linoleic acid intake and cancer risk (a review and meta-analysis), 1998

7/30/2019 Linoleic Acid Intake and Cancer Risk (a Review and Meta-Analysis), 1998

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ABSTRACT Replacement of saturated fat by the majordietary polyunsaturated fat linoleic acid reduces blood cholesterolconcentrations and the risk of coronary artery disease. However,there is concern that long-term consumption of large amounts oflinoleic acid might increase cancer risk. We reviewed the epi-demiologic and experimental literature on linoleic acid intake andcancer risk and performed additional meta-analyses of risk esti-

mates from case-control and prospective cohort studies. None ofthe combined estimates from within-population studies indicateda significantly increased risk of cancer with high compared withlow intakes of linoleic acid or polyunsaturated fat. For case-con-trol studies, the combined relative risks were 0.84 (95% CI: 0.71,1.00) for breast, 0.92 (95% CI: 0.85, 1.08) for colorectal, and 1.27(95% CI: 0.97, 1.66) for prostate cancer. For prospective cohortstudies, combined relative risks were 1.05 (95% CI: 0.83, 1.34) forbreast, 0.92 (95% CI: 0.70, 1.22) for colon, and 0.83 (95% CI:0.56, 1.24) for prostate cancer. Ecologic comparisons of popula-tions showed positive associations between cancer rates and percapita use of animal or saturated fat, but less so with per capita useof vegetable oil or polyunsaturated fat. Controlled studies of coro-nary artery disease in men did not, except for 1 study, show an

increased cancer incidence after consumption of diets with a veryhigh linoleic acid content for several years. Animal experimentsindicated that a minimum amount of linoleic acid is required topromote growth of artificially induced tumors in rodents; butabove this threshold, linoleic acid did not appear to have a specif-ic tumor-promoting effect. Although current evidence cannotexclude a small increase in risk, it seems unlikely that a highintake of linoleic acid substantially raises the risks of breast, colo-rectal, or prostate cancer in humans. Am J Clin Nutr1998;68:14253.

KEY WORDS Linoleic acid, n6 polyunsaturated fat, car-cinogenesis, tumors, breast cancer, colon cancer, rectal cancer,prostate cancer, risk factors, humans, meta-analysis

INTRODUCTION

Cancer risk in humans may be linked to the composition of thediet (1). In particular, dietary fat intake is often thought to beinvolved in the etiology of breast and colon cancer (2); both satu-rated and polyunsaturated fats have been implicated (3, 4). Anincreased intake of polyunsaturated fat is considered favorablebecause of its beneficial effects on blood cholesterol concentra-

tions. However, the possible adverse effects of a high polyunsatu-rated fat intake require scrutiny.

The major polyunsaturated fatty acid in most diets is linoleicacid (cis, cis-18:2n6). Linoleic acid is an essential fatty acid;it is required for the biosynthesis of eicosanoids but cannot besynthesized by the human body. An intake of 23% of dietaryenergy is probably enough to prevent deficiency (5). The aver-

age linoleic acid intake in the United States and WesternEurope has risen from 3% of energy in the 1950s to 67% atpresent, with a commensurate decrease in saturated fat (68). Afew populations (Northern Belgium and Israel) habitually con-sume 812% of their total energy intake as linoleic acid (912).

Replacement of saturated fat with linoleic acid is advocatedto improve serum lipoprotein profiles and reduce the risk ofcoronary artery disease (CAD) (5, 13, 14). Replacement of sat-urated fat with unsaturated fat does not cause a decrease inHDL cholesterol as occurs when saturated fat is replaced withcarbohydrates (15, 16). Some experts have recommended thatlinoleic acid consumption be raised to 10% of energy intake (5,13, 14). However, over the past 25 y the wisdom of recom-mending high intakes of polyunsaturated fatty acids has been

increasingly questioned (1722). The major concern is whetherdiets high in polyunsaturated fatty acids increase cancer riskbecause linoleic acid has been linked to the development ofcancer in animals (23, 24), and some population comparisonsreport positive associations with per capita use of polyunsatu-rated fatty acids (3, 4). An added concern is that polyunsatu-rated fat may be prone to oxidation, which may play a role incarcinogenesis (25, 26) and may increase the susceptibility ofLDL particles to oxidative modification (27). Such concernsled to the current recommendations that the average intake ofpolyunsaturated fats remain at 7% of total energy and that indi-vidual intake should not exceed 10% of total energy intake (28,

Linoleic acid intake and cancer risk: a review and meta-analysis13

Peter L Zock and Martijn B Katan

1

From the Wageningen Agricultural University, Department of Food Tech-nology and Nutritional Sciences, Division of Human Nutrition and Epidemi-ology, Wageningen, Netherlands.

