- Email: [email protected]
Response to dr walter willett's dissent
J Clia EpidemiolVol. 47, No. 3, pp. 227-230, 1994
Pergamon
08954356(93)EOO30-F
Copyright 0 1994 Elsevier Science Ltd Printed in Great Britain. All rights reserved
0895-4356/94$6.00+ 0.00
Response RESPONSE
TO DR WALTER
WILLETT’S
DISSENT
ERNST L. WYNDER,’ LEONARD A. COHEN,’ DAVID P. ROSE*and STEVEN
D. STELLMAN]
‘Division of Epidemiology, American Health Foundation, 320 East 43 Street, New York, NY 10017 and 2Division of Nutrition and Endocrinology, American Health Foundation, 1 Dana Road, Valhalla, NY 10595, U.S.A. (Received 17 November 1993)
We would like to reply to Dr Willett’s comments by addressing the specific issues he has raised. It is understood that studies in nutritional carcinogenesis are inherently imprecise-a problem compounded by the need to integrate data from widely disparate disciplines. Thus, it is not surprising that marked differences in opinion concerning the interpretation of data have arisen. In this context, open and constructive debate is to be welcomed as the best means of resolving these scientific issues. First, with regard to the 65-county study in China [l], Dr Willett notes that fat intake varied from 5 to 47% of total calories across the 65 counties and that, despite this broad range, there was only a “slight” variation in breast cancer mortality rates and these rates were about five times lower than in the U.S. (The overall age-adjusted breast cancer mortality rate for Chinese women is 4.7, while that for U.S. women is 24.6/100,000 [2]). Dr Willett then concludes, “Thus, in this ecological study, less confounded by general socio-economic conditions, there is evidence that the international differences cannot be explained simply by the percentage of calories due to fat.” A more circumspect reading of this paper would have shown that fat intake among the people in the 65 counties actually ranged from 5.9 to 25.4% of calories, with a single exception (County WA) where it was 45.2%. This county is unique in that it has a population density of only 3 inhabitants/km*, has 67% employed in agricul-
ture; its residents have a high intake of meat and dairy products and, except for wheat, a very low intake of plant products. Using the same database, Marshall et al. [3] reported a weak positive association between fat intake and breast cancer risk. Moreover, when these data were segregated into quintiles of fat intake, a lower mean of 14.9% and an upper mean of 22.6% were reported. Such a weak association would be expected assuming that the people in China as a whole represent a population with low-fat intake that is at low-risk. It is most intriguing that despite significantly lower fat intake, the mean total caloric intake for males in China is greater than that in the U.S., i.e. 2656 vs 2360 kcal/day [l]. From this perspective, the data from China appear to support rather than refute the fat hypothesis. Regarding the comments about the steadily rising incidence of breast cancer in the U.S. against a decline in fat intake, it should be noted that from 1948 until the early 198Os, fat intake has risen continuously in the U.S. [4]. Since then, a decline from a high of >40% to approximately 37% of calories has occurred according to NHANES II. Hence, the continued increase in breast cancer incidence could be the delayed biological expression of an earlier dietary pattern. Even though total fat intake has decreased, the proportion of linoleic acid in the fats used as part of the U.S. diet has steadily increased over the past 40 years [5]. This is of particular interest since linoleic acid is a
227
228
ERNSTL. WYNDERet al.
