Positive messages around healthful fats like CLA are needed to inform Canadians that healthy eating patterns include a wide variety of foods. For cancer prevention, the following messages for Canadians are relevant: • Follow the healthful eating plan in Canada’s Food Guide to Healthy Eating.40 • Eat plenty of fruit, vegetables and whole grains and cereals, which offer benefits in cancer prevention.2 • Include CLA-rich foods in your daily diet. • Be physically active and maintain a healthy body weight throughout life.41

Conclusion

Whereas CLA appears to have potent anticancer effects in animal and cell culture models, a preventive role for CLA in human cancer has not been proven.5 Encouraging Canadians to eat beef and dairy products–the two main dietary sources of CLA–as part of a healthy, balanced diet is a prudent approach to ensuring that current CLA intakes are maintained. Future research will determine the dietary level and mix of CLA isomers required to produce anticancer benefits in humans and will also address other areas that deserve further investigation, including the following:42 • Biologic effects of individual isomers; • Adverse effects and safety; • Adequacy of CLA food databases; • Optimum delivery form (foods vs. supplements); • Strategies for increasing the CLA content of foods; and • Dietary requirement for CLA.

A current list of CLA references can be found at www.wisc.edu/fri/clarefs.htm

References 1. National Cancer Institute of Canada. Canadian Cancer Statistics 2004. Available at www.ncic.cancer.ca 2. Canadian Cancer Society. Available at www.cancer.ca 3. Whigham LD, et al. Pharmacol Res, 2000; 42: 503-510. 4. Pariza MW, et al. Prog Lipid Res, 2001; 40: 283-298. 5. Belury MA. J Nutr, 2002; 132: 2995-2998. 6. Ip C, et al. Cancer, 1994; 74: 1050-1054. 7. Kramer JKG, et al. Proceedings of a Workshop on the Role of Conjugated Linoleic Acid in Human Health. Winnipeg, MB: Diabetes Research & Treatment Centre, 2003, pp. 3-4. 8. Chin SF, et al. J Food Comp Anal, 1992; 5: 185-197. 9. Ha YL, et al. Carcinogenesis, 1987; 8: 1881-1887. 10. Cohen LA, et al. Prostate, 2003; 54: 169-180. 11. Hansen Petrik MB, et al. J Nutr, 2000; 130: 2434-2443. 12. Ha YL, et al. Cancer Res, 1990; 50: 1097-1101. 13. Hubbard NE, et al. Cancer Lett, 2003, 190: 13-19. 14. Lavillonnière F, et al. Nutr Cancer, 2003; 45: 190-194. 15. Cheng JL, et al. Cancer Lett, 2003, 196: 161-168. 16. Schønberg S, Krokan HE. Anticancer Res, 1995; 15: 1241-1246. 17. Kemp MQ, et al. J Nutr, 2003; 133: 3670-3677. 18. Palombo JD, et al. Cancer Lett, 2002; 177: 163-172. 19. Knekt P, et al. Br J Cancer, 1996; 73: 687-691. 20. Voorrips LE, et al. Am J Clin Nutr, 2002; 76: 873-882. 21. Aro A, et al. Nutr Cancer, 2000; 38: 151-157. 22. Chajès V, et al. Cancer Epidemiol Biomarkers Prev, 2002; 11: 672-673. 23. Chajès V, et al. Nutr Cancer, 2003; 45: 17-23. 24. Ip C, et al. Cancer Res, 1991; 51: 6118-6124. 25. Ip C, et al. Carcinogenesis, 1996; 17: 1045-1050. 26. Ip C, et al. J Nutr, 1999; 129: 2135-2142. 27. Visonneau S, et al. Anticancer Res, 1997; 17: 969-973. 28. Hubbard NE, et al. Cancer Lett, 2000; 150: 93-100. 29. Ip C, et al. Nutr Cancer, 2002; 43: 52-58. 30. Ip C, et al. Cancer Res, 1994; 54: 1212-1215. 31. Ens JG, et al. Nutr Res, 2001, 21: 955-960. 32. Ritzenthaler KL, et al. J Nutr, 2001; 131: 1548-1554. 33. Moloney AP, et al. Proc Nutr Soc, 2001; 60: 221-229. 34. Dhiman TR, et al. J Dairy Sci, 2000; 83: 1016-1027. 35. Mir P, et al. Proceedings of a Workshop on the Role of Conjugated Linoleic Acid in Human Health. Winnipeg, MB: Diabetes Research & Treatment Centre, 2003, p. 9. 36. Gaullier J-M, et al. Lipids, 2002; 37: 1019-1025. 37. Leonard SW, et al. Am J Clin Nutr, 2004; 79: 86-92. 38. Boileau TW-M, et al. J Natl Cancer Inst, 2003; 95: 1578-1586. 39. Jacobs Starkey L, et al. Can J Diet Prac Res, 2001; 62: 61-69. 40. Canada’s Food Guide to Healthy Eating. Health Canada, 1992. 41. Byers T, et al. CA Cancer J Clin, 2002; 52: 92-119. 42. Proceedings of a Workshop on the Role of Conjugated Linoleic Acid in Human Health. Winnipeg, MB: Diabetes Research & Treatment Centre, 2003. 43. Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. National Academies Press, 2002, pp. 8-1-8-97. 44. Department of Justice Canada. Food and Drug Regulations, Part B, Foods, Division 1, General: Definition of trans fatty acid. Available at http://laws.justice.gc.ca/en/f-27/c.r.c.-c.870/125340.html