2 Supported by the Foundation for Nutrition and Health Research.3 Reprints not available. Address correspondence to MB Katan, Wagenin-

gen Agricultural University, Department of Food Technology and NutritionalSciences, Division of Human Nutrition and Epidemiology, Bomenweg 2, 6703HD Wageningen, Netherlands.

Received July 30, 1997.Accepted for publication December 26, 1997.

Am J Clin Nutr1998;68:14253. Printed in USA. 1998 American Society for Clinical Nutrition142

See corresponding editorial on page 5.


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LINOLEIC ACID AND CANCER RISK 143

29). However, the question remains whether high intakes oflinoleic acid do increase the risk of cancer, especially cancer ofthe breast, colon, and prostate.

METHODS

To identify studies of the relation between diet and cancers ofthe breast, colon and rectum, and prostate we searched the MED-

LINE database (National Library of Medicine, Bethesda, MD)for the years 1966-1996 and BIOLOGICAL ABSTRACTS forthe years 1989-1996 using the following key words: diet, fat,fatty acid, cancer, neoplasm, malignancy, carcinogenesis, tumor,carcinoma, and adenoma. We also checked citations in the iden-tified articles. In vitro studies were not considered.

We specifically selected epidemiologic studies that providedquantitative estimates of cancer risk and its SE with high com-pared with low intakes of linoleic acid or polyunsaturated fat.For combined estimates across studies, we used results of pub-lished meta-analyses and performed additional meta-analyseswhen necessary. To this end, we extracted from individual stud-ies the risk estimate that referred to the largest difference inintake and that reflected the greatest degree of control for other

environmental and dietary risk factors. When studies providedestimates of risk for subgroups of subjects, eg, older and youngersubjects, we used or calculated the risk estimate for all subjects.

For combining risk estimates, we used a random-effectsmodel (30) to take into account both the sampling variancewithin studies and the variation in the true underlying effectsacross the studies being combined. Such variation in underlyingeffects (heterogeneity) seemed plausible because of the differ-ences in populations, designs, and methods among studies. Amodel assuming equal sampling variances for each study, ie,each study having equal weight, and a fixed-effects modelassuming the same underlying effect across studies (homogene-ity) yielded similar results.

RESULTS

Breast cancer

Analytic studies within populations

Case-control studies. In the 16 case-control studies fromwhich we were able to extract a quantitative estimate of breastcancer risk, risk was not increased with high intakes of linoleicacid (Figure 1). The combined relative risk, involving a total of6910 cases and 8536 control subjects, was 0.84 (95% CI: 0.71,1.00). This outcome agrees with results of previous meta-analy-ses. Boyd et al (47) calculated a combined relative risk of 0.92(95% CI: 0.79, 1.08) from 9 case-control studies publishedbefore 1993. Two of these 9 studies (36, 37) showed a lower

breast cancer risk with higher polyunsaturated fat intake and theother 7 studies (3135, 38, 39) showed no significant effect(Figure 1). Howe et al (48) pooled the results of 8 studies thatprovided data on polyunsaturated fat. Among 5167 post-menopausal cases and control subjects, the univariate relativerisks for each extra 45 g/d were 1.25 for polyunsaturated, 1.46for saturated, and 1.41 for monounsaturated fat. In a model thatincluded all 3 types of fat, the relative risk for polyunsaturatedfat was 0.78 (95% CI: 0.51, 1.17). In 4 recent studies notincluded in previous meta-analyses (4043), the relative risks

for high compared with low polyunsaturated fat intakes ranged

from 0.7 to 1.3 (Figure 1).The studies mentioned above all assessed fat intake by self-report of subjects. Biomarkers of intake have also been used. Onestudy measured the fatty acid composition of erythrocyte phospho-lipids in 46 breast cancer cases and 53 control women in Moscowand found a significantly reduced risk of breast cancer associatedwith a high proportion of linoleic acid in phospholipids (44)(Figure 1). Erythrocyte phospholipids reflect diet in the pastweeks or months (49) and it is possible that patients changedtheir diets because of their disease or that the disease affected theproportion of linoleic acid in their erythrocytes. A better long-term biomarker is the fatty acid composition of adipose tissue(50). A study among Boston women found no associationsbetween breast cancer risk and n6 polyunsaturated fatty acidsin buttock fat from 380 breast cancer cases and 397 control sub-

jects (45). Similar findings were reported for women in NewYork (46) (Figure 1).