precursor to the biologically active eicosanoids which appear to play a specific role in mammary cancer development [6]. We should also acknowledge that the rising incidence in breast cancer may, in part, be attributed to the increased use of mammography for early detection [7]. Contrary to Willett’s claim that “the effect of fat is not consistent in tumor models which do not involve the use of high doses of carcinogens”, it is worth noting that the earliest demonstration of the effect of fat by Tannenbaum [8] was in dba and C3H strain mice which produce mammary tumors “spontaneously” in the absence of exogenous carcinogens. Moreover, studies with tumor implants indicate that metastasis of mammary tumor implants to distant organs can be regulated by dietary fat [9]. That a “much stronger and more consistent finding has been that energy restriction profoundly reduces mammary tumors” is, in a general sense, true. However, caloric restriction inhibits mammary tumorigenesis only if the degree of restriction is 20-25% of the ad libitum intake and it is always associated with a significant decrease in body weight gain. Moreover, two recent large-scale meta-analyses do not support a calorie hypothesis: one showed a stronger correlation for body weight gain and tumorigenesis than for caloric intake [lo], and the other a highly significant effect of fat per se (p < 0.001) in mammary tumor development in a combined analysis of over 100 studies in rats and mice [ll]. The caloric hypothesis is also doubtful because high-fat diets that are rich in the monounsaturated, oleic acid (Cl 8: 1, n-9), in medium chain length fatty acids (C8:0, ClO:O), and long chain n-3 polyunsaturates (C20:5, n-3; C22:6, n-3) do not promote mammary tumor development while diets that are rich in linoleic acid (C18:2, n-6) do so even though they contain the same caloric density [12]. Doubt has been expressed as to whether or not changes made after menopause would have any effect on risk. This is a valid point and has not been adequately tested since most animal model studies are conducted in young rodents. However, Katz and Boylan [9] have shown that low-fat diets decrease metastatic dissemination of mammary tumor implants in older “retired breeders” but not in young rats, suggesting that fat can exert effects in non-cycling “postmenopausal” rodents. It is true that a definitive mechanism of action for the effect of dietary fats on mammary cancer
is lacking. (Parenthetically, it is worth noting no such mechanism has been demonstrated for caloric restriction.) Evidence for various mechanisms has been reviewed [13]. Several investigators have reported that populations consuming low-fat diets exhibit relatively low levels of circulating estrogens-hormones which have been implicated in breast cancer development. In a comparison of British and ruraldwelling Chinese, this difference applied to both premenopausal and postmenopausal women [14]; a similar study of American and ruraldwelling Japanese was limited to those beyond menopause [15]. Dr Willett expresses concern that non-intervention groups were not included in the published studies of dietary fat and blood estrogens. While the relevance of his reference to cholesterol is uncertain, this aspect has, in fact, now been addressed. A study of postmenopausal breast cancer patients participating in the WINS Trial showed that those with reliably assayable levels of serum estradiol did respond to a low-fat dietary intervention; the non-intervention group showed no such reduction in estradiol over a 1Zmonths observation period [16]. Recent studies by Tillotson et al. [17] indicating an effect of linoleic acid on ~53 gene expression in cultured mammary tumor cells and research by Djuric et al. [18] suggesting that oxidative damage to DNA is increased in humans consuming a high fat diet indicate that fat may exert its effects via altered gene expression or increased free radical activity. Also, while it is true that total polyunsaturated fat intake is similar in the U.S. and Japan, the Japanese consume a larger proportion of n-3 polyunsaturates than Americans, which may serve as a protective effect with regard to breast cancer [19,20]. Dr Willett is correct in his remarks concerning the unreliability of serum and adipose tissue lipid measurements as biomarkers for fat intake. No doubt, this is because in nutritionally homogeneous populations like the U.S., differences in the fatty acid profiles of adipose tissue or serum lipids are minimal. Preliminary studies indicate that total serum triglycerides are lower in women who eat low-fat diets (J. Richie, AHF, personal communication); nonetheless, a reliable biomarker for total fat intake remains to be established. The issue of the unreliability of dietary questionnaires was raised because it is the central problem in nutritional epidemiology. Out of
