Health Effects of Cows’ Milk
http://www.eps1.comlink.ne.jp/~mayus/eng/

Incidence and Mortality of Testis and Prostate Cancers in
Relation to World Dietary Practices - Dairies are
Causatively Related to these Malignancies
Adapted from:

Ganmaa D, Li XM, Wang J, Qin LQ, Wang PY, Sato A.
Incidence and Mortality of Testicular and Prostatic Cancers in Relation to
World Dietary Practices.
International Journal of Cancer 2002;98:262-7.
Abstract
The incidence and mortality rates of testis and prostate cancers in 42 countries were correlatedwith the dietary practices in these countries using the cancer rates (1988-92) provided by theInternational Agency for Research on Cancer (IARC) and the food supply data (1961-90)
provided by the Food and Agriculture Organization (FAO). Among the food items we
examined, cheese was most closely correlated with the incidence of testis cancer at ages 20-39,
followed by animal fats and milk. The correlation coefficient (r) was highest (r = 0.804) whencalculated for cheese consumed during the period 1961-65 (maternal or prepubertal
consumption). Stepwise-multiple-regression analysis revealed that milk + cheese (1961-65)
made a significant contribution to the incidence of testis cancer (standardized regression
coefficient [R] = 0.654). Concerning prostate cancer, milk (1961-90) was most closely
correlated (r = 0.711) with its incidence, followed by meat and coffee.
Stepwise-multiple-regression analysis identified milk + cheese as a factor contributing to theincidence of prostate cancer (R = 0.525). The food that was most closely correlated with themortality rate of prostate cancer was milk (r = 0.766), followed by coffee, cheese and animal
fats. Stepwise-multiple-regression analysis revealed that milk + cheese was a factor
contributing most to the mortality of prostate cancer (R = 0.580). The results of our study
suggest an important role of milk and dairy products in the development and growth of testis
and prostate cancers. The close correlation between cheese and testis cancer and between milk
and prostate cancer suggests that further mechanistic studies should be undertaken concerning
the development of male genital organ cancers.

Introduction
Japanese lifestyle underwent drastic changes after the end of the Pacific War (1945). Most
conspicuous was the change in dietary practices. The intake of milk and dairy products, meat1and eggs increased 20-, 9- and 7-fold, respectively, during the 48 years between 1950 and
1998. It has been observed that in Japanese males born before 1945, death from testis cancer
peaked in their thirties or forties, whereas in those born after 1946, the peak was in their
twenties (a birth cohort effect). From these observations, Ganmaa et al. (1) presumed that thedevelopment of testis cancer in Japanese men is related to the dietary practices of Japanese
boys at the time of puberty or earlier.
The age-adjusted death rate of prostate cancer has risen 25-fold almost linearly
during the last 48 years from 1947-95, with no birth cohort effect on the death rate. From this,Ganmaa et al. (1) also presumed that the increased death from this cancer relates to an
accumulation of the effects of dietary factors throughout life.
The incidence of testis cancer in Western countries has steadily risen in the past 40
or 50 years (2-4). Prostate cancer is the most common cancer among men in most Westerncountries (5). The incidence and mortality of both malignancies vary greatly from country tocountry (6,7).
The correlation of incidence and mortality rate with the prevalence ofenvironmental agents in various geographical areas provides useful clues to the etiology ofcancer (8,9). In particular, correlation of cancer rates with dietary practices in different
countries is a worthwhile exercise.
With the availability of international cancer incidence and mortality data (6,7,10,11),a further correlation analysis is justified. In our study, we used incidence and mortality data
for testis and prostate cancers from each of 42 countries and correlated the rates with dietary
variables.

