Safety Concerns of Soy-based Infant Formula: Recommendations and Regulations

2. Soy-based Infant Formula: Concerns and Recommendations Suha Khoury, RD

3. To explore safety issues related to the use of soy-based infant formula as the main source of nutrition To present international regulations on the appropriate use of soy-based infant formula Purpose of Presentation

4. Historical background Safety issues and potential adverse effects Views of regulatory bodies Topics of Discussion

5. 1. Historical Background1 1. American Academy of Pediatrics Policy Statement, Pediatrics, 1998

6. 2. Safety Issues and Potential Adverse Effects

7. 2.1. Nutritional Adequacy

8. 2.1.1. Soy Phytates • Soybean contains highest phytic acid content of all legumes 1 • “…soy protein isolate formulas still contain 1.5% phytates”2 • Phytates affect absorption of following minerals: • Calcium & Phosphorous: • Until 1980, “mineral absorption from soy formulas was erratic” partly due to “the presence of excessive soy phytates in the formula”2 • 30%phosphorus bound to phytates2 • Soy infant formula may result in decreased bone mineralization 3,4,5 • Zinc:Absorption highest (41%) from human milk, lowest (14%) from soy formula 6,7 • Manganese:Absorption doubled after dephytinizing formula8 • Iron: bioavailability by removing phytic acid9 • Copper: copper absorption and status by  phytate content7 • Vitamins:Use of SPI  requirements for vitamins E, K, D & B1210

9. 2.1.2. Protease Inhibitors • Definition: Antitrypsin, antichymotrypsin, antielastin1 • Exposure estimates: • 80% to 90% of protease inhibitor activity is removed when SPI is heated1 • Trypsin inhibitor content of soy protein isolate can vary as much as fivefold2 • Soybean products retain 2.5-12.5% trypsin inhibitor activity of the whole soybean3 • Health concerns: • Trypsin inhibitors account for 40% of the growth inhibition of raw soy4 • Growth depressant5 • Stimulate pancreatic hyperplasia in test animals, including carcinoma5 • American Academy of Peditrics Policy Statement, Pediatrics, 1998 • Rackis et al, Qual Plant Foods Hum Nutr, 1985 • Miyagi Y et al, J Nutr Sci Vitaminol, 1997 • Liener IE , Arch Latinoam, Nutr, 1996 • Liener IE, J Nutr,1995

10. 2.1.3. Additional Factors • Protein quality • Soy protein contains only 1/3 of available nitrogen as essential or semi-essential amino acids1 • “Soy is not as good a protein source as cow's milk”2 • Presence of hemagglutinin • Growth depressant3 , might be resistant to dry heat4 • Devoid of cholesterol • Essential for brain cell development5 • Early exposure to cholesterol associated with improved fat metabolism in later life6 • Lactose replaced by sugar • Lactose & galactose crucial for neural myelination • Sugar is not favored because of its “potential effect on teeth and development of inappropriate eating habits”2 • Low in chloride • Reported cases of hypochloraemic alkalosis7

11. 2.2. Phytoestrogens

12. 2.2.1. Definition of Phytoestrogen 1. Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment- Working Group on Phytpestrogens, UK

13. 2.2.2. The Main Isoflavones in Soy Formulas1 Percentage Distribution of Total Isoflavone Equivants of the Three Main Isoflavonoids (i.e. Genistein, Diadzein, and Glycetein), their Glucosides, their Acetyl and Malonyl Derivatives • Murphy PA, J Agric Food Chem, 1997

14. 2.2.3. Isoflavones Exposure Estimates1 * Assumed 60 kg for adults, 6 kg for infants

15. 2.2.3. Isoflavones Exposure Estimates -con’t A 100 mg isoflavones = 1 contraceptive pill7

16. 2.2.3. Isoflavones Exposure Estimates1- con’d B Amount of Isoflavone kg-1 body weight-1

17. 2.2.4. Bioavailability of Phytoestrogens • Plasma concentration1,2 • Circulating concentrations of isoflavones in seven infants fed soy-based formula were • 13,000-22,000 times higher than plasma oestradiol concentrations in early life Greater than in infants fed breast milk and or cow-milk formulas • An order of magnitude higher per bodyweight than typical plasma concentrations of adults consuming soy foods • Urinary excretion3 • Infants fed soy infant formulas absorb isoflavones, as evidenced from the high but variable urinary concentrations 1. Setchell KD, Lancet, 19972. Setchell KD,  Am J Clin Nutr, 19983. Cruz et al, Pediatr Res, 1994

18. Thyroid Gland • A.1. Infants • A.2. Adults • A.3. Possible Mechanisms of Action • B. Sexual Development and Fertility • C. Immune System • D. Central Nervous System (CNS)

19. 2.2.5. Adverse Effects of Phytoestrogens A. Thyroid Gland A.1. Effects on Thyroid Gland in Infants • 1950s and 1960s: • 12 cases documented goitrogenic effect of soy flour infant formula1,2,3 that resulted in substituting soy flour with SPI and supplementing it with iodine 4 • Recent studies: • Infants with congenital hypothyroidism fed soy-based infant formula have an increased requirement for thyroxine by as much as 18-25% 5 • A significant increase in rate of thyroid disease in subjects fed soy-based infant formula as infants6 • Incidence of positive thyroid antibodies was 2 1/2 times higher in formula-fed diabetic children than in breast-fed ones7