229
Response: Response to Dr Walter Willett’s Dissent
some 85,000 nurses, Willett et al. [21] analyzed a subsample of 200 women by weighing and measuring food intake over a 28-day period. These results, according to Willett, were then compared with the food frequencies obtained from the entire cohort with “reasonably” good correlations. It is true that weighed records of food consumption are associated with fewer sources of error than estimates of past intake; yet, recent findings [22] with weighed food records, validated by nitrogen excretion assays, are also associated with substantial bias. In the lower reported range of fat intake, a majority of individuals underreported their fat intake. Addressing the issue of the relative homogeneity of fat intake in the U.S. population, Willett claims that the respondents to the revised 1984 questionnaire included women who consumed less than 25% as well as those who ate more than 50% calories as fat. However, Bingham has shown [22], that in typical western societies, the frequency of women who consume below 28% of calories as fat is vanishingly small and that the vast majority fall within the range of 3@-44% of caloric intake as fat. It is of interest in this regard that Toniolo et al. [23] reported in a case-control study in Northern Italy, a decrease in breast cancer risk for women who consumed less than 24% fat calories when compared to women consuming >40% calories as fat. Willett is correct when he states that “it is notable that in large prospective studies of this relationship that have recently been conducted, the findings are much more consistent and all report little or no association.” Such a result is understandable in light of the relative uniformity of fat intake in the societies studied (Netherlands, U.S., etc.), and considering measurement errors and the well accepted phenomenon of social desirability bias. Clearly, intra-country prospective studies will not provide any further information on this subject unless the study cohort comes from a country with a fat intake ranging from at least 20% to more than 40% of total calories. Undoubtedly, Willett and colleagues have made a valuable contribution to the debate on fat and breast cancer. Viewing the data in aggregate, including over half a century of animal model experimentation, ecological studies and analysis of plausible mechanisms, it is difficult to accept their conclusion that dietary fat is an insignificant risk factor for breast cancer.
In conclusion, on the issue of dietary fat as a causative factor for breast cancer, our view does not stand alone. The extensive reviews by the National Academy of Sciences [24] and the World Health Organization [25] generally support our interpretation of existing data. It is not surprising, as we already know from the long controversy about to dietary fat and atherosclerosis, that any issue involving nutrition, because of its complicated interrelationships as well as economic interests, will be open to public debate for a long time to come. No doubt, the work of Willett and his group, as well as our own, will continue to contribute to this debate. This should lead not only to increasingly better understanding of the scientific issues, but also to public health decisions that have to be made on the basis of relative costs and benefits, rather than unambiguous proof. Because various dietary fats have been shown to relate to many other diseases, including coronary disease, the major cause of death in the U.S., and also because fats obviously contribute more to total caloric intake than do proteins and carbohydrates, a public health recommendation to reduce specific dietary fats is both timely and consistent with much of the curre’nt evidence and, to quote Hippocrates, “would do no harm”.
REFERENCES 1.
Chen J, Campbell TC, Junyao L, Peto R. The Diet, Lifestyles,
and Mortality
Characteristics
of 65 Rural
Populations in tbe People’s Republic of China. Oxford: Oxford University Press; 1987. 2. American Cancer Society. Cancer Facts and Figures. Atlanta, GA: American Cancer Society; 1992. 3. Marshall JR, Yinshen Q, Junshi C, Purpia B, Campbell TC. Additional ecological evidence: Lipids and breast cancer mortality among women aged 5.5 and over in China. Eur J Cancer 1992: 28A00): 172&1727. 4. Wynder EL, Fujita Y, Harris RE: Hirayama T. Hiyama T. Comparative epidemiology of cancer between the United States and Japan. A second look. Cancer 1991; 67: 746-763.
5.
Stephan AM, Wald NJ. Trends in individual consumption of dietary fat in the United States 1920-1984. Am J Clin Nutr 1990; 52: 457469.
6.