Materials and Methods
Incidence of testis and prostate cancers
Cancer Incidence in Five Continents edited by Parkin et al. (6) provided us withcomparable data on the incidence of cancer between 1988-92 in different geographicallocations (183 populations in 50 countries). In our study, we used data from 42 of thesecountries, for which both cancer incidence rates and food consumption data (FAOSTAT
Database Collections) (12) were available.
In several countries, more than one cancer registry is operating. If more than one
registry was available for a country, those with the editors' comment that ‘The editors wereunable to verify these data’ (6) were excluded from our study. The remaining age-specificincidence rates in the same country were standardized to the world population. The meanvalue of the age-adjusted incidence rates was employed as a representative rate for thecountry (Australia, Brazil, China, France, Germany, India, Italy, Japan, Peru, Poland, Spain,
Switzerland, Thailand and UK). For example, in Japan, six cancer registries (Hiroshima,
Miyagi, Nagasaki, Osaka, Saga and Yamagata) are operating and the results are listed in2Cancer Incidence in Five Continents. The editors remarked on the data from Saga that ‘The
editors were unable to verify these data.’ (6) The data from Saga were therefore excluded andthe rates of the other five cancer registries were averaged after age-standardization to theworld population.
In several countries, only one cancer registry reported data to the IARC. The
incidence rate from the registry was then assumed to represent the incidence for the country(Algeria, Argentina, Austria, Columbia, Costa Rica, Ecuador, French Polynesia, Ireland,
Korea, Mali, Malta, Philippines, Uganda, Uruguay, and Vietnam).
In some countries, cancer registries provided data for different ethnic groups. In ourstudy, the rates for Africans were used for Zimbabwe; those for all Jews were used for Israel;
those for Kuwait were used for Kuwaitis; and those for Non-Maori were used for New
Zealand.
Canada, Denmark, Finland, Hong Kong, Iceland, The Netherlands, Norway andSweden collected data for their cancer registry on a national basis. The incidence rates forthese countries were used as provided.
Many cancer registries operate in the U.S. Among them, the registry for white
people by the SEER program was used as a representative registry for the U.S.
In most of the countries examined, the incidence of testis cancer peaked in groupsof ages 25-29 or 30-34 (6). Therefore, truncated age-adjusted incidence rates for
20-39-year-olds were used to evaluate the relationship between the incidence of testis cancer
and food intake. The incidence of prostate cancer increased with age (6). Therefore, for thiscancer, the age-adjusted incidence rates for all ages were used for the evaluation.
Mortality of testis and prostate cancers
The age-specific mortality rates of both cancers that are listed in tabulated form in
GLOBOCAN 1 (7) were employed in our study. The mortality data for French Polynesia are
not given in GLOBOCAN 1; data for the other 41 countries mentioned above in the section
on cancer incidence were used in the evaluation.
Food consumption
The consumption data (Mt/1,000 capita/year) for various food items from 1961-91
that are available from the FAOSTAT Database Collections (12) were used. The food items
used for our study were animal fats, meat (bovine meat, pig meat, poultry meat, and mutton
and goat meat), eggs, butter, milk excluding butter, whole milk, cereals excluding wine,
pulses, beans, soy beans, peas, fruits excluding wine, vegetables, tomatoes, coffee, tea andalcoholic beverages. Tomatoes were considered separately because they are claimed to be aprotective factor against prostate cancer (13-15). The consumption of each food or drink wasconverted from Mt/1,000 capita/year to g/capita/day.
3

To evaluate the relationship between food intake and testis cancer incidence, threefood intake values (average intake from 1961-65, from 1961-70 and from 1961-90) were used.
To evaluate the relationship between food intake and prostate cancer, the average food intake
from 1961-90 was used. The reason for this is that testis cancer development may relate to theprenatal environment or the environment of boys at or before puberty, whereas prostate cancer
development may relate to an accumulation of environmental factors throughout life (1).
Statistical analysis
All of the data were analyzed by Stat View (SAS Institute Inc., Cary, NC). The 0.05
level of probability was used as the criterion for significance. Simple correlation coefficients(r) were calculated to examine the association between the incidence or mortality rates oftestis and prostate cancers and the consumption of each food item. Consumption of several
food items was closely interrelated (collinearity, r > 0.8). For example, the r-value calculated
for the correlation between the amount of milk and cheese consumed in 1961-90 was 0.812.
Hence, consumption of milk and cheese in the same period was grouped as milk + cheese.
The contributions of these grouped food items to the incidence or mortality were evaluated by
stepwise-multiple-regression analysis. The food items selected for the analysis (independent
variables) were the following I 1 items: animal fats + butter, milk + cheese, eggs, meat,cereals, pulses, fruits, vegetables, vegetable oils, coffee, and alcohol.

