and low in the Adriatic coastal plain. Wynder et al. (1963) and Howson et al. (1986) both report on other studies which suggested links with climatic conditions, latitude and altitude factors. Correa et al. (1982) suggest the existence of a northsouth gradient in gastric cancer, one which is particularly marked within the northern hemisphere. Studies from the USA (Haenszel, 1958; Kriebel and Jowett, 1979; and Baker, 1980), Japan (Japan Ministry of Health and Welfare, 1983 - cited in Howson et al., 1986), China (Armstrong, 1980; and Day, 1984) and Yugoslavia (Wynder et al., 1963) all mention latitude as a factor. A northsouth division for England and Wales has been noted by Chilvers and Adelstein (1978). Elsewhere in Europe, Howson et al. (1986) cite examples from Iceland, Italy and Spain, and there is also evidence from Belgium (Verhasselt, 1981). In the southern hemisphere correspondingly the more southern latitudes seem to have the higher levels of gastric cancer incidence. Data from Colombia, Brazil and South Africa conform with this pattern. In summary, it appears that the higher geographic latitudes are associated with an increased gastric cancer risk. However, Coggon and Acheson (1984) suggest the association with climate is a loose and faint one, being neither pronounced nor consistent. Moreover, the countries with the highest rates of mortality (Austria, Chile, Iceland and Japan) have a variety of climates and so have countries with low rates (Canada and the USA). If climate does have an effect on the occurrence of gastric cancer, with a high incidence in colder and more temperate regions, it is probably mediated through its effect on diet.

Hirayama (1971) Suggested link with air-pollution (urban) Kendrick (1980)

researchers to suggest that the 'natural' environment may be more important. Studies in the UK, identify the clusters of gastric cancer around the industrial conurbations of Tyneside, Merseyside, West Midlands and South Wales (Howe, 1970; and Gardner et al., 1983). In the southern hemisphere, gastric cancer in Australia appears to be predominantly urban (Learmonth and Grau, 1969), although Kendrick (1980) was unable to confirm the urban emphasis in New Zealand. Similarly, Bradshaw et al. (1983) found a non-urban pattern in South Africa, and Armijo and Coulson (1975) found death rates from gastric cancer to be highest in agricultural regions of Chile. From the USA the picture is less clear. Hoover et al. (1975) identified high incidence rates in the major cities, and in areas with low socio-economic group populations. Rural and "Mountain" states all experience high gastric cancer incidence rates in their rural counties. In Colombia, the highest rates were in the mountainous regions, rather than the highly populated coastal areas (Correa et al., 1970). Similarly, in Yugoslavia Wynder et al. (1963) observed the link with altitude, with high

One method for evaluating the relative importance of 'nature versus nurture' involves assessing how gastric cancer risk is different in populations migrating between areas of different risk. Since 1960 a number of epidemiological studies have utilized migrant population groups, usually concerning subjects who have moved from high to low risk countries (see Table 4). This permits the study of genetically similar groups under different environmental conditions. Note that when epidemiologists refer to the term 'environmental' they usually stress personal and occupational factors, such as diet, lifestyle and social class, in addition to the 'natural' environment factors. Any differences in rates of disease between migrants and those who remained at home should be interpreted cautiously, since migrants are usually self-selected. When the differences are marked, the importance of environmental factors in the development of the disease is suggested. This has been the case with gastric cancer. Haenszel (1958, 1961), noted that migrants to the USA from high risk countries continued to experience the risks characteristic of the population of origin. This suggests the relevance of early exposure to cultural or natural environmental initiators. Haenszel and Correa (1975) indicate in their Colombian study that the experience of the first decade of life determines the magnitude of the risk for gastric cancer at later years. Others are more conservative, and believe the crucial early

S. A. Matthews

205

Table 4 Gastric cancer in international migrant population groups.

Origin

Destination

Author(s) and date

China Europe

United States United States

Europe Europe

Israel Auslralia

Iceland Japan

Canada Hawaii/USA

Japan South America

Brazil United States

King and Haenszel Newill Haenszel Bjelke Tulchinsky and Modan Staszewski et al. McMichael et al. Choi et al. Quisenberry Buell and Dunn Haenszel and Kurihara Haenszel et al. Prudente and Mirra Kmet

Table 5 Gastric cancer: sub-national migrant studies. Country

Author(s) and date

Columbia Chile Czechoslovakia Israel

Correa et al. Armijo et al. Gregor et al. Munoz and Steinitz

(1970) (1981) (1969) (1971)

exposure time is longer extending upto perhaps the first 25-30 years of life. In second, and later, generation migrants the risk of gastric cancer appears to be more similar to that of the host country. This frequently reported finding from studies of migrants from high to low risk countries undermines the genetic argument and suggests the significance of diet related factors. Coggon and Acheson (1984, p.338) suggest that, 'although genetic susceptibility may have some effect on the geographical distribution of stomach cancer, the fact that its incidence is often much lower in migrant populations than in their countries of origin would imply that environmental factors exert a more important influence.' In addition, to those studies of international migrants, there have been a number of sub-national examinations (see Table 5). Broadly speaking the findings from these studies confirms those observed at the international scale. First generation migrants have significant differences in their risk of gastric cancer from the 'destination' residents. Over time, the differences are eroded and second and later generation gastric cancer rates reflect their adopted area rates.

Environment or Genetic ?

Although it is widely accepted that the pathology of gastric cancer involves a combination of interacting environment and endogenous factors, these have not yet been identified

(1973) (1961) (1961) (1974) (1967) (1971) (1980) (1971) (1955) (1965) (1968) (1972) (1961) (1970)

with any precision, and the geographic distribution of gastric cancer is still only partially explained. Above, reference was made to the fact that migrant studies have suggested the importance of environmental factors. Howe (1979, p.411) observed that, "geographical differences in the incidence of and mortality from gastric cancer which have been observed globally and nationally support the view that gastric cancer are environmentally induced'. Similar opinions are expressed by the authors of recent 'review' papers, for example Oshima and Fujimoto (1983). In theory, environmental factors (for example, diet, smoking, occupational 'hazards', etc) can be identified and neutralised. That is, gastric cancer is potentially preventable if the clues suggested by epidemiological research are used to inform medical practice, in this section, genetic factors are considered first. Genetic Ethnicity: Coggon (personal communication) suggests that

for gastric cancer genetic factors are important but they are not major determinants of its geography and time trend patterns. However, Ashley and Davies (1966) and Ashley (1969) argue that the high incidence of gastric cancer in Wales is 'a genetic trait rather than a consequence of local environmental factors'. They stress that the major difference in environmental conditions among the inhabitants of England and Wales lies between the urban and rural habitat, and that for gastric cancer there is only a small degree of variation between different types of urban and rural areas. Ashley and Davies, using county data, show that the distribution of gastric cancer in the Principality follows closely the distribution of the Welsh people (percent of Welsh speaking people aud percent of Welsh surnames), and is highest particularly in those parts of Wales in which the indigenous language and culture play a major role in daily life. Observations of relatively high gastric cancer rates in the north and north-west of England, in Northern Ireland, and in south-west Scotland suggest a link with the Celtic peoples, and/or their lifestyles. Evidence from the USA is inconclusive, with some ethnic groupings revealing marked differences between