NUTRITION

e v i t c e Persp ased on current incidence rates, 38% of Canadian women and 43% of BCanadian men will develop cancer during their lifetimes. Since about one1

third of cancer deaths can be attributed to diet and physical activity patterns, there is great interest in identifying nutritional factors that reduce cancer risk.2 Conjugated linoleic acid (CLA) has attracted attention because it affects a variety of biological processes, including tumour suppression. CLA is a collective term that describes all conjugated derivatives of linoleic acid. CLA isomers appear to modulate cancer, body composition, body weight, immune function and glucose metabolism in experimental models.3,4 This Nutrition Perspective addresses several topics related to CLA: • Chemical structure and food sources; • Anticancer effects; • Trans fatty acid labelling; and • Nutrition education challenges and opportunities.

June 2003 June 2003 May 2003 Nov 2002 June 2002 June 2002 June 2002

Visit www.beefinfo.org/nutrition.cfm to download PDFs of each Nutrition Perspective and to subscribe for “HealthLink...a monthly health professional e-bulletin” on current nutrition issues.

Questions about Beef? Visit www.beefinfo.org or call 1-888-248-BEEF. May be reproduced without permission provided no changes are made and credit is given. Printed June 2004

2 0 0 4

In This Issue CLA Structure–The Devil is in the Details

1

Anticancer Effects of CLA

2

Food Sources of CLA

Achieving CLA’s Anticancer Effects in Humans CLA Supplement Use

CLA Structure – The Devil is in the Details

Nutrition Education Challenges and Opportunities

CLA isomers resemble linoleic acid in having two double bonds, but they differ from linoleic acid in the position and configuration of these bonds. In linoleic acid, the double bonds are separated by more than one single bond, making the double bonds isolated or non-conjugated. Both double bonds in linoleic acid are in the cis position (see Figure).

Reviewed By:

Chemical Structure of Linoleic Acid and c9, t11-CLA

Each includes a 2-page complementary fact sheet for your clients.

Convenient Nutrition: Helping Canadians Strike a Balance Understanding Use of Antibiotic and Hormonal Substances in Beef Cattle Beef Up Food Safety from Gate to Plate Zinc Deficiency: Impact on Health and Preventive Strategies Heart Healthy Eating Strategies: How Lean Beef Fits Cancer and Red Meat Intake:What are the Issues? Achieving Healthy Nutrient Intakes:The Contributions of Lean Beef

J u n e

Anticancer Effects of Conjugated Linoleic Acid (CLA)

T h e N u t ri t i o n Pe rs p e c t i v e S e ri e s

TOPICS:

Nutrition Perspective is a series of practical resources for health professionals on health issues of importance to Canadians. It is brought to you by the Registered Dietitians at the Beef Information Centre.

Cis-9, trans-11– Conjugated Linoleic Acid

Hydrogens in the trans position 9th carbon

Hydrogens in the cis position

Differences in the chemical structures of the CLA isomers and linoleic acid may account for the differences in their biologic effects. Linoleic acid has two double bonds, both carrying hydrogen molecules in the cis position. The c9, t11-CLA isomer has two double bonds, one with hydrogen molecules in the cis position and the other with hydrogen molecules in the trans position. (Used with permission of Catherine Field.)

Linoleic Acid (Cis-9, cis-12–18:2)

In CLA, the double bonds are conjugated, meaning they alternate with single bonds. The double bonds of CLA can occur in several positions in the carbon chain: 7,9; 8,10; 9,11; 10,12; or 11,13. Each double bond can exist in either the cis or trans form.5 The two most biologically active CLA isomers are cis-9, trans-11-CLA (c9,t11-CLA) or rumenic acid, as it is sometimes called, and trans-10, cis-12-CLA (t10,c12-CLA).

Conclusion

2

3

3

3

4

Aubie Angel, MD, Diabetes Research and Treatment Centre, Manitoba Catherine Field, PhD, RD, University of Alberta Pamela Piotrowski, RD, Juravinski Cancer Centre, Ontario

Written By:

Diane H. Morris, PhD, RD, Mainstream Nutrition, Ontario

Food Sources of CLA

milk intake and breast cancer occurrence. In contrast, CLA intake was associated with a small, statistically significant increase in breast cancer risk in the Netherlands Cohort Study, a prospective study begun in 1986.20 The discrepancy in results may be due to differences in dietary patterns, length of follow-up (25 years in the Finnish study vs. 6.3 years in the Netherlands study), and problems in estimating CLA intake from the dietary intake tools used in prospective studies.

