Israeli 'cancer shift' over heart disease mortality may be led by greater risk in women with high intake of n-6 fatty acids

My hypothesis is that higher female sensitivity to increased n-6 polyunsaturated fatty acids and their carcinogenic effect may contribute to the recent Israeli 'cancer shift' over heart disease mortality (23.1 vs. 22.3%, 1999). High n-6 polyunsaturated fatty acid intake was the presumed dietary risk underlying the 'Israeli paradox', the unexpected gap between 'ill' health and 'good' diet. Scientific literature and population health surveillance reports were reviewed. Cancer death rates for Israeli Arabs, who consumed a more traditional Mediterranean diet - more monounsaturated fatty acids, mostly olive oil, and less n-6 polyunsaturated fatty acids - are still 1.1-1.7 times (men-women) lower than in Israeli Jews, but are increasing faster (23.6 and 5.1% vs. 5.3 and -3.3%, 1980-2000), concurrently with dietary 'Israelization' - specifically, increased intake of n-6 polyunsaturated fatty acids. Israeli-Jewish women attained an earlier, much larger (29 vs. 7%, 1999) 'cancer : heart disease mortality shift' (ratio >1.0), ranked much worse for cancer (15th/44 European countries) than men (37th) and heart disease (38th and 34th, respectively), and had much higher cancer prevalence (1 : 3) than Israeli-Arab women (1 : 6), though dietary compositions were similar, save for higher n-6 polyunsaturated fatty acid and polyunsaturated fatty acid : monounsaturated fatty acid ratio. Population studies of Israeli Jews, Arabs, and women support the association of high n-6 polyunsaturated fatty acid intake with increased cancer risk and higher female sensitivity. Research findings suggest that gender and sex hormones may influence n-6 polyunsaturated fatty acid metabolism and carcinogenesis. This appears to be the first time gender has been proposed to modulate national cancer epidemiology, suggesting implications for differential nutritional prevention, warranting further research.

Introduction

Israeli cancer mortality rates recently surpassed those of heart disease (23.1 vs. 22.3%, 1999; ^{ICDC, 2004a}). This was attributed to improved heart disease prevention and care (^{ICDC, 2004a}).

The 'good' Israeli diet - balanced in kilocalories, high in fruits and vegetables, limited in total fat and saturated fat, and having a high polyunsaturated fatty acid (PUFA) : saturated fatty acid (P : S) ratio (^{ICDC, 2003a}) - is assumed to be consistent with dietary recommendations for heart protection. Despite the 'good' Israeli diet (^{ICDC, 2004b}) and medical care as indicated by high 5-year survival rates in Israeli Jews (relative survival rates of 79.7 vs. 80.5% in the United States, 2000) (^{ICDC, 2005b}), cancer mortality has barely decreased, annually by only 0.3% (^{ICDC, 1999}). An unexpected gap between the 'good' Israeli diet and 'ill' health, as manifested by higher rates of chronic diseases relative to those of other Mediterranean-but similar to those of Western- countries, has been identified (^{Yam et al., 1996}; ^{Dubnov and Berry, 2003}). Dubbed the 'Israeli paradox', it has been attributed to the high consumption and extremely high content in adipose tissue of n-6 PUFA, mostly linoleic acid (LA) (^{Enig et al., 1984}; ^{Kark et al., 2003}; ^{ICDC, 2004b}). Although high n-6 PUFA levels have exhibited a protective effect against high blood cholesterol, low-density lipoprotein cholesterol, and triacylglyceride (TG) levels - the widely accepted risk factors of heart disease (^{Grundy, 1999}; ^{Sacks and Campos, 2006}) - they may increase risks of metabolic disease (^{Okuyama et al., 1996}; ^{Rustan et al., 1997}; ^{Grundy, 1999}; ^{Berry, 2001a, b}; ^{Ailhaud and Guesnet, 2004}; ^{Ghafoorunissa et al., 2005}; ^{Sacks and Campos, 2006}) and cancer (^{Fang et al., 1996}; ^{Okuyama et al., 1996}; ^{Rose and Connolly, 2000}; ^{Berry, 2001a,b}; ^{Wirfalt et al., 2002}; ^{Bagga et al., 2002}; ^{Simopoulos, 2004}; ^{Binukumar and Mathew, 2005}).