Horrobin DF. The role of essential fatty acids and prostaglandins in breast cancer. In: Reddy BS, Cohen LA, Eds. Diet, Nutrition and Cancer: A Critical Evaluation Vol. I: Macronutrients and Cancer, Boca Raton, FL: CRC Press; 1986; 102. 124. I. Miller BA, Feuer EJ, Hankey BF. The increasing incidence of breast cancer since 1982; relevance of early detection. Cancer Causes and Control 1991; 2: 67-74. 8. Tannenbaum A. The genesis and growth of tumors. III. Effect of a high fat diet. Cancer Res 1942: 2: 468m~475.
230 9.
10. 11.
12.
13.
14.
IS.
16.
17.
ERNSTL. WYNDERet Katz EB, Boylan ES. Stimulatory effect of a high polyunsaturated fat diet on lung metastasis from the 13762 mammary adenocarcinoma in female retired breeder rats. J Natl Cancer Imrt 1987; 79: 351-358. Albanes D. Total calories, body weight and tumor incidence in mice. Cancer Res 1987; 47: 1987-1992. Freedman LS, Clifford C, Messina M. Analysis of dietary fat, calories, body weight and the development of mammary tumors in rats and mice. A Review. Cancer Res 1990; SO: 5710-5719. Cohen LA. The role of dietary fat in cancer. In Food, Fats and Health. Council for Aaricultural Science and Technology (CAST) Task Fo& Report, No. 118, pp. 75-80, 1991. Cohen LA. Dietary fat and mammary cancer. In: Reddy BS, Cohen LA, Eds. Diet, Nutrition and Cancer: A Critical Evahtation. Macro-nutrients and Cancer, Vol. 1. Boca Raton, FL: CRC Press; 1986: 78-100. Key TJA, Chen J, Wang DY, Pike MC et al. Sex hormones in women in rural China and in Britain. Br J Cancer 62: 1990; 631-636. Prentice. R. Thomoson D. Clifford C. Gorbach S et al. Dietary fat reduction and plasma kstradiol concentrations in healthy postmenopausal women. J Nat1 Cancer Iast 1990; 82: 129-134. Rose DP, Connolly JM, Chlebowski RT, Buzzard IM, Wynder EL. The effects of a low-fat dietary intervention and tamoxifen adjuvant therapy on the serum estrogen and sex hormone-binding globulin concentrations of postmenopausal breast cancer patients. Breast Center Res Treat 1993; in press. Tillotson JK, Darzynkiewicz Z, Cohen IA, Ronai Z. Effects of linoleic acid on mammary tumor cell pro-
18.
19. 20.
21.
22.
23. 24.
25.
al.
liferation are associated with changes in ~53 protein expression. Int J Oncol 1993; 3: 81-87. Djuric Z, Heilbrun LK, Reading B, Boomer A et al. Effects of a low fat diet on levels of oxidative damage to DNA to human peripheral nucleated blood or&. J Natl Cancer Inst 1991: 83: 766-769. Hirai A, Tamura Y. EPA and adult disease in Japan. n-3 News 1987; 2(4): l-3. Dolecek TA. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the muitipie risk factor intervention trial. Pmc Set EXDBiol Med 1992: 200: 177482. Willett WC, Huiter DJ, Stampfer MJ, Colditz G, Manson JE, Speigelman D, Rosner B, Hennekens CH, Speizer FF. Dietary fat and fiber in relation to risk of breast cancer. JAMA 1992: 268: 2037-2044. Bingham S and Nelson M. Assessment of food consumption and nutrient intake. In: Marquette BM, Nelson M, Eds. Dosign Concepts in Nutritional Epidemiology. Oxford: Oxford University Press; 1993; pp 154167. Toniolo P Riboli E, Protta F, Charrel M, Cappa APM. Calorie-providing nutrients and risk of breast cancer. J Nat1 Cemer Inst 1989; 81: 278-286. National Research Council, Committee on Diet and Health. Diet and Health Implications for Reducing Chronic Diseese Risk. National Research Council; 1989. Diet, Nutition, end the Prevention of Chronic Disease. Report of a WHO Study Group. World Health Organization Technical Report Series 797. Geneva, Switzerland: WHO; 1990.