CLA is a normal product of linoleic acid metabolism by bacteria in the gut of ruminants like cattle, sheep and goats. Other pathways of CLA synthesis appear to exist, since CLA is also found in meat from non-ruminants like hogs, chicken and turkey.6 More than 24 different CLA isomers have been identified in dairy fats.7 The main CLA isomer in beef and dairy products, which accounts for about 80-95% of total CLA, is c9,t11-CLA. The other main CLA isomers in these foods are trans-7, cis-9-CLA (t7,c9-CLA) and t10,c12-CLA. The concentration of CLA is greater in meat from ruminants than from non-ruminants.7,8

Some case-control studies have explored the relationship between dietary and serum CLA and breast cancer risk. In one study, dietary CLA and serum CLA were significantly lower in postmenopausal women with breast cancer than in controls.21 However, in other studies, there were no differences in the CLA content of adipose tissue of breast cancer cases and controls, and no relationship between the CLA content of breast adipose tissue and tumour size, lymph node status or extent of metastasis.22,23

CLA Content of Canadian Beef and Dairy Productsa Product mg CLA/g fat mg CLA/serving serving size _________________________________________________________ Cooked Beef Rib roast Ground beef b Sirloin tip roast Extra lean ground beef

2.9 1.8 2.8 1.2

77.6 36.2 28.7 11.5

The findings of epidemiologic and case-control studies published to date are not consistent.

100 g 100 g 100 g 100 g

Dairy Products

Animal Studies

Whole milk 3.4 25.6 250 mL 2% milk 5.0 25.8 250 mL 1% milk 4.3 10.5 250 mL Cheddar cheese 4.2 71.7 50 g Butter 4.7 64.1 15 g Yogourt 4.4 42.7 175 g _________________________________________________________

In rats fed diets supplemented with CLA at levels ranging from 0.5% to 1.5% by weight, which represented about 1%-3% of total energy in the animals’ diets, CLA decreased the incidence and total number of chemically-induced mammary tumours. CLA protected against mammary tumour development in a dose-dependent manner when fed at levels up to 1%, but offered no additional benefit at dietary levels greater than 1%.24 The level or type of dietary fat did not alter CLA’s anticarcinogenic effect–rats fed a diet containing 1% CLA experienced a 50% reduction in the number of mammary tumours, regardless of the dietary fat content.25

Values represent the mean of four brands of the same product or four samples of the same product from different locations. All products were obtained locally during the Canadian spring and summer months. bType of ground beef not specified. Source: Adapted with permission from Ma DWL, Wierzbicki AA, Field CJ and Clandinin MT. Conjugated linoleic acid in Canadian dairy and beef products. J Agric Food Chem. 1999;47:1956-1960. Copyright (1999) American Chemical Society. a

Anticancer Effects of CLA In 1987, a new anticarcinogen, designated CLA, was identified in fried ground beef patties.9 Since then, the major CLA isomers, alone or in combination, have been shown, with few exceptions,10,11 to inhibit cancers of the forestomach, mammary gland or colon in mice and rats.12-15 CLA also inhibits the proliferation of human lung, breast, colon and prostate cancer cells grown in cell cultures.16-18 Because mammary/breast cancer is among the most widely studied cancers in terms of CLA, it is the focus of the following discussion.

CLA exhibited an anticancer effect in rats, regardless of the level or type (saturated or unsaturated) of dietary fat.

Human Studies

Because CLA research in humans is in its infancy, only a handful of studies have been published. One longitudinal study followed 4,697 Finnish women who were initially free of cancer in 1966-1972.19 In this cohort, there was a significant inverse relationship between

2

When fed to rats during the pubertal period–a time of rapid morphological development of the mammary gland–CLA changed mammary tissue so that it became less susceptible to cancer processes later in life. Young rats fed a high-CLA butter fat diet showed decreased size, number and proliferation of the terminal end buds, the site at which tumours form in rat and human mammary cancers. Mammary cancer risk was decreased by 50% in these animals.26 CLA may also inhibit secondary tumour growth (metastasis).27,28

In rodent models, CLA inhibits tumour development in the initiation, promotion and progression phases of carcinogenesis, and may affect the growth of secondary tumours.5

Trans Fatty Acid Definitions and Labelling The Institute of Medicine defines trans fatty acids as unsaturated fatty acids that contain at least one double bond in the trans configuration.43 By this definition, those CLA isomers containing a trans double bond (e.g., c9,t11-CLA, t10,c12-CLA) are trans fatty acids. CLA isomers containing only cis double bonds are not trans fatty acids.

Most of this early work was done with synthetic mixtures of CLA. When newer CLA sources, formulated with different predominant CLA isomers, were compared, two CLA isomers–c9,t11-CLA and t10,c12CLA–emerged as being biologically active in cancer prevention in animals.29 Several mechanisms have been proposed for the anticancer effects of CLA in animals. CLA may have an antioxidant effect, thus protecting cells from damage by reactive oxygen compounds.9 CLA may also influence gene expression and fatty acid metabolism, and induce apoptosis or programmed cell death, resulting in less proliferation and spread of cancer cells.5,13,24