206


their incidence rates, while for others their appears to be little distinction. For example, Segi et al. (1960) observed that gastric cancer is twice as common among the Negro population than among the Caucasians. Smith (1957) reports no difference between US Indians and whites in their experience of gastric cancer. Warwick and Phillips (1954) suggest this is also the case for the Canadian Indians and whites. NewiU (1961) found that mortality from gastric cancer in the over-45s in New York was highest among the Jews, slightly lower among the Protestants, and lowest among the Catholics. Haenszel (1958) looked at the standardised mortality ratios for foreign-born ethnic groups, finding that those migrants from Eastern Europe had the highest ratios, closely followed by the Scandinavians and the Austrians. Of those reported, the Italians had the lowest standardised mortality ratio. These studies of European based migrants could well be biased by duration factors (i.e. different migration streams occur in different temporal periods, for example, the Irish after the 1840s famine, the Italians around the turn of the century, and the Jews from the 1930s onwards). Timing and inter-generational effects need to be considered in more detail when the focus is on migrant groups. Blood group and familial studies: A number of genetic

factors have been shown to be related to gastric cancer. In the 1950s a series of papers by Aird and Bentan (1953), Woolfe (1954) and Roberts (1959) all noted the high incidence of gastric cancer among persons with blood group A, than among other ABO blood types. Similarly, blood group A is primarily associated with diffuse type gastric cancer (Correa et al., 1973), although Howson et al. (1986) report, that when associated with pernicious anemia, a disease with a known genetic component, blood group A tends to be more closely related to intestinal type gastric cancer (see also Berkson et al., 1956; and Bjelke, 1974). This lack of specificity suggests that the association between blood group A and gastric cancer is modified by intermediary factors. An important observation has been noted by Gardner (1984). Using evidence from England and Wales of a high incidence of blood group A patients in areas where the incidence of gastric cancer is low, he argues against the significance of genetic factors in the aetiology of gastric cancer. Following Howson et al. (1986) familial aggregation studies have shown that gastric cancer exhibits some degree of familial clustering, with first generation relatives (especially those cases with early age at onset) showing a higher risk than more distant relatives. This phenomenon is particularly evident in diffuse type gastric cancer. Gastric cancer risk diminishes progressively in first generation relatives of cases with later disease onset, followed by more distant relatives. Graham and Lilienfeld (1958) found evidence indicating that relatives of gastric cancer patients have approximately twice as much gastric cancer as relatives of control patients (see also Macklin, 1955). Such studies, according to Howson et al. (1986, p.11), suggest that 'genetic susceptibility plays an important etiological role in the relatively small proportion of individuals with diffuse type gastric cancer'. The mechanism for blood

group/familial relationships is not known. In spite of the above discussion, much of the recent literature on gastric cancer suggests the inability of any one genetic factor to account for a substantial portion of the inter-population variation.

Occupational Environment Social class, socio-economic group and occupation

In view of the pervasiveness of social class running through all aspects of life experiences, it is not surprising that a marked gradient by class in morbidity and mortality is the rule rather than the exception in epidemiological studies. A frequently observed feature of gastric cancer is the marked inverse socio- economic gradient in risk. Reporting on data upto 1950 from the USA, Denmark and England and Wales Haenszel (1958) reveals increasing gastric cancer incidence with decreasing socio-economic status. Doll (1956) estimated that mortality among the poor is upto three times greater than the wealthier classes. Similarly, Haenszel and Correa (1975) suggest that the risk for the lower classes are roughly two-and-a-half times those of higher socio-economic status. More recently, Howson et al. (1986) in their review suggest the ratio is approximately 2:1. In the UK, there is a marked social class gradient in gasu-ic cancer incidence. For men of working age (15-64) the standardised mortality ratio rises steadily from 50 for social class I to 147 in social class V (O.P.C.S., 1978). A study comparing Bath and CaerphiUy by Burr et al. (1987) found that severe atrophic gastritis was more common among manual compared with non-manual workers. The distribution of the lower social class is in many ways similar to that of the high standardised mortality ratios (Gardner et al., 1983), for example, in the North West, the North East and Wales, especially the north coast and the south of Wales. However, Chilvers and Adelstein (1978) suggest that the inter-regional differences in mortality rates appear to be independent of social class. These observations could be related to nutritional factors, since differences in diet (for example, the consumption of starchy foods tend to be highest among the lower socio-economic groups) and consumption patterns are exacerbated by income. A forthcoming study by Coggon in North Wales using archive data on housing conditions during the 1930s reports high correlations between domestic crowding and risk of future gastric cancer. The review by Howson et al. (1986) suggests that this negative association of gastric cancer and socio-economic status does not appear to be related to those occupations reported as having increased risk. On practical grounds, occupation alone is often used in epidemiological studies as a measure of overall socio- economic status. The conditions under which people work vary enormously. Thus it is not surprising that occupationally related experiences can exert a profound effect on health and contribute to large differences in morbidity and mortality. A whole range of exposures are important, including, unfavourable physical working conditions (extreme cold, heat, changed atmospheric pressures), pollution and chemicals, noise and occupation induced stress. Findings from coal mining, smelting, textiles

S. A. Matthews

207

Table 6 Occupations and gastric cancer. Occupation

Country

Coal

(United States)

(United Kingdom) Asbestos Iron smelting Fishermen

(Canada)

Oil refineries

(United States)

(Iceland)

(United Kingdom) Textiles Chemicals General

(Japan) (Wales)

Author and date

Matolo et al. (1972) Ames (1982, 1983) Weinberg et al. (1985) Craven et al. (1979) Davies (1980) Selikoff et al. (1964) Kraus et al. (1957) Dungal (1961) Haenszel and Correa (1975) Hanis et al. (1979) Thomas et al. (1982) Rushton and Alderson (1981) Bross et al. (1978) Viadana et al. (1976) Hirayama (1971) Craven et al. (1979)

and chemicals have confirmed the high incidence of gastric cancer in manual low skilled workers (see Table 6), although they have not been successful in implicating any occupationally specific carcinogens. Coggon and Acheson (1984) point to the uniformity of the ratio of male-to-female incidence between and within countries and suggest that occupational factors do not play a major role in determining the geographical distribution of gastric cancer, certainly not as they and others argue, as strong as the factor of diet. Diet and personal behaviour Diet: Geographical variation, time trend and migrant

studies of gastric cancer all highlight the importance of dietary factors. It is reasonable to assume that dietary factors are aetiologically associated with gastric cancer because gastric mucosa is directly exposed to ingested foods. A number of dietary components seem to be implicated in the pathogenesis of gastric cancer. Tables 7a and 7b. summarise of the results of some international case control studies. Diet has been the focus of much research, partly because of large ethnic differences in rates of gastric cancer and because of substantial variations in styles of eating. However, validation of results has proved difficult. Early studies rarely compared the dietary habits of patients with gastric cancer to a given control group. Their data, in the main, came from descriptions of general dietary pattems of groups with varying incidence of gastric cancer. Correlations between some foods and gastric cancer risk have been reported, but no food can be identified that is common to all high risk populations. According to Coggon and Acheson (1984) conclusive identification of dietary factors is problematic. This is mainly because the aspects of diet which determine the geographical differences in gastric cancer frequency probably vary little within most communities, and their effects are therefore not apparent in ease-control studies. Moreover, cross-country comparisons are unable to disentangle the effects of individual foods

because their consumption is correlated one with another. Haenszel and Correa (1975) outlined three diet effects: (1) presence of a carcinogen or carcinogens in foods; (2) introduction of carcinogens during food preparation; and (3) absence of protective factors in some foods. Present knowledge about intestinal type gastric cancer suggests that it is a disease initiated early in life, most likely by the interaction between a carcinogen derived from a nitrate/nitrite rich diet and gastric mucosa damaged by a diet rich in salt and carbohydrate. Evidence from case-control studies also suggests that recent diet is important. The problem for research in this field is thus to try to capture accurate dietary information from both childhood days (up to 50 years before registration) and from the most recent time period. The marked decline in gastric cancer mortality in the USA, and in other countries, was preceded by major changes in dietary habits. Haenszel (1958) refers to increased consumption of fruit, particularly citrus, and soft drinks containing vitamin C, and a move away from bread, potatoes and cabbage, to beef, milk and green vegetables. Indeed, the most common finding of all dietary- studies, be they cohort studies, ease-control studies or intra- country comparisons, appears to be the protection provided by the consumption of fruit and vegetables. If high vegetable intake does indeed reduce gastric cancer risk, it does so despite the fact that most vegetables contribute greatly to the dietary nitrate load (Mirvish, 1983). According to Howson et al. (1986) the observed 'protective effect of a high vegetable intake may be due either to a protective dietary pattern associated with a high vegetable intake o r to the presence of vegetable-associated 'anti-carcinogens' such as vitamins A and C and the cruciferous-associated antioxidants' (see Michioka, 1985). E x p e r i m e n t a l l y vitamins A, C and E have demonstrated the capacity to inhibit chemical processes believed to be associated with gastric cancer. However, findings from human studies are inconsistent. A modest association with fruit intake is evident from inter-country

208


Table 7a Dietary f a c t o r s and gastric cancer.