Israeli Jews - a heterogeneous group representing various ethnic backgrounds, primarily Ashkenazi (^{ICDC, 2000}) - consume much more n-6 PUFA (mostly soy) and less n-9 monounsaturated fatty acid (MUFA) (i.e. olive) oils, and have a much higher cancer risk (1 : 3) than do Arabs (1 : 5 for men, 1 : 6 for women) (^{Barchana and Lifshitz, 2003}). Among Israeli Jews, women ranked internationally much worse for cancer incidence and mortality compared with men and compared to heart disease mortality in both genders (^{ICDC, 2004a, 2004b}).

The higher health risk of Israeli-Jewish women was initially attributed to immigration pressure (^{Kark, 1976}), and later to inadequate medical awareness (^{ICDC, 2000}). It has also formerly been suggested to be associated with BRCA1 and/or BRCA2 founder mutations present in approximately 2.5% of Ashkenazi Jews (^{Struewing et al., 1997}; ^{Rubinstein, 2004}), compared with 1% in non-Ashkenazi Jews and non-Jews (^{Vazina et al., 2000}). The hypothesis of higher sensitivity of women to increased n-6 PUFA consumption was first suggested in 1992 (^{Shapira, 1992}).

The Israeli 'cancer mortality shift' over heart disease is examined here with regard to its possible association with high intake of n-6 PUFA, specifically with the gender modulating effect of high consumption of n-6 PUFA.

Methods

Cancer over heart disease mortality shift

'Cancer shift' over heart disease mortality is defined here by (i) all-cancer : heart disease (ischemic and cerebrovascular) mortality ratio (>1.0) and (ii) cancer shift percent (%), calculated as [(cancer : heart disease mortality ratio-1)×100]. Population comparisons are based on official Israeli data, and international standardization, as follows:

* Cancer incidence is published by the Israel National Cancer Registry (INCR), a population-based central tumor registry established in 1960 (^{INCR, 2005}). Since 1982, INCR has required registry on the part of all public and private medical facilities in the country. It is linked to the population registry via computerized systems and each cancer patient's personal data - including demographic - are validated and retrieved. The version published in 2003, of 1991 data, concluded that completeness of registration was above 95% (^{ICDC, 2003b}).

* Cancer mortality data are also collected by INCR from District Health Authorities and the Central Population Register.

* Cancer survival is an absolute calculation of the number of women surviving - whether disease-free, in remission, or under treatment with evidence of cancer - usually 5 years after diagnosis. Relative survival rates are calculated with consideration for life-expectancy and other health risks. Both are based on INCR follow-up.

* Heart disease mortality data are based on the Israeli Central Bureau of Statistics File on Causes of Death 1979-1999 (^{ICBS, 1999}) and the official report, Health of the Arab Population in Israel 2004 (^{ICDC, 2005b}). The International Classification of Diseases (ICD-9) codes for heart disease employed from 1979 to 1998 were changed to ICD-10 (^{ICBS, 2003}), which could partially explain the sharp decrease in heart disease mortality numbers thereafter (^{ICDC, 2005b}).

Dietary analyses

Analyses are based, in part, on data from the first Israeli national health and nutrition survey, known as MABAT (1999-2001) (^{ICDC, 2003a, 2004b}), based largely on results of food frequency questionnaires distributed nationally to sample populations. Trends of oil consumption are taken from food balance sheets of the Food and Agriculture Organization (FAO) of the United Nations statistical databases (1961-2002) (^{FAO, 2005}).

Ethnic analyses

The comparisons between Jews and Arabs are based on the Trends in Cancer Incidence and Mortality in Israel 1970-1995 (^{ICDC, 1998}); Estimation of Malignant Diseases in Israel, publication no. 8 (^{Barchana and Lifshitz, 2003}); Women's Health in Israel Data Book (^{ICDC, 2000}); Health of the Arab Population in Israel 2004 (^{ICDC, 2005b}); and annual reports of the ^{Israeli Ministry of Health, and Israel National Cancer Registry (2005)}.