Achieving CLA’s Anticancer Effects in Humans

An anticarcinogenic effect of CLA in humans has not been firmly established, possibly because current CLA intakes are too low to produce an anticancer benefit. In animals, some studies,13,24,30 but not all,15 showed mammary tumour inhibition at dietary intakes as low as 0.1% CLA, which represents an intake of about 0.3 g CLA/1000 kcal. If extrapolated to humans, CLA intake would need to approach 0.6 g daily.31 Current estimates suggest that CLA intakes are considerably lower than 0.6 g daily. In a study of 22 free-living Canadian adults, the average intake of c9,t11-CLA was about 0.1 g/day (range = 0.02–0.17 g/day).31 Estimates of CLA intake in other countries ranged from about 0.2 g/day for U.S. adults32 and Dutch women20 to about 0.4 g/day for German adults (as cited in Voorrips et al.20). One strategy for helping Canadians increase their CLA intakes is to develop methods of enriching beef and dairy products with CLA. For example, beef and dairy foods derived from cattle grazed on pasture are higher in CLA than those from cattle fed grain. As the grass content in the diet of cattle increases, the saturated fat content decreases and the CLA content increases in the intra-muscular fat of beef.33 Rations high in total fat, soybean oil or flaxseed oil increase the CLA content of cow’s milk and, therefore, the CLA content of cheeses and other foods made with milk.4,34

CLA isomers in beef appear to be concentrated in intra-muscular fat (fat within muscle tissue, or marbling) and in subcutaneous fat (discarded fat found under the hide).35

In contrast, Health Canada defines trans fatty acids as unsaturated fatty acids that contain one or more isolated or non-conjugated double bonds in a trans configuration. Because the double bonds in CLA are conjugated, none of the CLA isomers are considered trans fatty acids for nutrition labelling purposes. Label statements regarding the trans fatty acid content of a food will not include CLA.44 Instead, the CLA content of a food is included in the total fat declaration on the nutrition information panel.

CLA Supplement Use Commercial CLA supplements represent another strategy for increasing CLA intakes. Some CLA supplements are formulated with a mix of four CLA isomers, whereas others consist chiefly of c9,t11-CLA and t10,c12-CLA. There are two issues to consider before recommending CLA supplements. First, the safety, efficacy and purity of commercial CLA supplements have not been widely tested.36 Secondly, the bioavailability of CLA from supplements may differ from CLA found naturally in foods. Recent studies suggest that form matters–in humans, vitamin E was more bioavailable from a fortified cereal than from capsules;37 while in rats, prostate cancer was inhibited by diets containing whole tomato powder, but not by diets supplemented with lycopene beadlets.38

Nutrition Education Challenges and Opportunities

The emerging story on the anticancer effects of CLA creates some interesting nutrition education challenges and opportunities for health professionals. Challenges lie in explaining to Canadians what CLA is; how CLA affects health; and why animal foods rich in CLA are important in the diet (they provide high-quality protein and essential vitamins and minerals), even though they contain saturated fat and cholesterol. Another challenge lies in keeping nutrition messages simple when the science is complex–not all trans fats behave in the same way. Opportunities lie in working to change the tone of current messages about fat. Negative messaging may have led some Canadians to manage their fat intake by eating less meat and dairy foods. Indeed, certain groups, particularly young women, reportedly consume less than the minimum recommended servings of milk products and meat and alternatives.31,39 Even so, many Canadians derive a substantial amount of dietary fat (about 30%) from “other” foods, which are likely to be less nutrient dense than meat and dairy foods.39

3

Food Sources of CLA

milk intake and breast cancer occurrence. In contrast, CLA intake was associated with a small, statistically significant increase in breast cancer risk in the Netherlands Cohort Study, a prospective study begun in 1986.20 The discrepancy in results may be due to differences in dietary patterns, length of follow-up (25 years in the Finnish study vs. 6.3 years in the Netherlands study), and problems in estimating CLA intake from the dietary intake tools used in prospective studies.

CLA is a normal product of linoleic acid metabolism by bacteria in the gut of ruminants like cattle, sheep and goats. Other pathways of CLA synthesis appear to exist, since CLA is also found in meat from non-ruminants like hogs, chicken and turkey.6 More than 24 different CLA isomers have been identified in dairy fats.7 The main CLA isomer in beef and dairy products, which accounts for about 80-95% of total CLA, is c9,t11-CLA. The other main CLA isomers in these foods are trans-7, cis-9-CLA (t7,c9-CLA) and t10,c12-CLA. The concentration of CLA is greater in meat from ruminants than from non-ruminants.7,8

Some case-control studies have explored the relationship between dietary and serum CLA and breast cancer risk. In one study, dietary CLA and serum CLA were significantly lower in postmenopausal women with breast cancer than in controls.21 However, in other studies, there were no differences in the CLA content of adipose tissue of breast cancer cases and controls, and no relationship between the CLA content of breast adipose tissue and tumour size, lymph node status or extent of metastasis.22,23

CLA Content of Canadian Beef and Dairy Productsa Product mg CLA/g fat mg CLA/serving serving size _________________________________________________________ Cooked Beef Rib roast Ground beef b Sirloin tip roast Extra lean ground beef

2.9 1.8 2.8 1.2

77.6 36.2 28.7 11.5

The findings of epidemiologic and case-control studies published to date are not consistent.