Pergamon
08954356(93)EOO30-F
Copyright 0 1994 Elsevier Science Ltd Printed in Great Britain. All rights reserved
0895-4356/94$6.00+ 0.00
Response RESPONSE
TO DR WALTER
WILLETT’S
DISSENT
ERNST L. WYNDER,’ LEONARD A. COHEN,’ DAVID P. ROSE*and STEVEN
D. STELLMAN]
‘Division of Epidemiology, American Health Foundation, 320 East 43 Street, New York, NY 10017 and 2Division of Nutrition and Endocrinology, American Health Foundation, 1 Dana Road, Valhalla, NY 10595, U.S.A. (Received 17 November 1993)
We would like to reply to Dr Willett’s comments by addressing the specific issues he has raised. It is understood that studies in nutritional carcinogenesis are inherently imprecise-a problem compounded by the need to integrate data from widely disparate disciplines. Thus, it is not surprising that marked differences in opinion concerning the interpretation of data have arisen. In this context, open and constructive debate is to be welcomed as the best means of resolving these scientific issues. First, with regard to the 65-county study in China [l], Dr Willett notes that fat intake varied from 5 to 47% of total calories across the 65 counties and that, despite this broad range, there was only a “slight” variation in breast cancer mortality rates and these rates were about five times lower than in the U.S. (The overall age-adjusted breast cancer mortality rate for Chinese women is 4.7, while that for U.S. women is 24.6/100,000 [2]). Dr Willett then concludes, “Thus, in this ecological study, less confounded by general socio-economic conditions, there is evidence that the international differences cannot be explained simply by the percentage of calories due to fat.” A more circumspect reading of this paper would have shown that fat intake among the people in the 65 counties actually ranged from 5.9 to 25.4% of calories, with a single exception (County WA) where it was 45.2%. This county is unique in that it has a population density of only 3 inhabitants/km*, has 67% employed in agricul-
ture; its residents have a high intake of meat and dairy products and, except for wheat, a very low intake of plant products. Using the same database, Marshall et al. [3] reported a weak positive association between fat intake and breast cancer risk. Moreover, when these data were segregated into quintiles of fat intake, a lower mean of 14.9% and an upper mean of 22.6% were reported. Such a weak association would be expected assuming that the people in China as a whole represent a population with low-fat intake that is at low-risk. It is most intriguing that despite significantly lower fat intake, the mean total caloric intake for males in China is greater than that in the U.S., i.e. 2656 vs 2360 kcal/day [l]. From this perspective, the data from China appear to support rather than refute the fat hypothesis. Regarding the comments about the steadily rising incidence of breast cancer in the U.S. against a decline in fat intake, it should be noted that from 1948 until the early 198Os, fat intake has risen continuously in the U.S. [4]. Since then, a decline from a high of >40% to approximately 37% of calories has occurred according to NHANES II. Hence, the continued increase in breast cancer incidence could be the delayed biological expression of an earlier dietary pattern. Even though total fat intake has decreased, the proportion of linoleic acid in the fats used as part of the U.S. diet has steadily increased over the past 40 years [5]. This is of particular interest since linoleic acid is a
227
228
ERNSTL. WYNDERet al.