Gender analyses

Analyses are based on data from annual reports of the ^{Israeli Ministry of Health and Israel National Cancer Registry (2005)}; Health Status of Israel, 2003 (^{ICDC, 2004a}); Women's Health in Israel 1999-2000 Data Book (^{ICDC, 2000}); World Health Organization Statistics, Annual Reports (^{WHO, 2000}) and Highlights on Health in Israel (^{WHO, 1996, 2004}); and Health Status of Israeli-Arab Populations in Israel 2004 (^{ICDC, 2005b}).

Results

Patterns leading to the 'cancer mortality shift' over heart disease

A 'cancer mortality shift' - here defined as an epidemiological turning point whereby cancer mortality (23.1%) has surpassed that of heart disease (22.3%), the traditional leading cause of death - has recently occurred in Israel (Fig. 1). Although cancer mortality percentage rates have increased from 19.3 to 23.1%, those for heart disease declined dramatically over the 20-year period from 1979 to 1999, from 32.0 to 22.3%, representing a difference of 30% (^{ICDC, 2004a}) and the rates themselves by 47.1 and 49.3% in Jewish men and women, respectively (^{ICBS, 1999}). The larger annual decline of all-heart disease mortality by 2.1%, and much smaller annual decline of all-cancer mortality by 0.3% (^{ICDC, 1999}) together led to the ultimate increase of cancer over heart disease mortality.

Fig. 1

Dietary analysis shows high n-6, n-6 : n-3, and n-6 : n-9 fatty acid intake

Compared with Israeli-Arab men, Israeli-Jewish men consume significantly higher amounts of energy, carbohydrates, total fat, saturated fatty acids, PUFA, and cholesterol. Compared with Israeli-Arab women, Israeli-Jewish women consume similar amounts of energy (1551 vs. 1481 kilocalories/day), carbohydrates (204 vs. 199 g/day), protein (58 vs. 57 g/day), and fiber (15 vs. 14 g/day), but slightly higher total fat (58 vs. 53 g/day) and saturated fat (17 vs. 14.7 g/day), and substantially more PUFA (15.5 vs. 12.0 g/day), specifically n-6 PUFA (13.3 vs. 10.6 g/day) (^{ICDC, 2004b}).

The average consumption of n-6 PUFA oils among Jews - mostly from soy oil, 40% of total fat intake - was initially much higher than in Arabs, and further increased during the time period of 1961-2002, from 11.5 to 17 kg/year per person (^{FAO, 2005}). Olive oil consumption predominated among Israeli Arabs, with a regional reference intake of about 5 kg/year during the years 1999-2002 (^{FAO, 2005}), but declined somewhat with increasing 'Israelization' (indirectly 'Westernization') and increasing consumption of high n-6 PUFA oils (Fig. 2). The average MUFA intakes (Fig. 2) were significantly higher in Israeli Arabs than in Israeli Jews (mostly n-9 oleic acid from olive oil) as reflected in a 50% higher ratio of MUFA : PUFA in both men and women (1.74 vs. 1.18) (^{ICDC, 2004b}).

Fig. 2

Ethnic analyses show lower, but faster-growing cancer rates in Israeli Arabs

The prevalence of cancer among Israeli Jews is much higher than among Israeli Arabs, 1 : 3 in Jews compared with Arab men (1 : 5) and women (1 : 6) for all cancer types, 1 : 8 compared with 1 : 22 for breast cancer, and 1 : 12 compared with 1 : 32 for prostate cancer (^{Barchana and Lifshitz, 2003}). From 1980-2002, however, cancer incidence (Fig. 3) increased much less in Israeli-Jewish men and women than in their Israeli-Arab counterparts (by 22 and 25% vs. 40 and 94%, respectively) (^{INCR, 2005}). The same was shown for cancer death rates, which are still lower in Israeli Arabs than in Jews, by a factor of 1.1 (128.2 vs. 143.2/100 000) in men and a factor of 1.7 (68.8 vs. 113.6/100 000) in women, but saw a much faster rate of increase during the time period of 1980-2000, by 23.6% in men and 5.1% in women, vs. an increase of 5.3% in Israeli-Jewish men and a 3.3% decrease in Israeli-Jewish women (^{ICDC, 2005b}).