100 g 100 g 100 g 100 g

Dairy Products

Animal Studies

Whole milk 3.4 25.6 250 mL 2% milk 5.0 25.8 250 mL 1% milk 4.3 10.5 250 mL Cheddar cheese 4.2 71.7 50 g Butter 4.7 64.1 15 g Yogourt 4.4 42.7 175 g _________________________________________________________

In rats fed diets supplemented with CLA at levels ranging from 0.5% to 1.5% by weight, which represented about 1%-3% of total energy in the animals’ diets, CLA decreased the incidence and total number of chemically-induced mammary tumours. CLA protected against mammary tumour development in a dose-dependent manner when fed at levels up to 1%, but offered no additional benefit at dietary levels greater than 1%.24 The level or type of dietary fat did not alter CLA’s anticarcinogenic effect–rats fed a diet containing 1% CLA experienced a 50% reduction in the number of mammary tumours, regardless of the dietary fat content.25

Values represent the mean of four brands of the same product or four samples of the same product from different locations. All products were obtained locally during the Canadian spring and summer months. bType of ground beef not specified. Source: Adapted with permission from Ma DWL, Wierzbicki AA, Field CJ and Clandinin MT. Conjugated linoleic acid in Canadian dairy and beef products. J Agric Food Chem. 1999;47:1956-1960. Copyright (1999) American Chemical Society. a

Anticancer Effects of CLA In 1987, a new anticarcinogen, designated CLA, was identified in fried ground beef patties.9 Since then, the major CLA isomers, alone or in combination, have been shown, with few exceptions,10,11 to inhibit cancers of the forestomach, mammary gland or colon in mice and rats.12-15 CLA also inhibits the proliferation of human lung, breast, colon and prostate cancer cells grown in cell cultures.16-18 Because mammary/breast cancer is among the most widely studied cancers in terms of CLA, it is the focus of the following discussion.

CLA exhibited an anticancer effect in rats, regardless of the level or type (saturated or unsaturated) of dietary fat.

Human Studies

Because CLA research in humans is in its infancy, only a handful of studies have been published. One longitudinal study followed 4,697 Finnish women who were initially free of cancer in 1966-1972.19 In this cohort, there was a significant inverse relationship between

2

When fed to rats during the pubertal period–a time of rapid morphological development of the mammary gland–CLA changed mammary tissue so that it became less susceptible to cancer processes later in life. Young rats fed a high-CLA butter fat diet showed decreased size, number and proliferation of the terminal end buds, the site at which tumours form in rat and human mammary cancers. Mammary cancer risk was decreased by 50% in these animals.26 CLA may also inhibit secondary tumour growth (metastasis).27,28

In rodent models, CLA inhibits tumour development in the initiation, promotion and progression phases of carcinogenesis, and may affect the growth of secondary tumours.5

Trans Fatty Acid Definitions and Labelling The Institute of Medicine defines trans fatty acids as unsaturated fatty acids that contain at least one double bond in the trans configuration.43 By this definition, those CLA isomers containing a trans double bond (e.g., c9,t11-CLA, t10,c12-CLA) are trans fatty acids. CLA isomers containing only cis double bonds are not trans fatty acids.

Most of this early work was done with synthetic mixtures of CLA. When newer CLA sources, formulated with different predominant CLA isomers, were compared, two CLA isomers–c9,t11-CLA and t10,c12CLA–emerged as being biologically active in cancer prevention in animals.29 Several mechanisms have been proposed for the anticancer effects of CLA in animals. CLA may have an antioxidant effect, thus protecting cells from damage by reactive oxygen compounds.9 CLA may also influence gene expression and fatty acid metabolism, and induce apoptosis or programmed cell death, resulting in less proliferation and spread of cancer cells.5,13,24

Achieving CLA’s Anticancer Effects in Humans

An anticarcinogenic effect of CLA in humans has not been firmly established, possibly because current CLA intakes are too low to produce an anticancer benefit. In animals, some studies,13,24,30 but not all,15 showed mammary tumour inhibition at dietary intakes as low as 0.1% CLA, which represents an intake of about 0.3 g CLA/1000 kcal. If extrapolated to humans, CLA intake would need to approach 0.6 g daily.31 Current estimates suggest that CLA intakes are considerably lower than 0.6 g daily. In a study of 22 free-living Canadian adults, the average intake of c9,t11-CLA was about 0.1 g/day (range = 0.02–0.17 g/day).31 Estimates of CLA intake in other countries ranged from about 0.2 g/day for U.S. adults32 and Dutch women20 to about 0.4 g/day for German adults (as cited in Voorrips et al.20). One strategy for helping Canadians increase their CLA intakes is to develop methods of enriching beef and dairy products with CLA. For example, beef and dairy foods derived from cattle grazed on pasture are higher in CLA than those from cattle fed grain. As the grass content in the diet of cattle increases, the saturated fat content decreases and the CLA content increases in the intra-muscular fat of beef.33 Rations high in total fat, soybean oil or flaxseed oil increase the CLA content of cow’s milk and, therefore, the CLA content of cheeses and other foods made with milk.4,34

CLA isomers in beef appear to be concentrated in intra-muscular fat (fat within muscle tissue, or marbling) and in subcutaneous fat (discarded fat found under the hide).35

In contrast, Health Canada defines trans fatty acids as unsaturated fatty acids that contain one or more isolated or non-conjugated double bonds in a trans configuration. Because the double bonds in CLA are conjugated, none of the CLA isomers are considered trans fatty acids for nutrition labelling purposes. Label statements regarding the trans fatty acid content of a food will not include CLA.44 Instead, the CLA content of a food is included in the total fat declaration on the nutrition information panel.