Table 7b Dietary factors and gastric cancer.

Higher-risk

Lower-risk

Author(s) and date

Vitamin C

Wynder et al. Dungal and Sigurjonsson

Salted foods

Salted fish Smoked fish Fish

Singed meat Fried foods Dried foods Pickled vegetables Cabbage Potatoes Carbohydrates

Cooked cereals Rice Hot foods Hot drinks

Author(s) and date

Hirayama and Yusa (1963) Dungal and Sigurjonsson (1967) MacDonald et al. (1967) Haenszel et al. (1972) Kurita (1974) Joossens et al. (1979) Hirayama (1984) Haenszel (1958) Bjelke (1974) Haenszel (1958) Dungal and Sigurjonsson (1967) Sato et al. (1959) Hirayama (1971) Alderson (1981 ) Meinsma (1964) Dungal and Sigurjonsson (1967) Haenszel (1958) Higginson (1966) Haenszel et al. (1972) MacDonald et al. (1967) Haenszel et al. (1972) Haenszel (1958) Eiseman et al. (1967) Wynder et al. (1963) Graham et al. (1967, 1972) Wynder et al. (1963) Modan et al. (1974) Correa et al. (1983) Hakama and Saxen (1967) Bjelke (1974) Segi and Kurihara (1960) Kurita (1974) Kurita (1974) Seely (1978)

comparisons, but for vitamins A, C and E intake the association is Ix)or (being strongest for vitamin A). This either reflects difficulties in data collection (i.e. ascertaining an accurate vitamin intake) or suggests that another correlate of fruit and vegetable consumption is the protective agent. Similarly, it may be that it is not quantity that it is important, but rather the regularity of consumption9 More work needs to be done on this. Seely (1978) looking at the time-trend in decline of gastric cancer suggests that the role of vitamins has been overestimated. He suggests that the anti-scorbutic effect of oranges and lemons was known more than a century ago and cod liver oil was popularised at the beginning of this century. Moreover, the impact of vitamins on diet was more sudden and widespread than the recession of gastric cancer. If the two events were related, the decline in both the USA and Europe should have been sooner. Evidence for milk is inconclusive, with some authors indicating that it could have a protective effect (Hirayama, 1984). This link with milk may illustrate the role of vitamin

Fruit

Citrus fruits

Vegetables

Salads Milk

Soft drinks Proteins

(1963) (1967) Burr et al. (1987) Bjelke (1974) Correa et al. (1983) Correa et al. (1985) Haenszel (1958) Meinsma (1964) Stahelin et al. (1984) Segi and Kurihara (1960) Wynder et al. (1963) Graham et al. (1967, 1972) Haenszel et al. (1972) Bjelke (1974) Stocks (1974) Armstrong (1980) Correa et al. (1983) Weisburger et al. (1983) Trichopolous et al. (1985) Hu et al. (1988) Weisburger et al. (1983) Hirayama and Yusa (1963) Stocks (1974) Hirayama (1984) Seely (1978) Wynder et al. (1963)

A. However, it is suggested that a protective mechanism, such as coating of the gastric mucosa, may be significant. From animal experiments, the evidence suggests that a high salt intake may enhance gastric cancer. A high salt intake can damage stomach mucosa, thereby rendering it more susceptible to the effects of a gastric carcinogen. For example, MacDonald et al. (1967) found that the consumption of pickled foods in highly- salted sauces lead to significant changes in gastric mucosa. When salt is studied separately, little association with gastric cancer is observed. Thus, salt may be a co-initiator. The association of salt with gastric cancer is highlighted when salt intake from salted-foods is considered, for example, fish. Salt dried fish prepared without being gutted has been found to contain nitrosomines. The countries with a high incidence of gastric cancer are well known for their high consumption of fish. This may be a factor, as may be the preparation by cooking in superheated fats and oils. In Kansas a mild correlation with fried foods was found and a similar correlation was also noted in Wales (Higginson, 1963). In Iceland, Dungal and Sigurjonsson (1967), greater quantities of singed food had been consumed in the areas of highest mortaliw_y rates. The same study noted both the lack of vitamin C and the regular consumption of salted foods in the diets of those residents in the high mortality areas. In a Japanese study, Segi et al. (1960) found that patients with gastric cancer consumed more rice than did conlrols. Nevertheless, they argued that rice could not be a

S. A. Matthews

key factor contributing to the incidence of gastric cancer because this disease is not frequent among the other nations of South-east Asia, where rice is the staple diet for a quarter of mankind. Similarly, gastric cancer risk is high in some countries, like Iceland, where little rice is consumed. It would seem, therefore, that rice as such can be eliminated as a possible factor in the development of gastric cancer. The inverse association between gastric cancer risk and socio-economic status led to the hypothesis that high carbohydrate intake at an early age predisposes to increased gastric cancer risk (Howson et al., 1986). Research has shown a positive, but inconsistent, relationship between the consumption of starch-like foods and gastric cancer mortality. Seely (1978) discussed the possible carcinogenic effects of hot food and drink. This area is little researched and remains outside mainstream thought. However, the arguments and findings are worthy of note. Seely (1978) suggests that the agent responsible for the high mortality in Japan may be tea. His arguments are based not on carcinogenic chemicals which might be found in the tea, but rather the association with the consumption of excessively hot water. In Britain more tea is consumed per capita, but its temperature is much reduced by the addition of milk. Moreover, ceremonial tea drinking in Japan involves drinking excessively large gulps, while as Seely argues, social tea drinking in Britain is consumed in sips. Seely goes on to suggest that the consumption of hot foods may also be important. Hot beverages are more likely to be harmful than hot solid foods, because they deliver most of their heat content to the stomach, while foods lose heat in the mouth during mastication. Another factor mentioned in the literature relates to the eating patterns. Segi et al. (1957) found in a Japanese study that gastric cancer was more prevalent among people who ate their food faster or had irregular meals. Again more research is needed to clarify and validate these findings. On a related issue, better m e t h o d s of food preservation, such as rapid freezing, may prevent molds from contaminating fc~xtstuffs to the extent that smoking and salting were unable to do formerly (Nobrega et al., 1983). A number of authors highlight the importance of refrigeration (Graham, 1975; Seely, 1978; Coggon and Acheson, 1984; Howson et al., 1986). From Iceland evidence suggests that the decline in gastric cancer was indeed related to decreasing use of food smoking techniques (Dungal and Sigurjonsson (1967). Moreover, the fall in incidence which has occurred in the USA suggests that modern food additives, preservation and processing have a beneficial effect on cancer of the stomach. In summary, collective evidence is generally interpreted as indicating that salted and starchy foods increase the risk of gastric cancer, whereas fresh fruits and vegetables reduce it. Howson et al. (1986), and many others, believe that the dietary factors offer the best explanation for the observed geographic, temporal and individual differences in gastric cancer risk. Bracken: The focus of recent interest in bracken as a health

hazard to man is emphasized by the fact that Japan, a huge consumer of bracken, has the highest incidence of gastric