Several case-control studies reported results in terms otherthan relative risk. A study in Hawaii (51) showed no differencein self-reported linoleic acid intake between breast cancer casesand control subjects. In studies from Finland (52) and Israel (53)there were no significant differences in the linoleic acid contentof breast adipose tissue between cases and control subjects. Insummary, the case-control studies analyzed showed either no ornegative associations between linoleic acid intake and breastcancer risk.

Prospective cohort studies. The prospective cohort studiesanalyzed also did not show positive associations betweenlinoleic acid intake and breast cancer risk (Figure 2). Hunter etal (59) conducted a pooled analysis on standardized data from 7major cohort studies of fat intake and breast cancer involving atotal of 4980 cases among 337 819 women (41, 5458, 66). Thepooled relative risk, corrected for dietary measurement error,was 1.05 (95% CI: 0.83, 1.34) for each 10-g/d increase inpolyunsaturated fat intake (Figure 2). In 3 cohort studies (6062)that did not meet the criteria of Hunter et al (59), the relativerisks for high compared with low polyunsaturated fat intakeranged from 0.73 to 1.23 (Figure 2). In a cohort from California,intake of all types of fat, including linoleic acid, was higher in 15

FIGURE 1. Relative risks of breast cancer with high compared withlow intakes of linoleic acid in case-control studies. Bars are 95% CIs.


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cases than in 575 women who did not develop breast cancer.These differences disappeared after adjustment for total energyintake (67). In a biomarker study that measured phospholipidfatty acids in blood sampled 0.516 y before the onset of breastcancer, a high proportion of linoleic acid was associated withreduced risk in women younger than 55 y (Figure 2), but not inthose older than 55 y (63).

Two studies investigated the effect of dietary fat intake afterdiagnosis on cancer survival. In a study of 161 white and 182Japanese breast cancer patients in Hawaii (64), the white womenwith a high polyunsaturated fat intake, not adjusted for energyintake, had a greater risk of death (Figure 2; relative risk: 1.72).In an Australian study (65), the relative risk of death of 412breast cancer patients was 1.57 at a high compared with a lowintake of polyunsaturated fat and 1.14 at a high compared with alow linoleic acid intake (Figure 2).

In summary, longitudinal epidemiologic studies (Figure 2) donot suggest that linoleic acid intake has a marked effect on thedevelopment of breast cancer. The 1 exception is a new analysisof the Swedish Mammography Screening cohort (68). An earlieranalysis showed no relation with polyunsaturated fat intake (41,59). The new analysis applied a mutual adjustment for intakes ofdifferent types of fat and found a relative risk of breast cancer of1.69 (95% CI: 1.02, 2.78) for each 5-g/d increase in intake ofpolyunsaturated fat (68). However, other studies also adjustedfor mutual confounding among the various types of fat and found

no increased risk of breast cancer with higher intakes of polyun-saturated fat (40, 58). Thus, the bulk of the data still suggest thatlinoleic acid does not have a marked effect on the risk of breastcancer. The findings on survival in breast cancer patients suggesta possible adverse effect on mammary tumor progression, but thedata are limited.

Ecologic comparisons between populations

Comparisons between countries generally show positive corre-lations between per capita disappearance of total fat and breastcancer incidence or mortality (6973). Some studies suggest that

these associations are mainly due to the use of animal and satu-rated fats rather than to the use of vegetables or polyunsaturatedfats (72, 7476), but others show positive associations of breastcancer rates with the use of polyunsaturated fat (3, 4, 77, 78).Carroll (76) reported that mortality from breast cancer is stronglyassociated with intakes of fat from animal sources but not withthe percentage of energy as polyunsaturated fat; in contrast, Pren-tice et al (3, 77) estimated that a 50% reduction in both saturated

and polyunsaturated fats would reduce breast cancer risk by half.Thus, results from ecologic comparisons are not consistent.In view of the uncertainties concerning food disappearance

data, population comparisons that use biomarkers of intake maybe more reliable. One study assessed intake from linoleic acid inthe adipose tissue of subjects from 10 European regions andIsrael (79) (Figure 3). Incidence in the Israeli women, whoselinoleic acid intakes have been some 1012% of energy for thepast decades (11, 12), was not higher than in women from north-western Europe, whose intakes were probably 47% of energy.The breast cancer rate in the Israeli women may have been addi-tionally inflated by the high frequency ofBRCA1 and BRCA2mutations in Ashkenazi Jews (80).