precursor to the biologically active eicosanoids which appear to play a specific role in mammary cancer development [6]. We should also acknowledge that the rising incidence in breast cancer may, in part, be attributed to the increased use of mammography for early detection [7]. Contrary to Willett’s claim that “the effect of fat is not consistent in tumor models which do not involve the use of high doses of carcinogens”, it is worth noting that the earliest demonstration of the effect of fat by Tannenbaum [8] was in dba and C3H strain mice which produce mammary tumors “spontaneously” in the absence of exogenous carcinogens. Moreover, studies with tumor implants indicate that metastasis of mammary tumor implants to distant organs can be regulated by dietary fat [9]. That a “much stronger and more consistent finding has been that energy restriction profoundly reduces mammary tumors” is, in a general sense, true. However, caloric restriction inhibits mammary tumorigenesis only if the degree of restriction is 20-25% of the ad libitum intake and it is always associated with a significant decrease in body weight gain. Moreover, two recent large-scale meta-analyses do not support a calorie hypothesis: one showed a stronger correlation for body weight gain and tumorigenesis than for caloric intake [lo], and the other a highly significant effect of fat per se (p < 0.001) in mammary tumor development in a combined analysis of over 100 studies in rats and mice [ll]. The caloric hypothesis is also doubtful because high-fat diets that are rich in the monounsaturated, oleic acid (Cl 8: 1, n-9), in medium chain length fatty acids (C8:0, ClO:O), and long chain n-3 polyunsaturates (C20:5, n-3; C22:6, n-3) do not promote mammary tumor development while diets that are rich in linoleic acid (C18:2, n-6) do so even though they contain the same caloric density [12]. Doubt has been expressed as to whether or not changes made after menopause would have any effect on risk. This is a valid point and has not been adequately tested since most animal model studies are conducted in young rodents. However, Katz and Boylan [9] have shown that low-fat diets decrease metastatic dissemination of mammary tumor implants in older “retired breeders” but not in young rats, suggesting that fat can exert effects in non-cycling “postmenopausal” rodents. It is true that a definitive mechanism of action for the effect of dietary fats on mammary cancer
is lacking. (Parenthetically, it is worth noting no such mechanism has been demonstrated for caloric restriction.) Evidence for various mechanisms has been reviewed [13]. Several investigators have reported that populations consuming low-fat diets exhibit relatively low levels of circulating estrogens-hormones which have been implicated in breast cancer development. In a comparison of British and ruraldwelling Chinese, this difference applied to both premenopausal and postmenopausal women [14]; a similar study of American and ruraldwelling Japanese was limited to those beyond menopause [15]. Dr Willett expresses concern that non-intervention groups were not included in the published studies of dietary fat and blood estrogens. While the relevance of his reference to cholesterol is uncertain, this aspect has, in fact, now been addressed. A study of postmenopausal breast cancer patients participating in the WINS Trial showed that those with reliably assayable levels of serum estradiol did respond to a low-fat dietary intervention; the non-intervention group showed no such reduction in estradiol over a 1Zmonths observation period [16]. Recent studies by Tillotson et al. [17] indicating an effect of linoleic acid on ~53 gene expression in cultured mammary tumor cells and research by Djuric et al. [18] suggesting that oxidative damage to DNA is increased in humans consuming a high fat diet indicate that fat may exert its effects via altered gene expression or increased free radical activity. Also, while it is true that total polyunsaturated fat intake is similar in the U.S. and Japan, the Japanese consume a larger proportion of n-3 polyunsaturates than Americans, which may serve as a protective effect with regard to breast cancer [19,20]. Dr Willett is correct in his remarks concerning the unreliability of serum and adipose tissue lipid measurements as biomarkers for fat intake. No doubt, this is because in nutritionally homogeneous populations like the U.S., differences in the fatty acid profiles of adipose tissue or serum lipids are minimal. Preliminary studies indicate that total serum triglycerides are lower in women who eat low-fat diets (J. Richie, AHF, personal communication); nonetheless, a reliable biomarker for total fat intake remains to be established. The issue of the unreliability of dietary questionnaires was raised because it is the central problem in nutritional epidemiology. Out of
229
Response: Response to Dr Walter Willett’s Dissent