209

cancer. Galpin and Smith (1986) review the literature on the effects of bracken in animals which shows bracken to be unequivocally carcinogenic (see Taylor, 1988). Studies on human populations are rare, although Hirayama (1979) showed that oesophageal cancer was three-times higher among those who consume bracken daily, compared with those who don't eat it. A useful review paper by Fenwick (1988) drawing on evidence from Japan, Brazil, New Zealand, France and North America discusses the sources of bracken carcinogens in the human diet. Although health in the UK is not threatened by the consumption of bracken fronds, the finding by Evans (1986) that bracken spores are carcinogenic is important and requires further research. In a study of the influence of natural environmental factors on the pattern of mortality from gastric cancer in North Wales, no positive correlation was obtained between such deaths and the extent of bracken infestation in water (Galpin and Smith, 1986). The authors point out that individual springs and wells serving isolated upland settlements might pose a risk as a result of the leaching of carcinogenic principles from the bracken, and that more knowledge is required about the effects of soil and other environmental factors on the leached carcinogens before any firm conclusions can be reported. According to Galpin and Smith (1986), and Fenwick (1988) a more probable risk is associated with a milk pathway. Exposure could occur in humans consuming contaminated milk and other dairy products, the risk being greatest when bulk dairy processing is not employed. Evidence from Latin America suggests a high correlation between the consumption of milk potentially contaminated with bracken carcinogens and gastric cancer (VillalobosSalazar, 1985). In this study incidence rates in humans were three-fold greater in areas of high bracken cover, compared with bracken-free zones. Smoking: Hirayama (1975, 1981) reports on the influence

of cigarette smoking. He notes that the influence of age at start of smoking is more striking than daily amount of smoking in the case of gastric cancer. In addition, smoking (reflecting earlier age at start of smoking and quantity smoked per day) is thought to be of particular significance in explaining the reason for the consistent preponderance of males in the number of registered gastric cancer cases. However, neither the inter-country variation nor the observed decline in gastric cancer incidence appears to be explained by the smoking factor. Parente et al. (1985) observed that cigarette smokers tended to have a high serum PG I levels. Other factors, primarily dietary, appear to be far more important in explaining both geographical variation and declining incidence. Similarly, little is known about different smoking habits (for example, smoking before meals, smoking cigars or cigarettes, etc.) and links between smoking and drinking. The natural environment Soil and geology: Much of the work in the field of soil

analysis connected with gastric cancer has been carried out in the UK. Studies have associated soil composition with gastric cancer risk, although the nature of the relationship varied from place to place. Most of the findings were based

210


on a search for coincidences in maps of geological formation and soil contents and maps of gaslric cancer risk. Soils with a high content of peat and other organic matter were incriminated in England and Wales, peat and clay soils in the Netherlands, and poorly drained alluvial and acidic soils in Japan. In 1951 and 1952 Legon, comparing gastric cancer mortality in different rural areas of Wales, concluded that there was an association of high mortality from gastric cancer and residence on peaty soils (high content of organic matter). He suggested that a deficiency of copper in such soils would be reflected in crops grown on them and in people who ate them, and that copper deficiency might predispose to gastric cancer. Later a study of Anglesey by Davies and Griffith (1964) found a positive association between gastric cancer rates and residence on soils with great biological activity in a long season. Soil acidity was noted to be closely related to the incidence of gastric cancel.

Stocks (1957) found mortality from gastric cancer to be high where igneous rock is near the surface and low in chalk and limestone areas. Geochemical studies also attempted to correlate the distribution of trace elements with gastric cancer. No statistical association with cancer was found for titanium, vanadium, lead or iron, and a negative association was found for nickel. However, correlations were found between mortality from gastric cancer and the amounts of organic matter, zinc, chromium, and cobalt in the soil, and between deaths from intestinal cancer and soil chromium (Stocks and Davies, 1960 and 1964). The association between deaths from gastric cancer and residence on particular types of soil was limited to persons following non- agricultural occupations, and a history of eating green vegetables grown on suspect soil was not associated with an especially high mortality from gastric cancer. They noted that soil rich in zinc or cobalt is found with excessive frequency where a case of gastric cancer has occurred but the geographical distribution of such soils appears to be unrelated to that of stomach cancer rateS.

Stocks and Davies (1964) found that the zinc/copper ratio in the soil was consistently higher in gardens at houses where persons had died of gastric cancer after a period of ten or more years' residence than it was among the control group. They found also that the zinc content, in potatoes correlated well with that in the soil in which the potatoes were grown. There is a big gap between the suggestion that the zinc/copper ratio in soils plays some part in determining the incidence of gastric cancer and any known carcinogenic mechanism in which this ratio is likely to be important. However, the influence of the content of trace metals such as zinc, should be studied further. The soil-vegetation-food relationship provides the main impetus for research into gastric cancer. However, the importance which might be attached to micronutrient deficiencies or to carcinogenic contaminants of vegetable foods in North Wales (Stocks, 1959; Davies and Griffiths, 1964; and Legon, 1952) has been doubted on the grounds that, with the exception of potatoes, eighty percent of vegetables are brought into North Wales (Howe, 1959; see also comments above relating to the findings of Stocks and

Davies, 1964). Results of studies relating trace elements to gastric cancer are doubted for three very good reasons. Firstly, the proportion of people who actually consume their own grown produce, or even local grown produce, is relatively small. Secondly, those that do, alter their gardens by adding fertilizers and other chemicals, so altering substantially the composition of the soil relative to the wider area norms. Lastly, dietary studies have repeatedly shown vegetables to be protective. A weakness of the hypothesized links with soil trace elements is the question of pathways. Tromp (1956) in reviewing the possible effects of geophysical and geochemical factors, discusses the possible process by which soil could affect the development of gastric cancer. Among direct physical influences, Tromp cited the earth's magnetic field, electric c o n d u c t i v i t y of the soil, radioactivity of the soil and the air above the soil. The indirect influences could be of a chemical nature, such as the influence of trace elements and other chemical compounds found in the soil because of drinking water, food grown in the soil, animal products, fertilizers, weed killers, insecticides, or atmosphere. Some may be of a biological nature. For example, the influence of soil on the development of parasitic worms, insects, micro-organisms and viruses and the influence of the type of vegetation, depending partly on the type of food consumed in the area. Finally, soil could be important, in terms of moisture content and its effect on the geological history of the area. The truth of the matter is no-one knows the pathway of causation. W a t e r and nitrates: Local geological conditions or

variations in the nature of the water supply have been considered repeatedly. Much research has been devoted to the possibility that nitrates in drinking water are transformed into nitrites in the body, perhaps with carcinogenic effects. Millar (1961), in North Wales, found no correlation between uranium dioxide content in drinking water and gastric cancer mortality. While, Coggon and Acheson (1984) cite work by Haenszel et al. (1976) which found a relationship between gastric cancer and the prolonged use of well water in Japan (see also Haenszel and Correa 1975). A l l e n - P r i c e ' s (1960) study of Horrabridge, Devon linked gastric cancer mortality rates to the origin of different water supplies; lowest mortality rates were associated with reservoir water from Dartmoor whereas highest mortality was associated with well or spring water derived from mineralised rock strata. The incidence of gastric cancer is thought to be high where the water is soft, as in parts of Britain and The Netherlands (Tromp and Diehl, 1955). An positive relationship with water hardness has been postulated by Boyd, Layman and Doll (1964), but this has not been confirmed with any certainty in other studies. A Danish study revealed a higher incidence of gastric cancer in a city with a higher concentration of nitrate in its water (Jensen, 1982), while a study from France (Vincent et al., 1983) showed no relation between cancer and nitrates in drinking water. In a British study, Beresford (1981) was able to dismiss the suggestion that recycled water in the South East had been responsible for the high gastric cancer