Animal studies

The hypothesis that dietary fat or specific fatty acids can causebreast cancer originates from studies in rodents by Tannenbaumin 1942 (81). Since then, a large number of animal experimentsshowed that the amount and type of fat can markedly influencethe growth of induced breast tumors in rodents during the pro-motion stage, but less so during the initiation stage (for a reviewsee reference 82). In rats, a diet rich in polyunsaturated fat pro-moted growth of chemically induced (dimethylbenz[a]anthraceneor N-nitrosomethylurea) or transplanted tumors more than did adiet rich in saturated fat (24, 8386). Other studies showed thatup to 45% of dietary linoleic acid in the diet promotes artificialmammary tumorigenesis in rats but that higher amounts have noadditional effects; once the diet contained 45% of energy as

linoleic acid, tumor yield and growth increased with the totalamount of dietary fat, but saturated fats had the same effect aspolyunsaturated fats (8790). On the other hand, in experiments

144 ZOCK AND KATAN

FIGURE 2. Relative risks of breast cancer with high compared withlow intakes of linoleic acid in prospective cohort studies. The pooledestimate was derived from the study by Hunter et al (59). Bars are 95%Cis. The study by Willett et al (58) refers to estimates from the NursesHealth study: A, follow-up from 1980 to 1986; B, follow-up from 1986

to 1991.

FIGURE 3. Breast cancer incidence in 11 European regions andIsrael by the average linoleic acid content of adipose tissue in 40164healthy subjects in the corresponding regions [control subjects from theEURAMIC (European Community Multicenter Study on Antioxidants,Myocardial Infarction, and Breast Cancer) study (79)].


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with athymic nude mice that were injected with human breastcancer cells, diets containing 16% or 24% of energy as linoleicacid increased tumor weight and pulmonary metastasis comparedwith a diet containing the same amount of total fat but only 4% ofenergy as linoleic acid (91, 92).

One study addressed the effect of long-term polyunsaturatedfat intake on spontaneous breast tumors in rats and mice (93, 94).In a set of experiments, 3578 female rats and mice received by

diet 10% of energy as fat and 2200 animals received by gavageadditional corn oil that increased fat intake to 30% of energy.The 2-y incidence of spontaneous breast tumors was the same orsomewhat higher with the low-fat diet (2.5% in the rats and 1.7%in the mice) than with the diet high in corn oil (1.5% in rats and1.3% in mice).

In summary, short-term experiments show that a minimumamount of linoleic acid is required to stimulate the growth ofartificially induced mammary tumors in rats. Above this thresh-old, it appears to be the total amount of fat, or dietary energy(9597), that promotes tumorigenesis, and that linoleic acid is aseffective as other types of fatty acids. A high linoleic acid intakedid stimulate carcinogenesis in 1 particular mouse model but along-term high intake of linoleic acid did not increase sponta-

neous development of breast tumors in rats and mice (93, 94).Colorectal cancer


Case-control studies. The case-control studies from which wewere able to extract quantitative estimates of risk showed noconsistent association between intake of linoleic acid orpolyunsaturated fat and colorectal cancer risk (Figure 4). Howeet al (108) combined the results of 13 studies on colorectalcancer and diet. Eleven studies involving a total of 5287 casesand 10 470 control subjects provided intake data onpolyunsaturated fat; 2 studies (103, 104) found a positiveassociation and the other 9 studies (98102, 105107) showed

no or weakly inverse associations. The pooled odds ratio per21.3 g polyunsaturated fat/d was 0.92 (95% CI: 0.85, 1.08) for

all subjects, 1.05 (95% CI: 0.90, 1.23) for the men, and 0.80(95% CI: 0.66, 0.98) for the women.

Case-control studies not included in the meta-analysis byHowe showed relative risks of colorectal cancer (109111) oradenomatous polyps (112) ranging from 0.29 to 1.63 with highcompared with low polyunsaturated fat intakes (Figure 4). Incase-control studies that did not report estimates of risk, colo-rectal cancer patients and control subjects consumed the same

amount of polyunsaturated fat (113, 114).Three case-control studies used biomarkers to assess linoleicacid intake (11, 114, 115). These studies are not represented inFigure 4 because no estimates of relative risk were given. Asmall study from Scotland reported a somewhat lower proportionof linoleic acid in red blood cells of 20 colon cancer pa tients thanin 20 control subjects (115); in other studies there were no dif-ferences between cases and control subjects in the proportionof linoleic acid in adipose tissue (11, 114) or red blood cells(114). Thus, the case-control studies analyzed showed no con-sistent association between linoleic acid intake and colorectalcancer risk.