CLA Supplement Use Commercial CLA supplements represent another strategy for increasing CLA intakes. Some CLA supplements are formulated with a mix of four CLA isomers, whereas others consist chiefly of c9,t11-CLA and t10,c12-CLA. There are two issues to consider before recommending CLA supplements. First, the safety, efficacy and purity of commercial CLA supplements have not been widely tested.36 Secondly, the bioavailability of CLA from supplements may differ from CLA found naturally in foods. Recent studies suggest that form matters–in humans, vitamin E was more bioavailable from a fortified cereal than from capsules;37 while in rats, prostate cancer was inhibited by diets containing whole tomato powder, but not by diets supplemented with lycopene beadlets.38

Nutrition Education Challenges and Opportunities

The emerging story on the anticancer effects of CLA creates some interesting nutrition education challenges and opportunities for health professionals. Challenges lie in explaining to Canadians what CLA is; how CLA affects health; and why animal foods rich in CLA are important in the diet (they provide high-quality protein and essential vitamins and minerals), even though they contain saturated fat and cholesterol. Another challenge lies in keeping nutrition messages simple when the science is complex–not all trans fats behave in the same way. Opportunities lie in working to change the tone of current messages about fat. Negative messaging may have led some Canadians to manage their fat intake by eating less meat and dairy foods. Indeed, certain groups, particularly young women, reportedly consume less than the minimum recommended servings of milk products and meat and alternatives.31,39 Even so, many Canadians derive a substantial amount of dietary fat (about 30%) from “other” foods, which are likely to be less nutrient dense than meat and dairy foods.39

3

Positive messages around healthful fats like CLA are needed to inform Canadians that healthy eating patterns include a wide variety of foods. For cancer prevention, the following messages for Canadians are relevant: • Follow the healthful eating plan in Canada’s Food Guide to Healthy Eating.40 • Eat plenty of fruit, vegetables and whole grains and cereals, which offer benefits in cancer prevention.2 • Include CLA-rich foods in your daily diet. • Be physically active and maintain a healthy body weight throughout life.41

Conclusion

Whereas CLA appears to have potent anticancer effects in animal and cell culture models, a preventive role for CLA in human cancer has not been proven.5 Encouraging Canadians to eat beef and dairy products–the two main dietary sources of CLA–as part of a healthy, balanced diet is a prudent approach to ensuring that current CLA intakes are maintained. Future research will determine the dietary level and mix of CLA isomers required to produce anticancer benefits in humans and will also address other areas that deserve further investigation, including the following:42 • Biologic effects of individual isomers; • Adverse effects and safety; • Adequacy of CLA food databases; • Optimum delivery form (foods vs. supplements); • Strategies for increasing the CLA content of foods; and • Dietary requirement for CLA.

A current list of CLA references can be found at www.wisc.edu/fri/clarefs.htm

References 1. National Cancer Institute of Canada. Canadian Cancer Statistics 2004. Available at www.ncic.cancer.ca 2. Canadian Cancer Society. Available at www.cancer.ca 3. Whigham LD, et al. Pharmacol Res, 2000; 42: 503-510. 4. Pariza MW, et al. Prog Lipid Res, 2001; 40: 283-298. 5. Belury MA. J Nutr, 2002; 132: 2995-2998. 6. Ip C, et al. Cancer, 1994; 74: 1050-1054. 7. Kramer JKG, et al. Proceedings of a Workshop on the Role of Conjugated Linoleic Acid in Human Health. Winnipeg, MB: Diabetes Research & Treatment Centre, 2003, pp. 3-4. 8. Chin SF, et al. J Food Comp Anal, 1992; 5: 185-197. 9. Ha YL, et al. Carcinogenesis, 1987; 8: 1881-1887. 10. Cohen LA, et al. Prostate, 2003; 54: 169-180. 11. Hansen Petrik MB, et al. J Nutr, 2000; 130: 2434-2443. 12. Ha YL, et al. Cancer Res, 1990; 50: 1097-1101. 13. Hubbard NE, et al. Cancer Lett, 2003, 190: 13-19. 14. Lavillonnière F, et al. Nutr Cancer, 2003; 45: 190-194. 15. Cheng JL, et al. Cancer Lett, 2003, 196: 161-168. 16. Schønberg S, Krokan HE. Anticancer Res, 1995; 15: 1241-1246. 17. Kemp MQ, et al. J Nutr, 2003; 133: 3670-3677. 18. Palombo JD, et al. Cancer Lett, 2002; 177: 163-172. 19. Knekt P, et al. Br J Cancer, 1996; 73: 687-691. 20. Voorrips LE, et al. Am J Clin Nutr, 2002; 76: 873-882. 21. Aro A, et al. Nutr Cancer, 2000; 38: 151-157. 22. Chajès V, et al. Cancer Epidemiol Biomarkers Prev, 2002; 11: 672-673. 23. Chajès V, et al. Nutr Cancer, 2003; 45: 17-23. 24. Ip C, et al. Cancer Res, 1991; 51: 6118-6124. 25. Ip C, et al. Carcinogenesis, 1996; 17: 1045-1050. 26. Ip C, et al. J Nutr, 1999; 129: 2135-2142. 27. Visonneau S, et al. Anticancer Res, 1997; 17: 969-973. 28. Hubbard NE, et al. Cancer Lett, 2000; 150: 93-100. 29. Ip C, et al. Nutr Cancer, 2002; 43: 52-58. 30. Ip C, et al. Cancer Res, 1994; 54: 1212-1215. 31. Ens JG, et al. Nutr Res, 2001, 21: 955-960. 32. Ritzenthaler KL, et al. J Nutr, 2001; 131: 1548-1554. 33. Moloney AP, et al. Proc Nutr Soc, 2001; 60: 221-229. 34. Dhiman TR, et al. J Dairy Sci, 2000; 83: 1016-1027. 35. Mir P, et al. Proceedings of a Workshop on the Role of Conjugated Linoleic Acid in Human Health. Winnipeg, MB: Diabetes Research & Treatment Centre, 2003, p. 9. 36. Gaullier J-M, et al. Lipids, 2002; 37: 1019-1025. 37. Leonard SW, et al. Am J Clin Nutr, 2004; 79: 86-92. 38. Boileau TW-M, et al. J Natl Cancer Inst, 2003; 95: 1578-1586. 39. Jacobs Starkey L, et al. Can J Diet Prac Res, 2001; 62: 61-69. 40. Canada’s Food Guide to Healthy Eating. Health Canada, 1992. 41. Byers T, et al. CA Cancer J Clin, 2002; 52: 92-119. 42. Proceedings of a Workshop on the Role of Conjugated Linoleic Acid in Human Health. Winnipeg, MB: Diabetes Research & Treatment Centre, 2003. 43. Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. National Academies Press, 2002, pp. 8-1-8-97. 44. Department of Justice Canada. Food and Drug Regulations, Part B, Foods, Division 1, General: Definition of trans fatty acid. Available at http://laws.justice.gc.ca/en/f-27/c.r.c.-c.870/125340.html