S. A. Matthews

rates observed in London. A major new impetus in geochemical studies originated from the discovery of the carcinogenic properties of nitrates. Studies of nitrates are attractive since they offer plausible pathways for the production of carcinogenic effects. From Chile, studies have revealed high correlations between gastric cancer and cumulative exposure to nitrate fertilizers (see Armijo et al., 1975; and Zaldivar and Robinson, 1973). Similarly, in Colombia, (Correa et al., 1975 and Hawksworth et al., 1974) a positive correlation has been established between nitrates in food and drinking water and gastric cancer. Difficulties with these theories are soon encountered. The main items of dietary nitrates are vegetables, which are themselves reported to be protective against gastric cancer (see MacLennan, DaCosta and Day, 1977; and others). Moreover, the fact that these are usually refrigerated and consumed raw would minimise their content of bacterially produced nitrite (Weisberger and Raineri 1975). In addition, the presence of vitamin C could act as a protective factor by limiting vivo nitrosation (Weisberger, 1985). Thus Gardner (1984), citing Frazer, reports that the evidence from epidemiological studies that nitrate is involved in the aetiology of gastric cancer is very weak. Summary This paper has attempted to synthesize the epidemiological literature and identify the salient factors associated with gastric cancer. Epidemiological knowledge largely based on observation studies suggests that of the many postulated risk factors studies of diet offer the greatest potential for e p i d e m i o l o g i c a l investigation of the disease. Unfortunately, disentangling the different food-stuffs has proven problematic. The most general findings suggest an increased risk of gastric cancer resultant from salted and starchy foods and a reduced risk from fruit and vegetable produce. In recent years, bracken has entered the frey as a possible contributing factor in gastric cancer incidence but the pathways need clarification. Natural environmental factors have also been the focus of much attention, with soil type and chemistry predominating in the literature. Intra-country studies also have suggested the relevance of altitude, temperature and latitude, together with geology, water and nitrate levels. The recent literature suggests that genetic or endogenous factors are not a major determinant of the distribution of gastric cancer. However, social class and socio-economic groupings do appear to be important.

Acknowledgements This "epidemiological review" originated in the author's involvement with a research project investigating hypothesised links between trace elements in soils and gastric cancer in the study area of Wales. This project was funded by the Welsh Office and was coordinated by Professor B.E. Davies (Environmental Sciences, Bradford) and Professor N. Wrigley and Dr CJ. Webster (both Town Planning, UWCC). David Coggon (Medical Research Council, Environmental Epidemiological Unit, Southampton General Hospital) provided useful pointers

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on the general findings from the epidemiological literature and commented on an earlier draft of this paper. Library staff at both the University of Wales College of Medicine (Heath Hospital, Cardiff) and the Aberconway and Science Libraries of UWCC were very helpful and assisted in the search for books, articles and reviews. Dr Michael Burr (MRC, Epidemiological Unit, Cardiff) supplied articles on atrophic gastritis and vitamin C, and Professor J. Taylor (Aberystwyth) and Dr I. Fenwick (A.F.R.C. InsL of Food Research, Norwich) provided articles on bracken carcinogenicity. Finally, thanks are due to Professor Brian Davies (Bradford) for his encouragement to publish. Needless to say the views and comments in this paper are those of the author alone.

References Aird, I and Bentall, H.H. 1953. Relationship between stomach cancer and ABO blood groups. British Medical J., 1,799-801. Alderson, M. 1981. International Mortality Statistics. Macmillan, London. Allen-Price, ED. 1960. Uneven distribution of cancer in West Devon, with particular reference to the divers water supplies. The Lancet, i, 12358. Ames, R.G. 1982. Gastric cancer in coal miners: some hypotheses for investigation. J. Soc. Occupational Medicine, 32, 73-81. Ames, R.G. 1983. Gastric cancer and coal mine dust exposure. Cancer, 52, 1346-50. Antonioli, D.A. and Goldman, H. 1982. Changes in the location and type of gastric adenocarcinoma. Cancer, 50, 775-781. Armijo, R., Orellana, M., Medina, E., Coulsou, A.H., Sayre, J.W. and Detels, R. 1981 a,b. Epidemiology of gastric cancer in Chile: 1. Case-control study; Epidemiology of gastric cancer in Chile: 2. Nitrate exposures and stomach cancer frequency, lntl J. Epidemiology, 10, 53-56 and 10, 57-62. Armijo, R. and Coulsou, A.H. 1975. Epidemiology of stomach cancer in Chile - the role of nitrogen fertilizers. Intl J. Epidemiology, 4, 301-309. Armstrong, B. 1980. The epidemiology of cancer in the People's Republic of China. Intl J. Epidemiology, 9, 305-315. Ashley, DJ.B. 1969. Gastric cancer in Wales. J. Medicine and Genetics, 6, 76-79. Ashley, D.J.B. and Davies, H.D. 1966. Gastric cancer in Wales. Gut, 7, 542-548. Baker, S.R. 1980. Pitfalls in evaluation of cancer data for geographic analysis. In: Melinda S. Meade (ed., Conceptual and Methodological Issues in Medical Geography, pp.155-169. University of North Carolina at Chapel Hill: Dept. of Geography Studies No.15 Beresford, S.A.A. 1981. Is nitrate in the drinking water associated with the risk of cancer in the urban United Kingdom? lntl J. Epidemiology 14, 57-63. Berkson, J., Comfort, M.W. and Buu, H.R. 1954. Occurrence of gastric cancer in persons with achlorhydria and with pernicious anaemia. Mayo Clinical Proceedings, 31, 583-596. Bjelke, E. 1974. Epidemiological studies of cancer of the stomach, colon and rectum, with special emphasis on the role of diet. Scandinavian J. Gastroenterology 9, supp 31, 1-253. Boyd, J., Langman, M. and Doll, R. 1964. The epidemiology of gastrointestinal cancer with special reference to causation. Gut, 5, 1%-200. 'Bradshaw, E., ttarringtou, J.S. and McGlashan, N.D. 1983. Geographical distribution of lung and stomach cancers in South Africa, 1968-1972. South African Medical J., 64, 655-663. Bross, I.D., Viadana, E. and Hooten, L. 1978. Occupational cancer in men exposed to dust and other e~avironmental hazards. Architecture Environmental and Health. 33, 300-307. Buell, P. and Donn, J.E. 1965. Cancer mortality among Japanese Issei and Nisei of California. Cancer, 18, 656-664. Burr, M.L., Samloff, I.M., Bates, CJ. and Holliday, R.M. 1987. Atrophic gastritis and vitamin C status in two towns with