Fig. 3

Breast cancer, the leading type of cancer among both Arab and Jewish women, is much less common in Israeli-Arab women by a factor of 2.6, but the incidence increased from 1980 to 2000 by 140%, compared with 37% in Israeli Jews. Death rates were lower in Arab women by a factor of 2.2, but increased by 47% (from 8.3 to 12.2/100 000), compared with an only minor increase in Jewish women (from 23.5 to 25.3/100 000) (^{ICDC, 2005b}).

Similar patterns were observed in colorectal and prostate cancers. Colorectal cancer incidence was much lower (by a factor of 2.5) in Israeli Arabs, but increased by 112%, compared with 19% among Israeli Jews. Death rates are now lower by factors of 1.2 and 1.3 in male and female Israeli Arabs, respectively, but had increased by 113.3 and 115.4% compared with 17.7 and 11.1% (^{ICDC, 2005b}) in Israeli Jews. Prostate cancer incidence was 19.9/100 000 compared with 55.4/100 000 in 1999, having increased in Israeli Arabs by a factor of 2.14 (from 9.33 to 19.9/100 000) vs. 2.54 (from 20.9 to 55.4/100 000) in Israeli Jews (1980-1999). Prostate cancer mortality was 8.7/100 000 compared with 13.9/100 000, respectively (1999), having previously increased 113.9 vs. 39.3% over a 20-year period (^{ICDC, 1998}).

Gender analyses suggest a higher cancer risk for women

The 'cancer mortality shift' over heart disease, defined by a cancer : heart disease mortality ratio >1.0, was first observed in Israeli-Jewish women in 1992 (Fig. 4), in which the ratio for men was only 0.76. By 1999, the cancer mortality rate in Israeli-Jewish women was 27% higher than that of their heart disease (145 : 114/100 000), whereas in men, the cancer mortality rate (186 : 174/100 000) was only 7% higher than that for heart disease (^{ICDC, 2004a}). This same trend of increased cancer :heart disease mortality ratios was also seen in Israeli Arabs (from 0.49 to 0.77 in men, 0.27 to 0.57 in women), but the latter still have far lower cancer and higher heart disease mortality rates, particularly the women (^{ICDC, 2005b}). An international comparison revealed that the cancer mortality rank for Israeli-Jewish women was much worse (15th) than for men (37th), and for the national cancer ranking (30th) compared with that for national heart disease mortality (35th) among 44 European countries (^{ICDC, 2004a}). In a previous comparison among 22 countries, Israeli-Jewish women ranked much worse than Israeli-Jewish men for cancer rates (15th compared with second), and, in gender-related disease, much worse for breast cancer mortality (17th) than for men's prostate cancer (fourth) (^{WHO, 2000}). Recent data among women show that although the all-cancer mortality rate for Israeli Jews is similar to that for Eur-A (Eur-A=Andorra, Austria, Belgium, Croatia, Cyprus, the Czech Republic, Denmark, Finland, France, Germany, Greece, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Monaco, the Netherlands, Norway, Portugal, San Marino, Slovenia, Spain, Sweden, Switzerland, and the United Kingdom), it is much lower for Israeli-Jewish men than for their Eur-A counterparts (by 25%). Furthermore, Israeli-Jewish women had an 18% higher breast cancer mortality rate than the Eur-A average in 2001 (^{WHO, 2004}). Within Israel, breast cancer has contributed 200% more to women's mortality than prostate cancer has to men's (21.4 vs. 9.8%), and to the national mortality (17.1 vs. 8.2%) (^{ICDC, 2004a}). Finally, although Israeli-Jewish men have much lower relative mortality rates in all cancer types compared with European averages (Fig. 5a) (^{WHO, 1996}), Israeli-Jewish women's rates from all-cancer (Fig. 6a) and breast cancer (Fig. 6b) are slightly higher than the European averages (^{WHO, 2004}).