Results
Incidence of testis cancer and food intake
The truncated age-adjusted incidence rates for testis cancer in the 20-39 age groupvaried greatly from one country to another; Switzerland had the highest rate at 22.2/100,000,
followed by Denmark (21.8) andGermany (20.2) (Fig. 1). The
lowest rate (0/100,000) was foundin Algeria and Zimbabwe, followedby Uganda (0.32), and Mali andChina (both 0.49).

Fig. 1. Correlation between testis cancer incidence rates at ages 20-39 years and per
capita cheese consumption (1961-65) in 42 countries.
4

The simple correlation
coefficients for the correlation
between the incidence rate of testis
cancer and food intake in 42
countries are shown in Table 1.
Among the food items consumed in
1961-65, cheese was the mostclosely correlated with cancer
incidence (r = 0.804), followed byanimal fats (0.770) and milk (0.741).
Concerning the years when cheese
was consumed, the correlation
coefficient was highest for cheese
consumption in the 1961-65 period.
On the other hand, cereals (-0.358)
and pulses (-0.442) were negatively
correlated with the incidence oftestis cancer.
Stepwise-multiple-regress
ion analysis to clarify the fooditems affecting testis cancer
incidence revealed that milk +cheese (1961-65) made a significant
contribution to increasing the incidence of testis cancer around 1990 (standardized regression
coefficient [R] = 0.654), followed by alcohol (0.272) (Table 2).
Mortality of testis cancer and food intake
In Norway, the age-adjusted incidence rate (per 100,000) was 8.0, whereas themortality rate was 0.36. The fatality rate (ratio of mortality to incidence) of testis cancer inthis country was less than 5%. On the other hand, the incidence rate in Algeria was 0.20, witha mortality rate of 0.19 (fatality rate, 95%). The average fatality rate in the 41 countries
examined was 24.6%. The correlation coefficient between age-adjusted incidence rate andage-adjusted mortality rate of testis cancer in these countries was 0.350.
Animal fats had the highest correlation coefficient (r = 0.317) for the age-adjusted
mortality rates of testis cancer. Using truncated age-adjusted mortality rates for ages 15-44
changed this correlation slightly; the coefficient for animal fats was increased to 0.390.
Incidence of prostate cancer and food intake
5The age-adjusted
incidence rate (per 100,000) of
prostate cancer was highest in the
U.S. (100.8), followed by Canada(64.7), Iceland (61.0) and Sweden(55.3). Korea had the lowest
incidence rate at 0.90, followed by
Vietnam (1.20), Algeria (1.80) andChina (1.90) (Fig. 2). The
difference between the highest andlowest incidence rates was as greatas 84-fold.
Fig. 2. Correlation between the age-adjusted incidence rates of prostate cancer and per
capita milk consumption (1691-90) in 42 countries.
Among the food items
examined, milk (1961-90) was mostclosely correlated with prostatecancer incidence (r = 0.711),
followed by meat (0.642) andcoffee (0.606) (Table 3). On theother hand, cereals were negatively
correlated with its incidence(-0.648). The correlation
coefficients for milk and meat
consumed in the 1961-65 period
were high (0.751 for milk and 0.657
for meat) compared to the values
for milk (0.711) and meat (0.606) inthe 1961-90 period.
Multiple-regression
analysis identified milk + cheese(1961-90) as a factor contributing toan increased incidence of prostatecancer (R = 0.525), whereas it
identified cereals as a factor
contributing to a decreased
incidence (-0.425) (Table 4).
6Mortality of prostate cancer and food intake
The highest rate (per 100,000) of age-adjusted mortality was 26.2 for Switzerland,followed by 24.8 for Norway and24.2 for Iceland. China had thelowest rate of 0.65, followed by
Vietnam (0.78) and Algeria (2.13)(Fig. 3).