212


different stomach cancer death rates. British J. Cancer, 56, 163167. Chilvers, C. and Adelstein, A. 1978. Cancer mortality: the regional pattern. Population Trends, 12, 4-9. Choi, N.W., Entwisde, D.W.,Mickaluk, W. and Nelson, N. 1970. Gastric cancer in Icelanders in Manitoba. Israel J. Medical Science, 7, 1500-1508. Clemmesen, J. 1977. Gastric carcinoma decreasing in incidence? Acta Pathologica et Microbiologica Scandinavica, supp 261, 65-75. Clemmeson, J. and Nielsen, A. 1957. Comparison of age-adjusted cancer incidence rates in Denmark and United States. J. National Cancer Institute, 19, 989-998. Coggon, D. and Acheson, E.D. 1984. The geography of cancer of the stomach. British Medical Bulletin, 40(4), 335-341. Correa, P. 1970. Geographic pathology of cancer in Colombia. lntl Pathology, 11, 16-22 (cited in Howson et al., 1986). Correa, P. 1982. Precursors of gastric and esophageal cancer. Cancer, $0, 2554-65. Correa, P., Cuello, C. and Duque, E. 1970. Carcinoma and intestinal metaplasia of the stomach in Colombian migrants. J. National Cancer Inst., 44, 297-306. Correa, P., Ctmllo, C., Fajardo, LF., Haenszel, W., Colanos, O. and De Ramirez, B. 1983. Diet and gastric cancer: nutrition survey in a high risk area. J. National Cancer Inst., 70, 673. Correa, P., Coello, C., Gordillo, L.F., et al. 1975. The gastric miesoenviromnent in populations at high risk to stomach cancer. National Cancer Inst. Monograph, 53, 167-170. Correa, P., Fontham, E., Pickle, L.W., Chen, V., Lin, Y.P. and Haenszel, W. 1985. Dietary determinants of gastric cancer in South Louisianian inhabitants. J. National Cancer Inst., 75, 645. Correa, P., Haenszel, W. and Tarmenbaum, S. 1982. Epidemiology of gastric cancer: review and future prospects. National Cancer Inst. Monograph, 62, 129-134. Correa, P., Sasano, N., Stemmermann, G.N. and Haenszel, W. 1973. Pathology of gastric carcinoma in Japanese populations: comparisons between Miyagi prefecture, Japan and Hawaii. J. National Cancer Inst., 51, 1449-59. Craven, J.L, Baom, M. and West, R.R. 1979. Variations in gastric cancer mortality in South Wales. Clinical Oncology, 5, 341-51. Cuello, C., Correa, P. and Haenszel, W. 1976. Gastric cancer in Colombia I: cancer risk and suspect environmental agents. J. National Cancer Inst., 57, 1015-1020. Davies, R.I. and Griffith, G.W. 1954. Cancer and soils in the county of Anglesey. British J. Cancer, 8, 56-66. Davies, J.M. 1980. Stomach cancer mortality in Worksop and other Nottinghamshire mining towns. British J. Cancer, 28, 562-567. Davies, LM. and Chilvers, C. 1980. The study of mortality variations in small administrative areas of England and Wales, with special reference to cancer. J. Epidemiology and Community Health, 34, 87-92. Day, D. 1981. Histopathology of gastric cancer. In: Fielding, J., Newman, C., Ford, C. and Jones, B. (eds.), Gastric Cancer pp.95- 110. Pergamon Press, Oxford. Day, N.E. 1984. The geographic pathology of cancers of the oesophagus. British Medical Bulletin, 40, 329-334. Devesa, S.S. and Silverman, D.T. 1978. Cancer incidence and mortality trends in the United States: 1935-74. J. National Cancer Inst., 60, 545-571. Doll, R. 1956. Environmental factors in aetiology of cancer of the stomach. Gastroenterologia, 86, 320-328. Doll, R. 1967. Worldwide distribution of gastrointestinal cancer. National Cancer Inst. Monograph, 25, 173-190. Dungal, N. 1961. Special problems of stomach cancer in Iceland: with partioxlar reference to dietary factors. J. Am. Medical Assoc., 178, 789-798. Dungal, N. and Sigurjonsson, J. 1967. Gastric cancer and diet. British J. Cancer, 21, 270-6. Evans, I.A. 1986. The carcinogenic, mutagenic and teratogenic toxicity of bracken. In: Smith, R.T. and Taylor, A. (eds.), Bracken, Ecology, Land Use and Control Technology, pp. 139-146. Parthenon Publishing Group, Camfoab. Fenwick, G.R. 1988. Bracken Pteridium aqnilinum - toxic effects and toxic constituents. J. Sci. Food Agriculture, 46, 147-173. Galpin, O.P. and Smith, R.M.M. 1986. Bracken, stomach cancer and water supplies: is there a link ? In: Smith, R.T. and Taylor, J.

A. (eds.), Bracken, Ecology, Land Use and Control Technology, pp.147-159. Parthenon Publishing Group, Camforth. Gardner, MJ. 1973. Using the environment to explain and predict mortality. J. Royal Statistical Soc., Series A, 136(3), 421-440. Gardner, MJ. 1984. Mapping cancer mortality in England and Wales. British Medical Bull., 40 4, 320-328. Gardner, MJ., Winter, P.D., Taylor, C.P. and Acheson, E.D. 1983. Atlas of Cancer Mortality in England and Wales 1968-1978. John Wiley & Sons, Chichester. Gillis, C.R. 1977. Malignant neoplasms. In: Howe, G.M. (ed.), A World Geography of Human Disease, pp.507-534. Grabiee, J. and Owen, D.A. 1985. Carcinoma of the stomach in young persons. Cancer, 56, 388-396. Graham, S. and Lilienfeld, 1958. Genetic studies of gastric cancer in humans: appraisal. Cancer, 11, 954-958. Graham, S., Lilenfeld, A.M. and Tidings, J.E. 1967. Dietary and purgation factors in the epidemiology of gastric cancer. Cancer, 20, 2224-2234. Graham, S., Scbotz, W. and Maaino, P. 1972. Alimentary factors in the epidemiology of gastric cancer. Cancer, 30, 927-938. Gregor, O., Toman, R., Prusova, F., Dmkova, V., Pastorova, J. 1969. Geographical distribution of stomach cancer in Czechoslavakia. Gut, 10, 150-154. Griffiths, W. and Davies, R.I. 1954. Cancer and soils in the county of Anglesey: a revised method of comparison. British J. Cancer, 8, 594-598. Griffith, G.W. 1968. The sex ratio in gastric cancer and hypothetical considerations relative to aetiology. British J. Cancer, 22, 163-172. Haenszel, W. 1958. Variations in the incidence of and mortality from stomach cancer, with particular reference to United States. J. National Cancer Inst., 21, 213-262. Haenszel, W. 1961. Cancer mortality among foreign-born in United States. J. National Cancer Inst., 26, 37-132. Haenszel, W., Kurihara, M., Segi, M. and Lee, R.K.C. 1972. Stomach cancer among Japanese in Hawaii. J. National Cancer Inst.. 49, 969-988. Haenszel, W., Kurihara, M., Locke, F.B., Shimuzu, K and Segi, M. 1976. Stomach cancer in Japan. J. National Cancer Inst., 56, 265- 274. Haenszel, W. and Correa, P. 1975. Developments in the epidemiology of stomach cancer over the past decade. Cancer Res., 35, 3452-3459. Haenszel, W. and Kurihara, M. 1968. Studies of Japanese migrants: 1. mortality from cancer and other diseases among Japanese in the United States. J. National Cancer Inst., 40, 43-68. Hakama, M. and Saxen, E.A. 1967. Cereal consumption and gastric cancer. Intl J. Cancer, 2, 265-268. Hanai, A., Fujimoto, I. and Taniguchi, H. 1982. Trends of stomach cancer incidence and histological types in Osaka. In: Magnus, K. ed.), Trends in Cancer Incidence: Causes and Practical Implications, pp. 143-154. Hemisphere Publishing Corporation, New York. Hanis, N.M., Stavraky, K.M. and Fowler, LL 1979. Cancer mortality in oil refinery workers. J. Occupational Medicine, 21, 167-174. Hawksworth, G., Hill, J., Gordillo, G. and Cuello, C. 1974. Possible relationships between nitrates, nitrosamines and gastric cancer in south-west Colombia. In: Bogovski, P., Walker, E.A. and Davies, W. (eds.), N-Nitroso Compounds in the Environment. International Agency for Research on Cancer No.9, pp.229-234. International Agency for Research on Cancer, Lyon. Higginson, J. 1966. Etiologic factors in gastro-intestinal cancer in man. J. National Cancer Inst., 37, 527-545. Hirayama, T. 1971. Epidemiology of stomach cancer. Gann Monograph, 11, 3-19. Hirayama, T. 1975. Epidemiology of cancer of the stomach with special reference to its recent decrease in Japan. Cancer Res., 35, 3460-3463. Hirayama. T. 1979. Diet and cancer, Nutrition and Cancer, 1(3), 67-81. Hirayama, T. 1981. A large scale cohort study on the relationship between diet and selected cancers of the digestive organs. In: Bruce, R.W., Correa, P. and Lipkin, M. (eds.), Gastrointestinal Cancer: Endogenous Factors, pp.409-429. Cold Spring Harbor Laboratory, New York. Hirayama, T. 1984. Epidemiology of stomach cancer in Japan: with

