Article

NTP-CERHR Expert Panel Report on the Developmental Toxicity of Soy Infant Formula

Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
Birth Defects Research Part B Developmental and Reproductive Toxicology (Impact Factor: 1.17). 10/2011; 92(5):421-68. DOI: 10.1002/bdrb.20314
Source: PubMed

ABSTRACT Soy infant formula contains soy protein isolates and is fed to infants as a supplement to or replacement for human milk or cow milk. Soy protein isolates contains estrogenic isoflavones (phytoestrogens) that occur naturally in some legumes, especially soybeans. Phytoestrogens are nonsteroidal, estrogenic compounds. In plants, nearly all phytoestrogens are bound to sugar molecules and these phytoestrogen-sugar complexes are not generally considered hormonally active. Phytoestrogens are found in many food products in addition to soy infant formula, especially soy-based foods such as tofu, soy milk, and in some over-the-counter dietary supplements. Soy infant formula was selected for National Toxicology Program (NTP) evaluation because of (1) the availability of large number of developmental toxicity studies in laboratory animals exposed to the isoflavones found in soy infant formula (namely, genistein) or other soy products, as well as few studies on human infants fed soy infant formula, (2) the availability of information on exposures in infants fed soy infant formula, and (3) public concern for effects on infant or child development. On October 2, 2008 (73 FR 57360), the NTP Center for the Evaluation of Risks to Human Reproduction (CERHR) announced its intention to conduct an updated review of soy infant formula to complete a previous evaluation that was initiated in 2005. Both the current and previous evaluations relied on expert panels to assist the NTP in developing its conclusions on the potential developmental effects associated with the use of soy infant formula, presented in the NTP Brief on Soy Infant Formula. The initial expert panel met on March 15 to 17, 2006, to reach conclusions on the potential developmental and reproductive toxicities of soy infant formula and its predominant isoflavone constituent genistein. The expert panel reports were released for public comment on May 5, 2006 (71 FR 28368). On November 8, 2006 (71 FR 65537), CERHR staff released draft NTP Briefs on Genistein and Soy Formula that provided the NTP's interpretation of the potential for genistein and soy infant formula to cause adverse reproductive and/or developmental effects in exposed humans. However, CERHR did not complete these evaluations, finalize the briefs, or issue NTP Monographs on these substances based on this initial evaluation. Between 2006 and 2009, a substantial number of new publications related to human exposure or reproductive and/or developmental toxicity were published for these substances. Thus, CERHR determined that updated evaluations of genistein and soy infant formula were needed. However, the current evaluation focuses only on soy infant formula and the potential developmental toxicity of its major isoflavone components, e.g. genistein, daidzein (and estrogenic metabolite, equol), and glycitein. This updated evaluation does not include an assessment on the potential reproductive toxicity of genistein following exposures during adulthood as was carried out in the 2006 evaluation. CERHR narrowed the scope of the evaluation because the assessment of reproductive effects of genistein following exposure to adults was not considered relevant to the consideration of soy infant formula use in infants during the 2006 evaluation. To obtain updated information about soy infant formula for the CERHR evaluation, the PubMed (Medline) database was searched from February 2006 to August 2009 with genistein/genistin, daidzein/daidzin, glycitein/glycitin, equol, soy, and other relevant keywords. References were also identified from the bibliographies of published literature. The updated expert panel report represents the efforts of a 14-member panel of government and nongovernment scientists, and was prepared with assistance from NTP staff. The finalized report, released on January 15, 2010 (75 FR 2545), reflects consideration of public comments received on a draft report that was released on October 19, 2009, for public comment and discussions that occurred at a public meeting of the expert panel held December 16 to 18, 2009 (74 FR 53509). The finalized report presents conclusions on (1) the strength of scientific evidence that soy infant formula or its isoflavone constituents are developmental toxicants based on data from in vitro, animal, or human studies; (2) the extent of exposures in infants fed soy infant formula; (3) the assessment of the scientific evidence that adverse developmental health effects may