NUTRITION

e v i t c e Persp ased on current incidence rates, 38% of Canadian women and 43% of BCanadian men will develop cancer during their lifetimes. Since about one1

third of cancer deaths can be attributed to diet and physical activity patterns, there is great interest in identifying nutritional factors that reduce cancer risk.2 Conjugated linoleic acid (CLA) has attracted attention because it affects a variety of biological processes, including tumour suppression. CLA is a collective term that describes all conjugated derivatives of linoleic acid. CLA isomers appear to modulate cancer, body composition, body weight, immune function and glucose metabolism in experimental models.3,4 This Nutrition Perspective addresses several topics related to CLA: • Chemical structure and food sources; • Anticancer effects; • Trans fatty acid labelling; and • Nutrition education challenges and opportunities.

June 2003 June 2003 May 2003 Nov 2002 June 2002 June 2002 June 2002

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Questions about Beef? Visit www.beefinfo.org or call 1-888-248-BEEF. May be reproduced without permission provided no changes are made and credit is given. Printed June 2004

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In This Issue CLA Structure–The Devil is in the Details

1

Anticancer Effects of CLA

2

Food Sources of CLA

Achieving CLA’s Anticancer Effects in Humans CLA Supplement Use

CLA Structure – The Devil is in the Details

Nutrition Education Challenges and Opportunities

CLA isomers resemble linoleic acid in having two double bonds, but they differ from linoleic acid in the position and configuration of these bonds. In linoleic acid, the double bonds are separated by more than one single bond, making the double bonds isolated or non-conjugated. Both double bonds in linoleic acid are in the cis position (see Figure).

Reviewed By:

Chemical Structure of Linoleic Acid and c9, t11-CLA

Each includes a 2-page complementary fact sheet for your clients.

Convenient Nutrition: Helping Canadians Strike a Balance Understanding Use of Antibiotic and Hormonal Substances in Beef Cattle Beef Up Food Safety from Gate to Plate Zinc Deficiency: Impact on Health and Preventive Strategies Heart Healthy Eating Strategies: How Lean Beef Fits Cancer and Red Meat Intake:What are the Issues? Achieving Healthy Nutrient Intakes:The Contributions of Lean Beef

J u n e

Anticancer Effects of Conjugated Linoleic Acid (CLA)

T h e N u t ri t i o n Pe rs p e c t i v e S e ri e s

TOPICS:

Nutrition Perspective is a series of practical resources for health professionals on health issues of importance to Canadians. It is brought to you by the Registered Dietitians at the Beef Information Centre.

Cis-9, trans-11– Conjugated Linoleic Acid

Hydrogens in the trans position 9th carbon

Hydrogens in the cis position

Differences in the chemical structures of the CLA isomers and linoleic acid may account for the differences in their biologic effects. Linoleic acid has two double bonds, both carrying hydrogen molecules in the cis position. The c9, t11-CLA isomer has two double bonds, one with hydrogen molecules in the cis position and the other with hydrogen molecules in the trans position. (Used with permission of Catherine Field.)