S. A. M a l t h e w s

special reference to the strategy for primary prevention. Japanese J. Clinical Oncology, 14, 159-168 (cited in HOWSON et al., 1986). Hirayama, T. and Yusa, Y. 1963. The epidemiology of cancer of the stomach in Japan, with special reference to the role of diet (cited in A. Oshima and I. Fnjimoto, 1983) Hoover, R., Mason, T.J., McKay, F.W. and Fraumeni, J.F. I975. Cancer by county: new resource for etiological clues. Science, 189, 1005-1007. Howe, G.M. 1959. Geographical distribution of disease with special reference to cancer of the lung and stomach in Wales. British J, Prev. and Soc. Medicine, 13, 204-210. Howe, G.M. 1970. National Atlas of Disease Mortality in the United Kingdom Nelson, London. Howe, G.M. 1972. Man, Environment and Disease in Britain. David and Charles, Newton Abbot. Howson, C.P., Hiyama, T. and Wynder, E.L. 1986. The decline in gastric cancer: epidemiology of an unplanned triumph. EpidemiologicalRev&ws 8, 1-27. Hu, J., Zhang, S., Jia, E., Wang, Q., Liu, S. Liu, Y. Wu, Y and Cheng, Y. 1988. Diet and cancer of the stomach: a case control study in China. Intl J. Cancer, 41, 331-335. Japan Ministry of Health and Welfare. 1983. Age-adjusted Mortality Rates of Selected Causes of Death. (cited by llowson etal., 1986). Jensen, O.M. 1982. Nitrate in drinking water and cancer in northern Jutland, Denmark, with special reference to stomach cancer. Ecotoxicol. Environ. Safety, 6, 258-267. Joossens, J.V., Kesteloot, H. and Amery, A. 1967. Salt intake and mortality from stroke. New England J. Medicine, 300, 1396. Kawashima, S. 1966. Early gastric cancer in Japan. Scandinavian J. Gastroenterology, 1, 248-253. Kendrick, B.L. 1980. A spatial, environmental and socio-economic appraisal of cancer in New Zealand. Social Sc&nce and Medicine, 14D, 205-214. King, tt. and Haenszel, W. 1973. Cancer mortality among foreignborn and native-born Chinese in the United States. J. Chronic Disease, 26, 623-646. King, P.E. 1979. Problems of spatial analysis in geographical epidemiology. Social Science and Medicine, 13D, 249-252. Kmet, J. 1970. The role of migrant populations in studies of selected cancer sites: a review. J. Chronic Disease, 23, 305-324. Karos, A., Levin, M. and Gerhardt, P.A. 1957. A study of occupational associations with gastric cancer. American J. Public Health, 47, 961-970. Kriebel, D. and Jowett, D. 1979. Stomach cancer mortaJity in the north central states: high risk is not limited to the foreign- born. Nutrition and Cancer, 1, 8-12. Lauren, P. 1965. The two histological main types of gastric cancer: diffuse and so-called intestinal type carcinoma: an attempt at a histol-clinical classification. Acta Pathologica et Microbiologicia Scandinavica, 64, 31-49. Learmonth, A.T.A. 1978. Patterns of Disease and tlunger. David and Charles, Newton Abbot. Learmonth. A.T.A. 1988. Disease Ecology (in press). Learmonth, A.T.A. and Grau, R. 1979. Maps of some standardised mortality ratios for Australia for 1965-1966 compared with 1959- 1963. School of Geography, Occasional Paper No. 8. Australian National University, School of General Studies, Canberra. (Cited in Learmonth, 1988.) Legon, C.D. 1951. A note on geographical variations in cancer mortality, with special reference to gastric cancer in Wales. BritishJ. Cancer, 5, 175-179. Legon, C.D. 1952. The aetiologieal significance of geographieat variations in cancer mortality. British Medical J., 2, 700-702. Levine, D.F. and Booer, M. 1984. Measurement of plasma group I pepsinogens. Postgraduate Medical J., 60, 582. MacDonald, W.C., Anderson, F.H. and Hashimoto, S. 1967. Histological effect of certain pickles on the human gastric mucosa: a preliminary report. Canadian Medical Assoc. J., 96, 1521-1525. McMichael, A.L, McCall, M.G., Hartshome, J.M. and Woodings, T.L. 1980. Patterns of gastro-intestinal cancer in European migrants to Australia: the role of dietary change. International J. Cancer, 25, 431-437.

213

Macklin, M.T. 1955. Role of heredity in gastric and intestinal cancer. Gastroenterology, 29, 507-514. Matolo, N.M., Klanber, M.R., Gorishek, W.M. and Dixon, J.A. 1972. High incidence of gastric carcinoma in a coal mining region. Cancer, 29, 733-737. Meinsma, L. 1964. Voeding en kanker. Voeding, 25, 357-365. (Cited in Howson et al., 1986.) Mesle, F. 1984. Cancers digestif et alimentation. Geosante Symposium~ pp.382-404. (Cited in Learmonth, 1988.) Michioka, O. 1985. Experimental and epidemiological studies on the mutagendepressive substances in vegetables. Akita J. Medicine, 11, 23766. Mirvish, S.S. 1983. The etiology of gastric cancer: intragastric nitrosamide formation and other theories. J. National Cancer Inst., 71, 63147. Millar. I.B. 1961. Gastro-intestinal cancer and geochemistry in noah Monmouthshire. British J. Cancer, 15, 175-199. Miller, A.B. 1982. Risk factors from geographic epidemiology for gastrointestinal cancer. Cancer, 50, 2533-2540. Modan, B., Lubin, F. and Barell, V. etal. 1974. The role of starches in the etiology of gastric cancer. Cancer, 34, 2087- 2092. Morris, LN. 1975. Uses ofEpidemiology, 3rd. Edn. Churchill Livingstone, London. Munoz, N. and Asvall, J. 1971. Time trends of intestinal and diffuse types of gastric cancer in No.,~vay. lntlJ. Cancer, 8, 144-157. Munoz,N., Correa, P., Cuello, C. and Duque, E. 1968. Histological types of gastric carcinoma in high and low risk areas. Intl J. Cancer, 3, 809-818. Munoz, N. and Steinitz, R. 1971~ Comparative histology of gastric cancer in migrant groups in Israel. israel J. Med. Science, 7, 1479-1487. Newill, V.A. 1961. Distribution of cancer mortality among ethnic subgroups of white population of New York City 1953-58. J. National Cancer Inst., 26, 405-417. Nobrega, F.T,. Sedlack, J.D., Sedlack, R.E., Dockerty, M.B., Ilstrup, D.M. and Kurland, L.T. 1983. A decline in carcinoma of the stomach: a diagnostic artifact? Mayo Clinical Proceedings, 58, 255-260. Office of Population Censuses and Surveys. 1978. Occupational mortality: The Registrar General's decennial supplement for England and Wales 1970-72. H.M.S.O., London. Olinder, O. 1953. (Cited by HaenszeI, 1958.) Oshima, A. and Fujimoto, I. 1983. Cancer of the stomach. In: Bourke, G.J. (ed.), The Epidemiology of Cancer, pp. 116-130. Croom Helm, London. Parente, F., Lazzaruni, M., Sangaletti, O., Baroni, S. and Porto, G.B. 1985. Cigarette smoking, gastric acid secretion, and serum pepsinogen I concentrations/11 duodenal ulcer patients. Gut, 26, 1327. Parkin, D.M., Stjernsward, J. and Muir, C.S. 1984. Estimates of the worldwide frequency of twelve major cancers. Bull. Worm Health Organisation, 62, 163-182. Petersen, E. and Magnus, K. 1961. Gastro-intesfinal cancer in Norway. Acta Unio Inlernat. cotara Cancrum, 17, 373-379. Phillips, A.J. and Owchar, M. 1955. Mortality trends in Canada for various sites of cancer. Canadian Medical Assoc. J., 73, 626630. Prudente, A. and Mirra, A.P. 1961. Gastric cancer in Japanese people living in Brazil. Acta Unio Internat. contra Cancrum, 17, 851-857. Quisenberry, W.B. 1955. Stomach cancer in ttawaii. Med&al Arts and Science, 9, 74-81. Roberts, J.A.F. 1959. Some assoc~atious between blood groups and disease. British Medical Bull., 15, 129-133. Rushton, L. and Alderson, M.R. 1981. ,qn epidemiological study of eight oil refineries in Britain. British J. Industrial Medicine, 38, 225-234. Sandier, R.S. and Holland, K.L. 1987. Trends in gastric cancer sex ratio in the United States. Cancer, 59, 1032-1035. Sato, T., Fukuyama, T. and Suzuki, T. 1959. Studies of the causation of gastric cancer: 2. The relation between gastric cancer mortality rate and salted food intake in several places in Japan. Bull. Inst. Public Health, 8, 187-198. (Cited in Howsou etal., 1986.) Saxon, E. 1961. Gastro-intestinal cancer in Finland. Acta Unio