Prospective cohort studies. Prospective data on fat and colo-rectal cancer risk are limited; the relative risks (Figure 5) of

colorectal cancer or adenomatous polyps in subjects with highcompared with low intakes of linoleic acid were measured in 3large cohorts from the United States (116, 117, 119121) and 1from the Netherlands (118). In these 4 studies involving a totalof 782 patients with colorectal cancer among 292 768 persons,the risk of developing colon cancer during 36 y of follow-upwas not associated with previously reported intakes of linoleicacid or polyunsaturated fat (116119). We calculated a combinedrelative risk of 0.92 (95% CI: 0.70, 1.22).

Risk of adenomatous colorectal polyps in male health profes-sionals who underwent endoscopy was nonsignificantly increasedwith a high polyunsaturated fatty acid intake (120) (Figure 5). Riskof hyperplastic colorectal polyps in the same population was non-significantly decreased with a high polyunsaturated fatty acid

intake, as was the risk of hyperplastic colorectal polyps in theNurses Health Study (121). The combined risk of adenomatousand hyperplastic colorectal polyps with high compared with lowpolyunsaturated fat intakes, based on a total of 564 cases among35 545 persons, was 1.06 (95% CI: 0.55, 2.05). Thus, theseprospective cohort studies showed no association of polyunsatu-rated fat intake with the risk of colorectal cancer.

Ecologic comparisons between populations

International comparisons showed strong associationsbetween per capita use of total fat and incidence or mortalityfrom colorectal cancer (70, 71, 122124). However, unlikebreast cancer, the association was consistently limited to satu-rated or animal fats; there was no association with polyunsatu-

rated or vegetable fats (3, 75, 78, 122124).This finding agrees with hitherto unpublished prospectivedata from the Seven Countries Study. Between 1958 and 1964,12 763 men from 16 cohorts were enrolled in this study (125).Dietary information was collected at baseline from random sam-ples of 849 men from each cohort. In 1987, food compositesrepresenting intake at baseline were collected locally and ana-lyzed for fatty acids (126). The vital status of all men was veri-fied after 25 y of follow-up (127). Linear regression analysis wasused to relate average linoleic acid intake in the 16 cohorts withage-adjusted mortality rates from colorectal cancer [Interna-


FIGURE 4. Relative risks of colorectal cancer with high comparedwith low intakes of linoleic acid in case-control studies. The pooled esti-mates were derived from the study by Howe et al (108). Bars are 95% CIs.


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tional Classification of Diseases (ICD) 152154] and all

cancers (ICD 140209). Intakes of dietary fiber and energywere added to the model as possible confounders.Average linoleic acid intake ranged from 8 g/d in Japan,

Rome, and eastern Finland to 22 g/d in Belgrade, Serbia(Figure 6). Mortality from colorectal cancer was not asso-ciated with linoleic acid intake. Adjustment for dietaryfiber and energy intakes did not change this result. Mortal-ity from all cancers was also not associated with linoleicacid intake (D Kromhout, E Feskens, personal communica-tion, 1996). Thus, population comparisons showed no asso-ciation of linoleic acid consumption with the risk of colo-rectal cancer.

Animal studies

Results from animal experiments that studied the effect ofdietary fat on artificially induced colon cancer varied with themodel and methods used (for review see references 128 and129). Diets high in polyunsaturated fat promoted tumor growthin rats after initiation of the tumors, but not during the initia-tion stage (130). Some studies in rats indicated that polyunsat-urated n6 fatty acids promote the growth of chemicallyinduced colon tumors more so than do saturated fatty acids (23,131, 132), but others showed no difference (133) or found thatn6 fatty acids promote tumor growth less so than do saturatedfatty acids (134). In a meta-analysis of 14 rat studies (135),total fat intake adjusted for energy intake increased tumorgrowth in Fischer 344 rats, but not in Sprague-Dawley rats. InFischer 344 rats, both n6 polyunsaturated and saturated fats

increased tumor growth more so than did monounsaturated orn3 polyunsaturated fats (135). The minimum amount ofdietary essential fatty acids needed to induce colon tumors inrats is 1% of energy (136), which is much lower than the4.5% of energy needed to induce breast tumors (88). In mice,increasing amounts of dietary linoleic acid stimulated growthof transplanted colonic adenocarcinoma tumors up to 4% ofenergy intake, but not at higher intakes (137). Thus, there issome evidence that n6 polyunsaturated fat promotes thegrowth of artificially induced colorectal tumors in rodents, butthe data are inconsistent.