Fig. 4

Fig. 5

Fig. 6

Discussion

Higher female sensitivity to increased dietary n-6 PUFA and their carcinogenic effect may be a leading contributor to the increased cancer risk in women, leading to the recent general Israeli 'cancer mortality shift' over heart disease. The higher health risk of Israeli-Jewish women was initially attributed to immigration pressure (^{Kark, 1976}) and later to inadequate medical awareness (^{ICDC, 2000}).

Another possible factor is the assumed higher risk of breast cancer in Jewish vs. non-Jewish women, owing to the high prevalence (2.5%) of particular BRCA1 and BRCA2 founder mutations in Ashkenazi Jews (^{Robson et al., 1997}; ^{Rubinstein, 2004}) - 55% of Israeli-Jewish women (^{ICDC, 2000}) - present in only up to 1% of non-Jews and non-Ashkenazi Jews (^{Vazina et al., 2000}). These mutations are believed to be responsible for a portion of cases of breast cancer in Ashkenazi Jewish women (^{Fodor et al., 1998}; ^{Rubinstein, 2004}; ^{McClain et al., 2005a}) and men (^{Frank et al., 2002}; ^{Rubinstein, 2004}), prostate cancer in men (^{Struewing et al., 1997}; ^{Drucker et al., 2000}), and colorectal cancers in both genders (^{Struewing et al., 1997}; ^{Giusti et al., 2003}).

Recent research, however, has suggested that BRCA1 and BRCA2 mutations may be associated with substantially lower cancer risk than has previously been reported (^{Satagopan et al., 2001}; ^{Levy-Lahad and Plon, 2003}; ^{McClain et al., 2005b}). Research investigating links with ethnicity have raised the possibility that other susceptibility mutations (^{Vehmanen et al., 1997}; ^{Cortesi et al., 2006}; ^{Malone et al., 2006}) and nongenetic factors - such as diet, hormone levels, and environmental exposure - may modify genetic predisposition (^{Palli et al., 2004}; ^{Kotsopoulos and Narod, 2005}; ^{Simchoni et al., 2006}), as suggested by the substantial increase in breast cancer cases in BRCA1 and BRCA2 'positive' Jews born after 1940 (^{Levy-Lahad and Plon, 2003}), concurrently with a significant increase in food processing in the Western world.

N-6 PUFA (particularly LA) have been associated with the upregulation of key enzyme activity and aberrant cell cycle proteins, as well as modulation of hormone receptors, leading to increased proliferation of several cancer cell lines (^{Reyes et al., 2004}). They have also been observed to enhance the predisposition to cancers associated with BRCA1 germline mutations (^{Kachhap et al., 2000}), and may provide a key explanation for inconsistencies found in relationships between genetics and cancer incidence (^{Feldman, 2001}). In contrast, n-3 PUFA and n-9 MUFA (particularly oleic acid) have been observed to provide an antitumor effect by inhibiting oncogenic overexpression, that is HER-2/neu-driven fatty acid synthase (antigen-519), in breast cancer cells (^{Menendez et al., 2004a, b}).

This research collectively suggests that the association of increased cancer risk with genetic mutation, that is BRCA1 and BRCA2, not only does not preclude the role of nutrition-based prevention, but also may in fact increase its importance. A gender-nutritional hypothesis of higher sensitivity to high n-6 PUFA in women was already suggested in 1992 (^{Shapira, 1992}).

The recent 'cancer shift' over heart disease mortality (Fig. 1) has been attributed to improved heart disease prevention and care, presumably including diet, that have drastically reduced heart disease mortality (^{ICDC, 2004b}), but have not appeared to reduce cancer risk. Although the change in ICD-9 codes for heart disease (1979-1998) to ICD-10 (1998) may have contributed to the sharp decrease in numbers for primary heart disease mortality observed thereafter, trends in reduction of heart disease rates were already significant (^{ICDC, 2005b}). A dichotomy of diseases was already reported within the Israeli population according to distinct ethnic diets (^{Green, 1998}). The suggested dietary risk factor has been high n-6 PUFA consumption (^{Yam et al., 1996}) and high n-6 : n-3 ratio (^{Dubnov and Berry, 2003}). High intake of n-6 PUFA (mostly LA) in Israel was not found to be associated with increased heart disease risk (^{Kark et al., 2003}). Moreover, when high n-6 PUFA intake could contribute to reduced heart disease risk by lowering total and low-density lipoprotein cholesterol and triacylglyceride (TG) levels, it has recently been associated - indirectly and directly - with hyperinsulinemia, insulin resistance, metabolic syndrome, obesity, and atherogenesis (^{Okuyama et al., 1996}; ^{Rustan et al., 1997}; ^{Grundy, 1999}; ^{Berry, 2001a, b}; ^{Ailhaud and Guesnet, 2004}; ^{Ghafoorunissa et al., 2005}; ^{Sacks and Campos, 2006}), as well as carcinogenesis (^{Fang et al., 1996}; ^{Okuyama et al., 1996}; ^{Berry, 2001a, b}; ^{Simopoulos, 2004}).