Fig.3. Correlation between the age-adjusted mortality rates of prostate cancer and per
capita milk consumption (1961-1990).
Mortality rates of prostatecancer were highly correlated with
its incidence rates (r = 0.790). In
some countries, however, a great
difference was found between
mortality and incidence. For
example, the ratio of mortality toincidence (%) in the U.S. was 18.4
and that in Canada was 27.6.
The food (1961-90) mostclosely correlated with mortality of
prostate cancer was milk (r = 0.766),
followed by coffee (0.633), cheese (0.618) and animal fats (0.606) (Table 5). In contrast,
cereals was negatively correlated with the mortality (-0.661).
Consistent with the analysis of prostate cancer incidence, stepwise-multiple-regression analysis revealed that milk + cheese (1961-90) made a most significant
contribution to the mortality of prostate cancer (R = 0.580), whereas cereals contributed
negatively to the mortality (-0.418) (Table 4).

Discussion
7

The ecological studies that correlate cancer incidence/mortality rates with the dietary practices
in various geographical areas have certain shortcomings. The rates of incidence and mortalityof any cancer are affected by regional differences in the diagnosis, registration/certificationand the fatality rate of the cancer. It is certain that the cancer incidence and mortality data setsfrom developing countries are less complete than those from developed countries because ofproblems with under-diagnosis and under-certification of death due to the local medical andeconomic background and problems enumerating the population. Also, the consumption data
for each food item in a country are not based on actual nutrition surveys, but are a roughestimate from the following equation: food supply per capita = (production + import + stockchanges - export - feed - seed - processing - waste - other use)/population. Hence, it isdifficult to determine the extent to which the available food data translates into daily percapita consumption. Nevertheless, the overall relationships are convincing, plausible and at
least serve as guides for further epidemiological and experimental studies (8,9).
Testis cancer
Early diagnosis (biomarkers such as human chorionic gonadotropin andα-fetoprotein, CT scan, biopsy, etc.) and treatment (radiotherapy, chemotherapy including
cisplatin [cis-diamminedichloro-platinum], etc.) of testis cancer may have improved thesurvival of patients with the disease. Indeed, cisplatin-based chemotherapy (a combination ofplatinum, vinblastine and bleomycin [PVB]) markedly improved the clinical outlook of malepatients with disseminated germ cell tumors (16). This may explain why the correlation
coefficient between the incidence and mortality of testis cancer was as low as 0.350. In thisregard, incidence is a better index for this malignancy than mortality.
In most populations, testis cancer has a peak incidence rate in people in their
twenties or thirties (6). The increased incidence of testis cancer in Western countries during
the last 4 or 5 decades is associated with birth cohort effects (2-4). In Japan, where dramatic
lifestyle changes occurred after the Pacific War, the peak death rate in the population born
before the war was in their thirties or forties, whereas for those born after the war it was intheir twenties (1). This birth cohort effect on the incidence/mortality of testis cancer suggeststhat the causative factors relating to this malignancy operate early in life, possibly in the fetal(i.e., maternal), perinatal (also, maternal), or prepubertal period.