Prostate cancer


Case-control studies. Case-control studies of the relationbetween dietary fat and prostate cancer generally show a positiverelation with total fat intake (for review see reference 138), butfew studies collected data on specific fatty acids. For the 3 case-control studies from which we were able to extract quantitativeestimates of risk (139141), involving a total of 654 cases and 924control subjects, we calculated a combined relative risk of prostate

cancer of 1.27 (95% CI: 0.97, 1.66) with high compared with lowintakes of polyunsaturated fat (Figure 7). One study found anincreased risk with high polyunsaturated fat intake in older men,but not in younger men (139). Another study found an increasedrisk with a high proportion of linoleic acid in erythrocyte mem-branes and fat tissue (141).

A few studies measured polyunsaturated fat intake, but did notreport estimates of risk. In 1 study (144, 145), prostate cancerpatients consumed the same (144) or somewhat lower amounts oflinoleic acid than did control subjects (145). Another study foundno association between polyunsaturated fat intake and prostatecancer (146). In a study from Scotland, the polyunsaturated fatintake of 20 patients was higher than that of 20 control subjectsaccording to a food-frequency questionnaire, but not according to

the proportion of linoleic acid in red blood cells (115). Thus, thelimited amount of data from case-control studies show either no orpositive associations between linoleic acid intake and prostatecancer risk.

Prospective cohort studies. Several prospective cohort studieshave investigated dietary factors in relation to prostate cancer (forreview see reference 138), but only 2 (142, 143) have investigatedthe relation between prostate cancer and polyunsaturated fatintake (Figure 7). In 2 cohorts, 1 of US health professionals (142)and 1 of US physicians (143), linoleic acid showed no or a weaklynegative association with prostate cancer. The combined relative

146 ZOCK AND KATAN

FIGURE 5. Relative risks of colon cancer and colorectal polyps withhigh compared with low intakes of linoleic acid in prospective cohortstudies. Bars are 95% CIs.

FIGURE 6. Age-adjusted mortality from colorectal cancer after 25 yof follow-up in the Seven Countries Study, by linoleic acid intake atbaseline in 1960. A description of the cohorts is as follows: A, US rail-road; B, Belgrade, Serbia; C, Crevalcore, Italy; D, Dalmatia, Croatia; E,east Finland; G, Corfu, Greece; K, Crete, Greece; M, Montegiorgio,Italy; N, Zutphen, Netherlands; R, Rome railroad; S, Slavonia, Croatia;T, Tanushimaru, Japan; U, Ushibuka, Japan; V, Velika Krsna, Serbia; W,

west Finland; Z, Zrenjanin, Serbia. Data were kindly provided by DaanKromhout and Edith Feskens of the National Institute of Public Healthand the Environment, Bilthoven, Netherlands.


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found no associations between linoleic acid intake and cancerrisk. Furthermore, prospective cohort studies, which are notsubject to recall bias, also showed no associations. Thus, recallbias is not the most likely explanation for the absence of associa-tions in case-control studies.

Errors in measurements of dietary intake in epidemiologic studiesare generally large. Random (nondifferential) measurement errorattenuates estimates of relative risk toward 1. Most of the studiesreviewed here did not correct risk estimates for this type of error, butHunter et al (59) found that correction had little effect on the outcomeof their pooled analysis of cohort studies on breast cancer. This sug-gests that this type of error cannot totally explain the absence of asso-ciations. However, Prentice (160) criticized the existing methods forcorrection and argued that dietary measurement error may also besystematic (ie, not random). He concluded that dietary self-reportinstruments may be inadequate for analytic studies. On the otherhand, assessment of dietary intake with biomarkers avoids such sys-tematic error, and, except for 1 study (141), studies that used bio-markers also found no (45, 46) or negative (44, 63, 161) associations

between linoleic acid intake and cancer incidence. It is unclear towhat extent dietary measurement error may have affected the esti-mates of risk in studies that relied on self-reported intake.