20. 2.2.5. Adverse Effects of Phytoestrogens A. Thyroid Gland A.2. Effects on Thyroid Gland in Adults • Duncan et al, J Clin Endocrinol Metab, 1999a • Duncan et al, J Clin Endocrinol Metab, 1999b • Persky et al, Am J Clin Nutr, 2002 Levy et al Proc Soc Exp Biol Med, 1995 • Ishizuki Y et al, Nippon Naibunpi Gakkai Zasshi, 1991 • Bell DS et al, EndocrPract, 2001

21. 2.2.5. Adverse Effects of Phytoestrogens A. Thyroid Gland Isoflavones in soy-based infant formula may influence thyroid function in infants by: Acting as a mild goitrogen Reducing absorption of iodine from the gut Increasing loss of thyroxine via the enterohepatic circulation Inhibiting the activity of thyroid peroxidase A study found no free isoflavones in the plasma of four infants after 4 weeks of continuous feeding on soy-based infant formula Huggett AC, Pridmore S, Malnoe A, Haschke F, Offord EA.Phyto-oestrogens in soy-based infant formula. Lancet 1997 Sep 13;350(9080):815-6 A.3. Possible Mechanisms of Action1 1. Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment- Working Group on Phytpestrogens, UK

22. 2.2.5. Advert Effects of Phytoestrogens B. Effects on Development and Fertility

23. 2.2.5. Adverse Effects of Phytoestrogens C. Effects on the Immune System • Strom BL et al, JAMA, 2001 • Zoppi G et al, Lancet, 1983 • Zoppi G et al, J Pediatr Gastroenterol Nutr, 1982 • Alexandersen P, JAMA, 2001

24. 2.2.5. Potential Effects of Phytoestrogens D. Effects on the CNS • Yakisich JS et al, Exp Neurol, 1999 • White LR et al, J Am Coll Nutr, 2000 • File SE et al, Psychopharmacol, 2001

25. Nitrites Formed during spray-drying1,2 Lysinoalanine Formed during alkaline processing1,2 Phytoestrogens Dietary bioflavonoids may contribute to infantile leukemia3 Genistein may be largely responsible for the development to Infantile Acute Leukemia (IAL)4 Genistein5,6 or soy phytoestrogens7,8 may stimulate proliferation of breast cancer cells “According to their concentration in vitro genistein and daidzein can slow up or stimulate the growth of tumorous cells”9 2.3. Presence of Pontential Carcinogens

26. 2.4. Aluminum

27. 2.4. Aluminum2.4.1. Exposure Estimates Mean plasma aluminum concentration in soy-based formula fed infants is 45% higher than breastfed children, and 36% higher than infants fed cow milk-based formulas • American Academy of Pediatrics, Pediatrics, 1996 • Hawkins NM et al, J Pediatr Gastroenterol Nutr, 1994

28. Concerns associated with increased aluminum intake from soy-based infant formula: Interferes with a variety of cellular and metabolic processes in the nervous system and in other tissues 1 Increased aluminum deposition in CNS 2 Osteopenia2 Infants at increased risk of aluminum toxicity2 Preterm infants Children with renal failure Infants with intrauterine growth retardation 2.4. Aluminum 2.4.2. Safety Issues • American Academy of Pediatrics, Pediatrics, 1996 • Koo WWK et al, J Am Coll Nutr, 1988

29. 2.5. Manganese

30. 2.5. Manganese2.5.1. Exposure Estimates Mangnaese content of soy-based infant formula is 2400% than that of breastmilk 1. Position of the United Soybean Board: Manganese and Soy-Based Infant Formula

31. 2.5. Manganese2.5.2. Safety Issues • Human Studies • May be present at higher levels in hair of hyperactive children and children with learning disabilities compared with levels in normal children1 • Chronic manganese exposure associated with poor verbal and visual memory2 • Animal Studies • Accumulates in the brains of animals exposed at young ages3 • Exposure to young animals can cause neurodegenerative changes4 • Neonatal manganese exposure is related to neurocognitive and developmental deficits in rodent5 • Collip PJ et al, Ann Nutr Metab, 1983 • Woolf A et al, Enviro Health Perspect, 2002 • Dorman DC et al, J Appl Toxicol, 2000 • Pappas BA et al, Neurotoxicol and Teratol, 1997 • Tran TT et al, NeuroToxicol, 2002

32. 2.6. Allergicinity of Soy 1. Tonz O et al, Paediatricia, 1997 2. Eastham EJ et al, J Pediatr, 1978 3. Miskelly FG et al, Arch Dis Child, 1988 4. Hill DJ et al, Clin Rev Allergy, 1984 5. Gruskay FL et al, Clin Paediatr, 1982