^{Wirfalt et al. (2002)} found that high n-6 PUFA intake (15.6 g/day) and P : S ratio (0.92), both similar to Israeli levels, were closely associated with a two-fold increase in the incidence of postmenopausal breast cancer in Swedish women. The high n-6 PUFA consumption in Israeli Jews as compared with Israeli Arabs (13.5 and 10.6 g/day) (^{ICDC, 2004b}) and higher n-6 : n-3 and n-6 : n-9 ratios (Fig. 2) have been associated with their higher cancer risk (1 : 3) compared with Israeli-Arab men (1 : 5) and women (1 : 6) (^{Barchana and Lifshitz, 2003}). Israeli Arabs currently have lower cancer rates, but these are increasing and may ultimately reach the higher rates of Israeli Jews, owing to the 'Israelization' of their diet. As an example, the incidence of breast cancer in Israeli-Arab women is currently 2.6 times lower than, but increased at a rate 3.8 times that of their Israeli-Jewish counterparts from 1980 to 2000, and although the death rate is 2.2 times lower, it increased 5.0 times faster (^{ICDC, 2005a}).

The consumption of total PUFA and n-6 PUFA were substantially higher (by 25%) in Israeli-Jewish compared with Israeli-Arab women, whereas other nutritional variables potentially associated with increased cancer risk (^{Franceschi and Favero, 1999}) were either comparable with (intake of total energy, carbohydrates, and protein) or only slightly higher than (total fat and saturated fat) that of Arab women (^{ICDC, 2004b}). Moreover, Arab women have a much higher incidence of overweight and central obesity, which is a known cancer risk factor (^{Rose et al., 2002}; ^{Stephenson and Rose, 2003}; ^{Kaur and Zhang, 2005}; ^{Carmichael, 2006}; ^{Ghosh et al., 2006}), than do Israeli-Jewish women (74.6% with BMI >25 vs. 54%, 41.2% with BMI >30 vs. 22.2%, and 72.3 vs. 49% with waist-to-hip ratio >0.8) (^{ICDC, 2003a}). This further narrows in on a causal relationship between higher n-6 PUFA consumption and cancer risk in Jewish women, and concurrent increases in both among Arab women in Israel.

Inadequate n-3 PUFA intake in Israeli Jews could suggest another nutritional risk factor (^{Dubnov and Berry, 2003}), given that n-3 PUFA have been found to protect against some common cancers, including breast, colon, and prostate (^{De Deckere, 1999}; ^{Simopoulos, 2001, 2004}; ^{Larsson et al., 2004}; ^{Menendez et al., 2005a}). Although the reported n-3 PUFA intake among Israeli Jews appears to be close to recommended levels - and is higher than that of Israeli Arabs, who have had much lower cancer rates (^{ICDC, 2004b}) - the long-known (^{Yam et al., 1996}; ^{Dubnov and Berry, 2003}; ^{Kark et al., 2003}) and recently confirmed (^{ICDC, 2003a}) high average n-6 : n-3 PUFA ratio is well over that recommended for cancer prevention (^{Okuyama et al., 1996}; ^{Sugano and Hirahara, 2000}; ^{Simopoulos, 2001, 2004}; ^{Goodstine et al., 2003}; ^{Gago-Dominguez et al., 2003}; ^{Wakai et al., 2005}), and could confer increased risk of associated cancers (e.g. breast), as has been demonstrated in US studies (^{Bagga et al., 2002}), especially in premenopausal women (^{Goodstine et al., 2003}).