A narrow range of linoleic acid intake in the population may beanother reason why associations were not found. In the studies reviewedhere, linoleic acid intake in the highest category was typically twice thatin the lowest category of intake, with differences ranging from5 to 25g/d. This is comparable with the normal range of intake of 410% of dailyenergy. However, it cannot be excluded that cancer risk within popula-tions would be affected by larger differences in linoleic acid intake. Yetanother reason for not finding a significant association in an individualepidemiologic study is the limited number of subjects, which results inlow statistical power. However, the combined risk estimates presentedhere, involving large numbers of patients, also did not show associations

between linoleic acid intake and cancer risk.Confounding must also be considered. For example, people who con-sume high amounts of linoleic acid may also consume high amounts ofvegetables and fruit, which might obscure increases in colorectal cancerrisk caused by a high linoleic acid intake. Possible confounders in studiesof breast cancer are body weight and intake of total energy or of otherfatty acids. Such confounders are often not taken into account or cannotbe completely adjusted for. Thus, bias of risk estimates by con-founding factors cannot be excluded. Also, linoleic acid intakereflects the use of vegetable oils such as rapeseed and soybean oils.It remains possible that associations reported for linoleic acid or

polyunsaturated fat are affected by other substances from these oils.Publication bias is not plausible because studies showing positive asso-ciations between linoleic acid intake and cancer risk would be morelikely to be published than would studies showing negative associ-ations.

Many of the analytic studies reviewed measured the intake of allpolyunsaturated fats and not linoleic acid intake per se. Polyunsatu-rated fat in human diets consists mainly of linoleic acid, but it alsoincludes-linolenic acid and long-chain n3 fatty acids from fish oil.It has been suggested that these n3 fatty acids may have specificeffects on cancer risk (162164). If so, then a risk estimate for polyun-saturated fat would not be the same as a risk estimate for linoleic acid.However, studies that measured polyunsaturated fat intake and stud-ies that specifically measured linoleic acid intake showed no consis-tent associations with cancer risk. Therefore, it is plausible that dif-ferences in polyunsaturated fat intake reflected differences in linoleicacid intake, and that n3 fatty acids did not materially affect the riskestimates for polyunsaturated fat.

Thus, there are several methodologic reasons analytic studies

within populations may have missed a possible association betweenlinoleic acid intake and cancer risk. The question becomes whethersuch studies, when applying similar methods in similar populations,can at all detect associations between fatty acid intake and diseaserisk. For example, do within-population studies reveal the expectedrelation between linoleic acid intake and the risk of CAD? Indeed, asubstantial proportion of prospective cohort studies did show inverseassociations between polyunsaturated fat intake and the risk of CAD(165169), although the remainder of the studies did not (170174).Thus, epidemiologic studies of this type should be able to detect anassociation between linoleic acid intake and disease risk, if one exists.In addition, several of the studies described above showed associa-tions between cancer risk and food components other than linoleicacid, such as animal fat and red meat (107, 116). Therefore, if a sub-

stantial association between linoleic acid intake and cancer risk exists,it is unlikely that virtually all analytic studies would fail to find suchan association purely because of methodologic limitations. However,the evidence from these analytic studies cannot exclude the possibil-ity of a small increase in cancer risk with high intakes of linoleic acid.

Evidence from other types of studies

Ecologic comparisons

Ecologic studies compare average cancer rates of countries orregions rather than risks of individuals. Such studies have major

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TABLE 1

Cancer incidence in clinical trials of highlinoleic acid diets and coronary artery disease in men1

Duration of study Number of cancer cases

Study Linoleic acid intake (diet + follow-up) Experimental Control Relative risk (95% Cl)2

% of energy y

Oslo Diet-Heart Study (153) 20.7 5 + 6 10/206 7/206 1.4 (0.5, 3.8)Medical Research Council soybean oil (154) 17.0 4.5 + 3 2/199 8/194 0.2 (0.1, 1.2)Finnish Mental Hospital (155) 12.0 6 4/327 4/254 0.8 (0.2, 3.1)

Faribault (156) 17.4 1.5 + 5 1/167 1/57 0.3 (0.0, 5.5)Los Angeles Veterans (157) 13.8 6.5 + 2 67/424 52/422 1.3 (0.9, 1.9)Combined 16.23 5 + 33 84/1323 72/1133 1.004 (0.7, 1.4)

1 Adapted from the study by Ederer et al (152), who estimated a combined relative risk of 1.15 (95% Cl: 0.81, 1.63) by the method of Gart (158).2 High compared with low linoleic acid intakes.3 Mean.4 Crude risk ratio of the pooled data.