33. 2.7. Genetically-Modified (GM) Soy • GM soy might contain: • Lower levels of phytoestrogens by 12-14%1 • Higher trypsin inhibitorlevels2,3 • By 27% in raw RR soy • By 18% in toasted RR soy • Lower choline levels in lecithinby 29%3 • Lower levels of phenylalanine3 • Double the amount of lectins (hemaglutinin)3 • An additional segment of DNA4 • Higher concentration of the herbicide glyphosate5 • Lappé MA et al, J Med Food, 1999 • Padgette SR, J Nutr, 1999 • Keeler B, Los Angeles Times, 2001 • Palevitz, The Scientist, 2000 • Masaharu, Nagoya University, Japan, 2001

34. 3. Position of Various Regulators

35. 3.1. American Academy of Pediatrics American Academy of Paediatrics, Paediatrics, 1998

36. 3.1. American Academy of Pediatrics- con’d • Soy-based formulas have no proven value in: • Management of acute gastroenteritis for most previously-well infants • Prevention or management of infantile colic • Prevention of atopic disease in healthy or high-risk infants • Cow milk protein-induced enteropathy or enterocolitis • Soy-based formulas not designed or recommended for: • Infants with documented cow milk protein-induced enteropathy or enterocolitis • Preterm infants who weigh <1800 g

37. 3.2. Australian College of Paediatrics • Soy formula is not to be indiscriminately used: • In infants with vague symptoms and signs not proven to be due to cow’s milk protein intolerance • As prophylaxis in infants thought to be at risk of developing allergy • Soy formula may be appropriately prescribed for: • Galactosemia • Lactose intolerance • The use of soy-based infant formula may not be without side effects: • Its use mayimpair immunity • The long-term effects of soy (e.g. aluminum and phytoestrogens) are unknown The Australian College of Paediatrics, J Paediatr Child Health, 1998

38. Soy-based infant formula can be used under medical supervision for the treatment of: Transient lactose intolerance Galactosemia IgE mediated cow’s milk allergy Soy-based infant formula can be used under medical supervision in infants whose parents wished to feed their child a vegetarian diet Soy-based formula is not recommended for: Routine use in infants Preterm infants Cows’ milk protein induced enterocolitis or enteropathy Treatment colic Atopic disease 3.3. Food Safety Authority of Ireland Food Safety Authority of Ireland, Recommendations for a national feeding policy, 1999

39. 3.4. Joint Working Group of Canadian Paediatric Society Nutrition Committee, Dietitians of Canada, and Health Canada • Restrict use of soy-based formulas only for infants who: • “Cannot be fed dairy-based products for health, cultural or religious reasons, including galactosemia or a vegan lifestyle” • Soy-based infant formula not recommended: • In the management of infants with an allergy to cows’ milk protein • For the prevention of atopic diseases Health Canada, Nutrition for Healthy Term Infants, 1998

40. 3.5. New Zealand Ministry of Health • Soy formula may be appropriately prescribed only for: • Proven cow’s milk protein intolerance or allergy • Lactose intolerance • Galactosemia • Potential interaction between soy infant formula and thyroid function to be considered: • Thyroxine replacement should be monitored closely • Assessment of thyroid function should be considered if satisfactory growth and development is not achieved or maintained New Zealand Ministry of Health, Soy based infant formula, 1998

41. 3.6. Swiss Federal Commission on Food • Use of soya-bean products as baby foods should be made “very restrictive” and is allowed only in a few medical conditions: • Lactose intolerance • Galactosemia • (Possibly) Cow’s milk allergy • Soya-bean products should not be used: • Routinely in preparation of food for healthy babies • For ecological, ideological or ethical reasons • “Hydrolyzed or lactose-free products are probably better than those based on the soya bean” • Tonz O et al, Paediatricia, 1997

42. 3.7. United Kingdom Health Authorities • United Kingdom Department of Health - 1996 • Breastfeeding is the best feeding choice and cow’s milk formulae are preferable for most bottle-fed babies. • Babies being fed soya-based formula on a healthcare professional’s advice should continue to do so • Babies being fed soya-based formula by choice of parents should continue to so so, but parents should seek the advice of a healthcare professional. • Food Advisory Committee - 1996 • Infant formulae manufacturers should investigate ways to reduce the levels of phytoestrogens in soy-based infant formula 1. Department of Health, London, UK, 1996 2. MAFF, London, UK 1996

43. Scientific Advisory Committee on Nutrition, 20031 Considers that “there is cause for concern about the use of soy-based infant formula. Additionally, there is neither substantive medical need for, nor health benefit arising from, the use soy-based infant formulae.” Working Group of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment (COT)1 – 2003 Recommends to amend the advise of the Department of Health to read as follows: “…soy-based infant formulae be fed to infants only when indicated clinically.” 3.7. United Kingdom Health Authorities- con’d 1. Working Group of the Committee on Toxicity of Chemicals in Food, Consumer Products and the Environment, 2003 http://www.food.gov.uk/multimedia/pdfs/2003-03.pdf

44. “The use of soy formulas as a large, uncontrolled, and basically un-monitored human infant experiment continues unabated”. Dr. Daniel Sheehan National Center for Toxicological Research of the USFDA