The significantly higher intake of MUFA, mainly oleic acid (^{FAO, 2005}), and higher MUFA : PUFA ratio in the diets of Israeli Arabs compared with that of Israeli Jews (Fig. 2) - especially in Arab women, who appear to adhere more to their traditional habits than do men (^{ICDC, 2004b}) - is compatible with the habitual intake trends of high n-6 PUFA soy oil that has long been the predominant oil in Israeli Jews' diet (approximately 40% of total fat) compared with olive oil among Israeli Arabs (Fig. 7) (^{FAO, 2005}).

Fig. 7

Extra virgin olive oil has been found to be highly cancer-protective and antigenotoxic (^{Rojas-Molina et al., 2005}). It has been associated with reduced colon and breast cancer in animal models and humans (^{Reddy and Maeura, 1984}; ^{Cohen et al., 1986a, b}; ^{Gallus et al., 2004}; ^{Trichopoulou et al., 1995}; ^{Binukumar and Mathew, 2005}), reduced mammographic breast density (^{Masala et al., 2006}), and reduced Her-2/neu gene expression (^{Menendez et al., 2005b}) by up to 46%. High olive oil intake has also been shown to be protective against male type urinary cancer in Israeli Arabs (^{Bitterman et al., 1991}). Hence, increasingly high n-6 PUFA consumption substituting for olive oil may be diminishing olive oil's protective influence in Arabs.

Among 44 European countries, Israeli-Jewish women have been ranked 15th with regard to cancer-related mortality, in contrast to the relatively better cancer rankings of Israeli-Jewish men and the nation as a whole, as well those for heart disease among Israeli Jews (^{ICDC, 2004a}). This unexpected deviation may lead to the hypothesis of a 'women's nutritional paradox' of higher cancer risk, rather than a general 'Israeli paradox' with the Israeli diet (^{Yam et al., 1996}; ^{Dubnov and Berry, 2003}). This is supported by an earlier and larger shift in the cancer : heart disease mortality ratio (>1.0) (Fig. 4) from 1992 to 1999 and a higher ranking of Israeli-Jewish women's mortality owing to cancer when compared with European and international rates (Fig. 5, ^{WHO, 1996}; Fig. 6, ^{WHO, 2004}).

The proposed gender-related carcinogenic effect of n-6 PUFA has been supported by observations of increased risk of breast cancer in conditions of interactions between n-6 PUFA and estrogen (^{Kachhap et al., 2000}; ^{Rose and Connolly, 2000}; ^{Escrich et al., 2004}; ^{Liu et al., 2004}; ^{Reyes et al., 2004}; ^{Binukumar and Mathew, 2005}). Furthermore, a recent study on the DNA of white blood cells revealed an unexpected 40-fold increase in malonaldehyde-derived etheno-DNA adducts in women compared with men upon high consumption of n-6 PUFA (^{Nair et al., 1997}). These findings strongly suggest a significant sex-related effect on n-6 PUFA metabolism and carcinogenesis.

Overall, the data may suggest that high n-6 PUFA consumption, especially when unopposed by adequate n-3 PUFA and/or n-9 MUFA, that is from olive oil, may be associated with recent trends of high cancer rates among Israeli Jews, as well as a rapidly increasing cancer risk among Israeli Arabs. Further research on the cancer-preventive potential of decreased n-6 : n-3 PUFA and n-6 : n-9 FA ratios in the Israeli diet is warranted. The unexpected and significantly higher cancer risk for Israeli-Jewish women relative to rankings for both their male counterparts and the country as a whole - for either cancer or heart disease mortality (15th compared with 30-37th among 44 European countries) - may suggest an Israeli 'women's paradox', and supports the hypothesis of a higher sensitivity to increased n-6 PUFA consumption leading a 'cancer over heart disease mortality shift' in this population. This appears to be the first time gender has been suggested to modulate dietary risks and benefits. Therefore, relationships between Israeli gender and dietary trends may serve as population studies to better understand cancer epidemiology, with implications for sexual dimorphism in nutritional prevention.