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limitations. There are multiple differences between populationsthat may affect cancer risk and there is no or only a limited pos-sibility to adjust for these confounders. Also, the use of percapita use data to assess dietary intake is questionable, and thequality of mortality or incidence data from national cancer reg-

istrations may be different for different countries, which maybias the associations. Nevertheless, ecologic comparisons offerthe advantage of involving large differences in intakes betweenpopulations. Furthermore, some ecologic comparisons assessintake by aggregating individual intake data and in this wayeliminate random dietary measurement error. Two ecologic com-parisons that assessed intake by aggregating individual intake orbiomarker data showed no association between linoleic acid andcancer risk despite large differences in linoleic acid intake (79)(Figures 3 and 6). Studies that assessed linoleic acid intake fromper capita use data indicated that saturated and animal fats ratherthan polyunsaturated fat or linoleic acid may play a role inincreased cancer risk. Thus, the ecologic comparisons we ana-lyzed did not suggest a major influence of linoleic acid on the

risk of breast or colorectal cancer.Controlled trials of highlinoleic acid diets

Controlled trials that were designed to study the effects oflinoleic acid on CAD did not show an increased number of can-cer cases in groups of subjects that consumed high amounts oflinoleic acid (16% of energy intake) for 17 y. These trialsinvolved mostly men and therefore provide no information onbreast cancer. Also, the number of cases was small and the expo-sure period may have been too short to show any effect oflinoleic acid intake on cancer incidence. Thus, the strength of theevidence from controlled trials of highlinoleic acid diets is lim-ited. Nevertheless, except for 1 trial (17), the findings do notsupport the hypothesis that a high linoleic acid intake increases

cancer risk.Animal experiments

The relevance of short-term experiments in animals with arti-ficially induced tumors to the development of human cancersover decades is unclear. Profound and consistent effects oflinoleic acid on initiation of tumorigenesis have not been shown(82). Linoleic acid promotes tumor growth in rodents only undercertain conditions and in certain models (129, 175). For exam-ple, breast tumors induced by hormones were less responsive todietary fat than were those induced by chemicals (176), and

dietary fat increased colorectal tumor growth in 1 strain of labo-ratory rats but not in another (135). Nevertheless, there appearsto be a minimum required intake of linoleic acid for tumor devel-opment in rodents. However, this requirement is about as low orlower than intakes recommended to prevent deficiency of essen-tial fatty acids, and reducing linoleic acid intake to below theseamounts is neither realistic nor desirable. We feel that experi-ments in rodents are of limited value for addressing the question

of whether a life-long high intake of linoleic acid increases therisk of spontaneous cancers in humans.

Implications

The available evidence does not suggest that a high intake oflinoleic acid substantially raises the risk of breast, colorectal, orprostate cancer. Nevertheless, a small increase in risk cannot beexcluded. When applied to the total population, a small increasein risk may still have a large effect on public health. For example,an increase in breast cancer risk of 10% would increase the num-ber of breast cancer cases occurring in the United States each yearby 18 000 (177). A relevant question for public health policy iswhether a possible adverse effect of linoleic acid would be out-weighed by beneficial effects on CAD risk. Replacement of satu-

rated fatty acids with oleic acid instead of linoleic acid would alsoreduce CAD risk and at the same time avoid worries about anypossible increase in cancer risk; however, it is not clear whetheroleic acid is as effective as linoleic acid in improving the serumlipid profile and reducing CAD risk (15, 178). Therefore, futurestudies should determine the benefit of linoleic acid comparedwith that of oleic acid on CAD risk. If such studies show thatlinoleic acid and oleic acid have similar effects on CAD risk, thenit may still be prudent to restrict linoleic acid intake. However,the currently available evidence does not provide a compellingargument for such a restriction.

We thank E Feskens, D Kromhout, and M Jansen for providing data fromthe Seven Countries Study, and N Boyd, L Holmberg, G Howe, D Hunter, RKaaks, P Toniolo, and A Wolk for supplying additional information abouttheir studies.

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TABLE 2

Summary of the evidence concerning the relation between linoleic acidintake and cancer risk1

Cancer site

Type of study Breast Colon Prostate All

Epidemiologic studiesWithin-population studies

(combined relative risk)

Case-control study 0.8 0.9 1.3Cohort study 1.1 1.0 0.8Comparisons between populations +/= = +/=

Controlled clinical trials oncoronary artery disease

Animal studies +/= +/= NA =1 +/=, inconsistent positive association; =, no association; NA, not

available.


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