214


Internat. contra Cancrum, 17, 367-372. Seely, S. 1978. The recession of gastric cancer and its possible causes. Medical Hypotheses, 4(1), 50-57. Segi, M., Fukushima, I., Fujisaku, S., Kuriliara, M., Saito, S., Asano, K. and Kamoi, M. 1957. Epiderniological study on cancer in Japan. GANNMonograph, 48, supp 1-63. (Cited in Wynder et al., 1963.) Segi, M. 1960. Cancer mortality for selected sites in twenty-four countries 1950-1957. Department of Public Health, Tohoku University Sehcol of Medicine, Sendai, Japan. (Cited in Wynder et al., 1963.) Segi, M. and Kurihara, M. 1960. Cancer in Japan from viewpoint of geographical pathology. Tohoku J. Experimental Medicine, 72, 169- 193. Segi, M. and Kurihara, M. 1972. Cancer mortality for selected sites in twenty-four countries 1966-1967. Cancer Studies, pp.1- 137. Tohyo, Japan Segi,/VL Aoki, K. and Kuriliara, M. 1981. World cancer mortality. In: Segi, 1VL,Tominaga, S., Aoki, K. and Fujimoto, I (eds.), Cancer Mortality and Morbidity Statistics, Japan and the World. GANN Monograph on Cancer Research No. 26(3), p.121. Selikoff, I.L, Churg, J. and Hammond, E.C. 1964. Asbestos exposure and neoplasia. J. Am. Medical Assoc., 188, 142-146. Sigurjansson, J. 1966. Geographical variations in mortality from cancer in Iceland, with particular reference to stomach cancer. J. National Cancer Inst., 37, 337-346. Siurala, M., Isokosk, M., Vails, K. and Kekki, M. 1968. Prevalence of gastritis in a rural population: bioptic study of subjects selected at random. Scandinavian J. Gastroenterology, 3, 211. Smith, R.L 1957. Mortality attributed to cancer in Hawaiians and Filipinos of Hawaii and other racial groups of United States and Hawaii. J. National Cancer Inst., 18, 397-405. Stahelin, H.B., Rosel, F., Buess E. and Bmbacher, G. 1984. Cancer, vitamins and plasma lipids: prospective Basel study. J. National Cancerlnst., 73, 1463. Staszewski, J. McCall, M.G. and Stenhouse, N.S. 1971. Cancer mortality in 1962-66 among Polish migrants to Australia. British J. Cancer, 25, 599-610. Stocks, P. 1936. Distrilmtion in England and Wales of cancers of various organs. 14th Annual Report, British Empire Cancer Campaign, pp.239-280. British Empire Cancer Campaign, London. Stocks, P. 1957. Cancer in North Wales and Liverpool region. 35th Annual Report, British Empire Cancer Campaign, pp.51-66 and 95- 113. British Empire Cancer Campaign, London. Stocks, P. and Davies, R.I. 1960. Investigation of a localised high incidence of gastric cancer. Public Health, (August). Stocks, P. and Davies, R.I 1964. Zinc and copper content of the soils associated with the incidence of cancer of the stomach and other organs. British J. Cancer, 18, 14-24. Svendsen, J.H., Dalai, C., Svendsen, L.B. and Christiansen, P.M. 1986. Gastric cancer risk in achlorhydric patients: a long-term follow up study. Scandinavian J. Gastroenterology, 21, 16. Takehashi, E. 1978. Ecologic Human Biology. Medical Information Service, Japan. Taylor, J.A. 1988. Biological control of bracken report on the International Bracken Group Meeting at York on the 8th October 1987. Area, 20(2), 165-166. Thomas, T.L, Waxweiler, R.L and Moure-Eraso, R. 1982. Mortality patterns among workers in three Texas oil refineries. J. OccupationalMedicine, 24, 135-141. Trichopoulos, D., Ouranis, G., Day, N.E., et al. 1985. Diet and cancer of the stomach: a case-centrol study in Greece. Intl J. Cancer, 36, 291. Tromp, S.W. 1956. Geographical distribution of cancer of stomach in

Netherlands period 1946-1952. British J. Cancer, 10, 265-281. Tromp, S.W. and Diehl, J.C. 1955. A statistical study of the possible relationship between cancer of the stomach and soil. British J. Cancer, 9, 349-357. Tulchinsky, D. and Modan, B. 1967. Epidemiological aspects of cancer of the stomach in Israel. Cancer, 20, 1311-1317. Verhasselt, Y. 1981. Geography of stomach cancer in Belgium: an approach. GeographicalMedicine, xx, 104-115. Viadana, E., Bross, I.D. and Hooten, L 1976. Cancer experience of men exposed to inhalation of chemicals or to combustion products. J. Occupational Medicine, 18, 787-792. Villako, K., Kekki, M., Tamm, A. et al. 1982. Epidemiology and dynamics of gastritis in a representative sample of an Estonian urban population. Scandinavian J. Gastroenterology, 17, 601. Villako, K., Tamm, A., Savisaar, E. and Ruttas, M. 1976. Prevalence of antral and fundic gastritis in a randomly selected group of an Estonian rural population. Scandinavian J. Gastroenterology, 11, 817. Villalobos-Salazar, J 1986. Biological control of bracken. AREA, 20(2), pp.165-66. (Cited by Taylor, 1988.) Wahrendorf, J. 1986. The changing face of cancer epidemiology. Statistics in Medicine, 5, 547-553. Warwick, O.H. and Phillips, J. 1954. Cancer among Canadian Indians. British J. Cancer, 8, 223-230. Waterhonse, J. 1985. International epidemiology of cancer. J. Royal College of Physicians, 19, 10-22. Waterhouse, J., Muir, C. and Correa, P., et al. (eds), 1976. Cancer Incidence in Five Continents, Vol.3. Intemational Agency for Research on Cancer No. 15. International Agency for Research on Cancer, Lyon. Waterhouse, J., Muir, C., Shaumugaratnam, K. and Powell, L 1986. Cancer Incidence in Five Continents, Vol.4. Imemational Agency for Research on Cancer No. 42. Imemational Agency for Research on Cancer, Lyon. Weinberg, G.B., Kuller, L.H. and Stehr, P.A. 1985. A case-control study of stomach cancer in a coal mining region of Pennsylvania. Cancer, 56, 703-713. Weisberger, J.H. 1985. Nutrition and cancer prevention: gastrointestinal cancer. GANN Monograph, 31, 275-283. Weisburger, J.H. and Rained, R. 1975. Assessment of human exposure and response to N-Nitroso components: a view on the etiology of digestive tract cancers. ToxicoL Applied Pharmacology, 31, 369-374. Weisburger, J.H., Reddy, B.S. and Fiala, E.S. 1983. Update on gastrointestinal carcinogenesis. In: Glass, G.B.J. and Sherlock, P. (eds.), Progress in Gastroenterology, Vol.4., pp.327-344. Grune and Stratton, New York. Welsh Office. 1988. Cancer Registration in Wales: 1974-1984. Welsh Ofice Government Statistical Service, UK. Wilson, N.A. 1970. The Sociology of Health: an Introduction~ Random House, New York. Woolfe, C.M. 1954. A further study on the familial aspects of carcinoma of the stomach. American J. Human Genetics, g, 102-109. Wynder, E.L., Kmet, J., Dungal, N. and Segi, M. 1963. An epidemiological investigation of gastric cancer. Cancer, 16, 1461-1496. Zaldivar, R. and Robinson, H. 1973. Epidemiological investigation on stomach cancer mortality in Chileans: associations with nitrate fertilizer. Z. Krebsforsch, 80, 289-295. (Cited in Coggon and Acheson, 1984.) (Manuscript No.202: Received August 1, 1989 and accepted for publication after revision on November 3, 1989.)

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