Linoleic Acid (Cis-9, cis-12–18:2)

In CLA, the double bonds are conjugated, meaning they alternate with single bonds. The double bonds of CLA can occur in several positions in the carbon chain: 7,9; 8,10; 9,11; 10,12; or 11,13. Each double bond can exist in either the cis or trans form.5 The two most biologically active CLA isomers are cis-9, trans-11-CLA (c9,t11-CLA) or rumenic acid, as it is sometimes called, and trans-10, cis-12-CLA (t10,c12-CLA).

Conclusion

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Aubie Angel, MD, Diabetes Research and Treatment Centre, Manitoba Catherine Field, PhD, RD, University of Alberta Pamela Piotrowski, RD, Juravinski Cancer Centre, Ontario

Written By:

Diane H. Morris, PhD, RD, Mainstream Nutrition, Ontario

e v i t c e p s Per NUTRITION

F a c t

S h e e t

Conjugated Linoleic Acid and Cancer A bout 4 in 10 Canadians will develop cancer during their lifetimes. Because many cancers may be linked to what you eat, the food choices you make every day may reduce your cancer risk. Eating red meat and dairy foods as part of a healthy diet may help reduce cancer risk because these foods contain a type of fat with anticancer effects. The fat is called conjugated linoleic acid, or CLA for short. What is CLA?

Does CLA Protect Against Cancer?

All fats are made up of smaller units called fatty acids. Conjugated linoleic acid (CLA) is a family of fatty acids. Members of the CLA family come in at least 24 different forms. Just like family members, the forms of CLA are alike in some ways and different in others. Two forms of CLA protect against cancer in animals and may have anticancer potential in humans.

Most studies on CLA focus on breast cancer protection and have been done in rats. Feeding CLA to young rats protected the breast tissue, making the breast less likely to get cancer later in life. The risk of breast cancer was lowered by half in these rats. Rats fed a diet rich in CLA had more protection against breast cancer than rats fed a CLA-poor diet.

CLA is a naturally occurring fat. Some forms of CLA are trans fats. Unlike the trans fats formed during the processing of vegetable oils, the naturally occurring trans fats found in red meat and dairy foods do not seem to have the same negative effect in the body. In fact, naturally occurring trans fats, like CLA, have health benefits.

Does CLA Have Anticancer Effects in Humans? An anticancer effect of CLA in humans has not been proven yet, possibly because we eat too little CLA from food. In one study, young Canadian adults ate about 100 mg per day of one form of CLA. The amount of CLA we eat from food may need to increase to 600 mg daily to protect against cancer.

What Other Health Benefits Does CLA Have? CLA affects body fat and weight in animals and may affect body fat in humans. CLA may also help control blood glucose and protect against heart disease, stroke and the common cold and flu.

How Can I Increase My CLA Intake? The main food sources of CLA are red meat and dairy products such as beef, milk, cheeses, butter and yogourt. (See Table) Foods with a bit more fat such as rib roast and 2% milk contain more CLA than extra lean ground beef and 1% milk. These foods are a good way to get CLA and also fit within a healthy, balanced diet. When choosing beef, aim for a portion about the size of a deck of cards or 50-100 grams cooked. You need 2-3 servings from the Meat and Alternatives food group every day. When choosing dairy products, aim for a portion size of 1 cup (250 mL) of milk, 3/4 cup (175 g) of yogourt or 2 slices (50 g) of processed cheese. Adults need 2-4 servings of Milk Products every day.

CLA Content of Canadian Beef and Dairy Productsa Food

mg CLA/serving

Cooked Beef (100 g serving) Rib roast Ground beef b Sirloin tip roast Ground beef, extra lean

78 36 29 12

Milk (250 mL serving) Whole milk 2% milk 1% milk

26 26 10

Other Dairy Foods Cheddar cheese (50 g serving) Butter (15 g serving) Yogourt (175 g serving)

72 64 43

Values represent the average of four brands of the same product or four samples of the same product from different locations. All products were obtained locally during the Canadian spring and summer months. bType of ground beef not specified. Adapted with permission from Ma DWL, Wierzbicki AA, Field CJ and Clandinin MT. Conjugated linoleic acid in Canadian dairy and beef products. J Agric Food Chem. 1999;47:1956-1960. Copyright (1999) American Chemical Society. a

Tips to boost your CLA intake: • Add milk to soups

How Can I Reduce My Cancer Risk?

• Top salads with cheese or cooked beef strips

• Follow the healthful eating plan in Canada’s Food Guide to Healthy Eating.

• Add ground beef to bean chili • Fix a quick stir-fry of beef and vegetables

Are CLA Supplements a Good Idea? There are two reasons to choose food over supplements. First, CLA supplements have not been widely tested for safety and on how well they work. Second, the body may absorb CLA better from food than from a supplement.

• Eat plenty of fruit, vegetables and whole grains and cereals, which offer benefits in cancer prevention. • Include CLA-rich foods in your daily diet. • Be physically active and maintain a healthy body weight throughout life.

This nutrition resource is brought to you by the registered dietitians at the Beef Information Centre. Questions about Beef? Visit www.beefinfo.org or call 1-888-248-BEEF. May be reproduced without permission provided no changes are made and credit is given. Printed June 2004