some 85,000 nurses, Willett et al. [21] analyzed a subsample of 200 women by weighing and measuring food intake over a 28-day period. These results, according to Willett, were then compared with the food frequencies obtained from the entire cohort with “reasonably” good correlations. It is true that weighed records of food consumption are associated with fewer sources of error than estimates of past intake; yet, recent findings [22] with weighed food records, validated by nitrogen excretion assays, are also associated with substantial bias. In the lower reported range of fat intake, a majority of individuals underreported their fat intake. Addressing the issue of the relative homogeneity of fat intake in the U.S. population, Willett claims that the respondents to the revised 1984 questionnaire included women who consumed less than 25% as well as those who ate more than 50% calories as fat. However, Bingham has shown [22], that in typical western societies, the frequency of women who consume below 28% of calories as fat is vanishingly small and that the vast majority fall within the range of 3@-44% of caloric intake as fat. It is of interest in this regard that Toniolo et al. [23] reported in a case-control study in Northern Italy, a decrease in breast cancer risk for women who consumed less than 24% fat calories when compared to women consuming >40% calories as fat. Willett is correct when he states that “it is notable that in large prospective studies of this relationship that have recently been conducted, the findings are much more consistent and all report little or no association.” Such a result is understandable in light of the relative uniformity of fat intake in the societies studied (Netherlands, U.S., etc.), and considering measurement errors and the well accepted phenomenon of social desirability bias. Clearly, intra-country prospective studies will not provide any further information on this subject unless the study cohort comes from a country with a fat intake ranging from at least 20% to more than 40% of total calories. Undoubtedly, Willett and colleagues have made a valuable contribution to the debate on fat and breast cancer. Viewing the data in aggregate, including over half a century of animal model experimentation, ecological studies and analysis of plausible mechanisms, it is difficult to accept their conclusion that dietary fat is an insignificant risk factor for breast cancer.
In conclusion, on the issue of dietary fat as a causative factor for breast cancer, our view does not stand alone. The extensive reviews by the National Academy of Sciences [24] and the World Health Organization [25] generally support our interpretation of existing data. It is not surprising, as we already know from the long controversy about to dietary fat and atherosclerosis, that any issue involving nutrition, because of its complicated interrelationships as well as economic interests, will be open to public debate for a long time to come. No doubt, the work of Willett and his group, as well as our own, will continue to contribute to this debate. This should lead not only to increasingly better understanding of the scientific issues, but also to public health decisions that have to be made on the basis of relative costs and benefits, rather than unambiguous proof. Because various dietary fats have been shown to relate to many other diseases, including coronary disease, the major cause of death in the U.S., and also because fats obviously contribute more to total caloric intake than do proteins and carbohydrates, a public health recommendation to reduce specific dietary fats is both timely and consistent with much of the curre’nt evidence and, to quote Hippocrates, “would do no harm”.
REFERENCES 1.
Chen J, Campbell TC, Junyao L, Peto R. The Diet, Lifestyles,
and Mortality
Characteristics
of 65 Rural
Populations in tbe People’s Republic of China. Oxford: Oxford University Press; 1987. 2. American Cancer Society. Cancer Facts and Figures. Atlanta, GA: American Cancer Society; 1992. 3. Marshall JR, Yinshen Q, Junshi C, Purpia B, Campbell TC. Additional ecological evidence: Lipids and breast cancer mortality among women aged 5.5 and over in China. Eur J Cancer 1992: 28A00): 172&1727. 4. Wynder EL, Fujita Y, Harris RE: Hirayama T. Hiyama T. Comparative epidemiology of cancer between the United States and Japan. A second look. Cancer 1991; 67: 746-763.
5.
Stephan AM, Wald NJ. Trends in individual consumption of dietary fat in the United States 1920-1984. Am J Clin Nutr 1990; 52: 457469.
6.
Horrobin DF. The role of essential fatty acids and prostaglandins in breast cancer. In: Reddy BS, Cohen LA, Eds. Diet, Nutrition and Cancer: A Critical Evaluation Vol. I: Macronutrients and Cancer, Boca Raton, FL: CRC Press; 1986; 102. 124. I. Miller BA, Feuer EJ, Hankey BF. The increasing incidence of breast cancer since 1982; relevance of early detection. Cancer Causes and Control 1991; 2: 67-74. 8. Tannenbaum A. The genesis and growth of tumors. III. Effect of a high fat diet. Cancer Res 1942: 2: 468m~475.