The food that was most closely correlated with the incidence of testis cancer was
cheese, followed by animal fats and milk (Table 1, Fig. 1). Cheese consumption in the period
from 1961-65 was highly correlated (r = 0.804) with the incidence around 1990.
Stepwise-multiple-regression analysis also revealed that milk + cheese consumed in 1961-65
contributed most to the incidence. Patients who were diagnosed with the malignancy at age 29(the middle age of 20-39) in 1990 were born in 1961. If cheese or milk is a cause of testis
cancer, then that consumed before birth (maternal consumption) or in the prepubertal period8may be associated with the development of the cancer. Pregnant women are encouraged toconsume milk and dairy products to meet their calcium requirements during pregnancy.
Prepubertal boys are also preferentially encouraged to consume milk and dairy products
because of their growth-promoting effect.
In most countries, the incidence rate of testis cancer, which is lowest in boys 5-14
years old, increases sharply in boys aged 15-19 years. This is thought to reflect the fact that
testis cancers develop and grow in the presence of sex hormones or gonadotropins, i.e., after
the onset of puberty (2).
In addition to fats, protein and calcium, milk and dairy products containconsiderable amounts of female sex hormones such as estrogens and progesterone (17). The
high hormone content in milk is because present-day milk is produced from pregnant cows
(18). It is not unreasonable to hypothesize that estrogens or progesterone in milk and dairy
products are associated with the development of testis cancer.
Consumption of dairy products is said to be excessive in Western countries, a trendthat probably started in the 1940s and 1950s (19). The increased incidence of testis cancer inthe past 50 years in Western countries (2-4,20) may be associated with the increased
consumption of milk and dairy products.
The adverse effects of milk on the male testis are only sparsely discussed in theliterature. One reason for this may be that precise evaluation of individual milk intake isdifficult because milk and its products (cheese, cream, butter, fermented milk, powdered milk)
are used in a variety of foods, including cakes, candies, ice cream and chocolates, making
retrospective evaluation of milk intake at young ages far more difficult.
Davies et al. (21) tested the hypothesis that milk and dairy products are risk factors
for testis cancer in a case-control study undertaken in East Anglia, UK. All of the responding
subjects completed a dietary questionnaire that included questions on their current andadolescent consumption of milk, dairy products, fruits and vegetables. Those with testis
cancer had consumed significantly more milk during adolescence than had controls.
Prostate cancer
The age-adjusted incidence and mortality rates of prostate cancer have risen almost
linearly all over the world during the 20-year in the period from 1973-77 to 1988-92 (5). The
exponential increase of these rates with age is coincident with the general feature of solid
malignant tumors. In Japan, where the age-adjusted mortality rate of the cancer has risen
almost linearly about 25-fold over the last 48 years (1950-98), no birth cohort effect isobserved in the mortality rate (1). This finding suggests that the recent increase in theincidence and mortality of prostate cancer may relate to the accumulation throughout life ofenvironmental factors affecting the development and growth of prostate cancer.
The age-adjusted incidence rate (per 100,000) of prostate cancer in the U.S. was
9