230 9.
10. 11.
12.
13.
14.
IS.
16.
17.
ERNSTL. WYNDERet Katz EB, Boylan ES. Stimulatory effect of a high polyunsaturated fat diet on lung metastasis from the 13762 mammary adenocarcinoma in female retired breeder rats. J Natl Cancer Imrt 1987; 79: 351-358. Albanes D. Total calories, body weight and tumor incidence in mice. Cancer Res 1987; 47: 1987-1992. Freedman LS, Clifford C, Messina M. Analysis of dietary fat, calories, body weight and the development of mammary tumors in rats and mice. A Review. Cancer Res 1990; SO: 5710-5719. Cohen LA. The role of dietary fat in cancer. In Food, Fats and Health. Council for Aaricultural Science and Technology (CAST) Task Fo& Report, No. 118, pp. 75-80, 1991. Cohen LA. Dietary fat and mammary cancer. In: Reddy BS, Cohen LA, Eds. Diet, Nutrition and Cancer: A Critical Evahtation. Macro-nutrients and Cancer, Vol. 1. Boca Raton, FL: CRC Press; 1986: 78-100. Key TJA, Chen J, Wang DY, Pike MC et al. Sex hormones in women in rural China and in Britain. Br J Cancer 62: 1990; 631-636. Prentice. R. Thomoson D. Clifford C. Gorbach S et al. Dietary fat reduction and plasma kstradiol concentrations in healthy postmenopausal women. J Nat1 Cancer Iast 1990; 82: 129-134. Rose DP, Connolly JM, Chlebowski RT, Buzzard IM, Wynder EL. The effects of a low-fat dietary intervention and tamoxifen adjuvant therapy on the serum estrogen and sex hormone-binding globulin concentrations of postmenopausal breast cancer patients. Breast Center Res Treat 1993; in press. Tillotson JK, Darzynkiewicz Z, Cohen IA, Ronai Z. Effects of linoleic acid on mammary tumor cell pro-
18.
19. 20.
21.
22.
23. 24.
25.
al.
liferation are associated with changes in ~53 protein expression. Int J Oncol 1993; 3: 81-87. Djuric Z, Heilbrun LK, Reading B, Boomer A et al. Effects of a low fat diet on levels of oxidative damage to DNA to human peripheral nucleated blood or&. J Natl Cancer Inst 1991: 83: 766-769. Hirai A, Tamura Y. EPA and adult disease in Japan. n-3 News 1987; 2(4): l-3. Dolecek TA. Epidemiological evidence of relationships between dietary polyunsaturated fatty acids and mortality in the muitipie risk factor intervention trial. Pmc Set EXDBiol Med 1992: 200: 177482. Willett WC, Huiter DJ, Stampfer MJ, Colditz G, Manson JE, Speigelman D, Rosner B, Hennekens CH, Speizer FF. Dietary fat and fiber in relation to risk of breast cancer. JAMA 1992: 268: 2037-2044. Bingham S and Nelson M. Assessment of food consumption and nutrient intake. In: Marquette BM, Nelson M, Eds. Dosign Concepts in Nutritional Epidemiology. Oxford: Oxford University Press; 1993; pp 154167. Toniolo P Riboli E, Protta F, Charrel M, Cappa APM. Calorie-providing nutrients and risk of breast cancer. J Nat1 Cemer Inst 1989; 81: 278-286. National Research Council, Committee on Diet and Health. Diet and Health Implications for Reducing Chronic Diseese Risk. National Research Council; 1989. Diet, Nutition, end the Prevention of Chronic Disease. Report of a WHO Study Group. World Health Organization Technical Report Series 797. Geneva, Switzerland: WHO; 1990.