100.8, while the mortality rate in this country was 18.6 (Figs. 2 and 3). Because the recent
increase in the reported incidence may be associated with the introduction in the mid-1980s of
prostate-specific antigen (PSA) for prostate cancer screening (22), the mortality rate may be
more reliable than the incidence rate for elucidating the true nature of prostate cancer in somecountries. The correlation coefficient between testis and prostate cancer incidence was 0.614,
whereas the coefficient between testis cancer incidence and prostate cancer mortality was ashigh as 0.743.
Fat intake, especially that of animal origin, has long been listed as the major risk
factor of prostate cancer (23-29). According to a recent review article by Kolonel et al. (30),
however, although early epidemiologic studies implicated dietary fat as a likely causal factor
for this cancer, scientific support for such an association has diminished in recent years as
more epidemiologic evidence has accrued.
Attention has recently been focused on phytoestrogens, such as isoflavonoids,
flavonoids and lignans, as a possible explanation for the contrasting rates of prostate cancer
between Western and Asian countries (31-36). Soya is a major source of the isoflavonoids,
daidzein and genistein (33). According to Griffiths et al. (34), a Japanese male consumes
approximately 20 mg of isoflavones per day, whereas Western men consume less than 1
mg/day. They say that this is reflected in a high mean plasma concentration of genistein (180ng/ml, n = 72) in Japanese men, compared to a level of less than 10 ng/ml for Western men.
Soybeans may possibly have a protective effect against the development and growthof prostate cancer. The simple correlation coefficients between the incidence and mortality of
prostate cancer and the consumption of pulses were -0.302 and -0.283, respectively (Tables 3
and 5). According to Ganmaa et al. (1), however, the consumption of pulses, including
soybeans, in Japan almost doubled between 1947 (43.8 g/day) and 1998 (72.5 g/day). In
addition, the supply of soybeans as food in Japan also increased between 1961 and 1998, from
7.7 to 9.0 kg/capita/year. Thus, the remarkable increase in the death of Japanese men fromprostate cancer in the last 48 years is contradictory to the claimed protective effect ofsoybeans against prostate cancer.
Tomatoes, which contain a carotenoid, lycopene, have been claimed to be a negativerisk factor for prostate cancer (13-15). In our study, however, no significant association wasobserved between the consumption of tomatoes and the incidence (r = 0.148) or mortality rate(-0.015) of prostate cancer (Tables 3 and 5).
Consumption of milk and dairy products has been listed as a risk factor for prostatecancer in several reports (9,23,26,37-43), most without precise biological interpretations.
Dairy products are hypothesized to be a risk factor of prostate cancer because of
their high content of calcium (42.44). The basis of this hypothesis is that calcium suppresses
the formation of 1,25-dihydroxyvitamin D (1,25(OH)2D) from 25-hydroxyvitamin D. Thisdecreases the level of circulating 1,25(OH)2D, the biologically active form of vitamin D,
10which reduces cellular proliferation and enhances cellular differentiation (45). However, anested case-control study of serum vitamin D metabolite levels and prostate cancer in a cohortof 3,737 Japanese-American men in Hawaii failed to find a significant correlation between
vitamin D metabolites and prostate cancer (46). According to this study, the odds ratio for thehighest quartiles relative to the lowest was 1.0 (CI = 0.5-2.1) for 1,25(OH)2D.
Androgens are crucial for the normal development of the prostate gland and formaintaining its functional state in the adult (47). The development of prostate cancer has long
been associated with androgens, because orchidectomy androgen ablation with GnRH
analogues and antiandrogen administration appear to be useful remedies for prostate cancer(48,49).
Prostate cancer, however, usually develops in men in their sixties or older (6), when
the testosterone/estradiol ratio is declining (50). The decrease in androgens in elderly men is
amplified by an age-related increase in plasma sex hormone-binding globulin (SHBG), which
results in a relatively greater decrease in free androgens compared to total androgens (51).
These findings suggest that androgens are not necessarily the only determining factor
affecting the development and growth of prostate cancer.
A prospective, nested case-control study conducted in the US suggests that
increased levels of plasma testosterone increase the risk of prostate cancer (52). A longitudinal,
population-based, nested case-control study in Finland, however, found no association
between serum testosterone concentration (determined between 1968-72) and the subsequent
occurrence of prostate cancer (a follow-up period of 24 years) (53). A comparison of serum
testosterone concentrations in young adult Japanese men (a population at low risk for prostatecancer) with those of young adult white and black Americans (a population at high risk forprostate cancer) also found no significant differences (54).
The growth of human prostate cancer cells (the LNCaP cell line) is significantly
stimulated by physiological concentrations of estradiol and the growth increase is comparable
to that induced by either testosterone or dihydrotestosterone (55). In fact, alpha and beta
estrogen receptors are expressed in both normal and malignant prostate epithelial cells (56). In
addition, testosterone and dihydrotestosterone is not the only ligands for androgen receptor(AR). Estradiol-17β represents another important natural ligand for AR and may play anessential role in AR function and the development of the male reproductive system (57).
These suggest that estrogens play a role in the development and growth of prostate cancer,
although the exact nature of their role has not been clearly defined.
In our study, the consumption of milk was most closely correlated with theincidence and mortality of prostate cancer (Table 3, 4 and 5). As discussed in the section on
testis cancer, milk contains considerable amounts of estrogens (16). We hypothesize that theassociation between milk and the incidence and mortality rates may be due to the high content
of estrogens in milk. The man is the only mammal that consumes milk after weaning. Regular11

milk intake throughout life may affect the incidence and mortality of this malignancy.
In conclusion, we propose a hypothesis that female sex hormones in milk and dairy
products may have an effect on the development of testis and prostate cancers. It is clear,
however, that the high correlation between cheese and testis cancer and between milk andprostate cancer should be taken as a suggestion for further epidemiological and mechanistic
studies.

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