be associated with such exposures; and (4) knowledge gaps that will help establish research and testing priorities to reduce uncertainties and increase confidence in future evaluations. The Expert Panel expressed minimal concern for adverse developmental effects in infants fed soy infant formula. This level of concern represents a "2" on the five-level scale of concern used by the NTP that ranges from negligible concern ("1") to serious concern ("5"). The Expert Panel Report on Soy Infant Formula was considered extensively by NTP staff in preparing the 2010 NTP Brief on Soy Infant Formula, which represents the NTP's opinion on the potential for exposure to soy infant formula to cause adverse developmental effects in humans. The NTP concurred with the expert panel that there is minimal concern for adverse effects on development in infants who consume soy infant formula. This conclusion was based on information about soy infant formula provided in the expert panel report, public comments received during the course of the expert panel evaluation, additional scientific information made available since the expert panel meeting, and peer reviewer critiques of the draft NTP Brief by the NTP Board of Scientific Counselors (BSC) on May 10, 2010 (Meeting materials are available at). The BSC voted in favor of the minimal concern conclusion with 7 yes votes, 3 no votes, and 0 abstentions. One member thought that the conclusion should be negligible concern and two members thought that the level of concern should be higher than minimal concern. The NTP's response to the May 10, 2010 review ("peer-review report") is available on the NTP website at. The monograph includes the NTP Brief on Soy Infant Formula as well as the entire final Expert Panel Report on Soy Infant Formula. Public comments received as part of the NTP's evaluation of soy infant formula and other background materials are available at. Reports can be obtained from the web site or from: Kristina A. Thayer, PhD, NIEHS/NTP K2-04, PO Box 12233, Research Triangle Park, NC 27709. E-mail: [email protected]
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    • "Narrative review of soya infant formulas; includes studies considered in this review Pedrosa, 2006 (79) Analysis of palatability of soya and other infant formulas D'Auria, 2006 (80) Letter to editor related to paper by Seppo on the impact of soya formulas on growth Osbron, 2006 (81) Systematic review of the efficacy of soya in preventing allergy Ostrom, 2006 (82) RCT on soya infant formula efficacy for regurgitation treatment Ballmer-Weber, 2007 (83) Clinical characteristics of allergy to soya Fortres, 2007 (84) Portuguese paper on phyto-oestrogen intake and thelarche Halm, 2007 (85) Comparison of phyto-oestrogen levels in urine between children and adults eating soya nuts Turck, 2007 (86) Narrative review of indications of soya and safety issues Song, 2007 (87) Narrative review of the positive and negative effects of soya; studies on soya formula already considered Agostoni, 2007 (88) Effects of soya on weight/age and length/age in children aged 6– 12 months; does not include reports on the basal and final measurements of weight-only and height-only differences Wolff, 2008 (89) Cohort study related to puberty in girls analysing exposure to soya, but not to a soya infant formula Zuidmeer, 2008 (90) Prevalence of plant allergies, including allergy to soya, across countries; no safety parameters on infant formulas reported Johnson, 2008 (91) Narrative review of some articles that describe safety issues regarding soya infant formulas, already considered in this review Ngamphaiboon, 2008 (92) Description of CMPA in Thai children Mehr, 2008 (93) Food choices for CMPA; no safety parameters on soya analysed Boucher, 2008 (94) Epidemiological study of the early intake of soya and protective effect against breast cancer Kemp, 2008 (95) Consensus about the best treatment for CMPA; no safety parameters on soya analysed Bernbaum, 2008 (96) Pilot study to evaluate the validity of different techniques to measure breast bud, testicular volume and breast adipose tissue in children; no correlationship study between soya intake and maturation abnormalities Koplin, 2008 (97) Use of soya and allergy to peanuts; no other safety parameters analysed Caminiti, 2009 (98) Analysis of cross-reaction to soya; no other safety parameters analysed Antunes, 2009 (99) Analysis of allergy to soya and extensively hydrolysed formulas; no other safety parameters reported Badger, 2009 (100) Narrative review of some basic and clinical studies of the effects of soya on health; includes some papers considered in this review Lee, 2009 (101) Epidemiological study of the intake of soya during adolescence and protective effect against breast cancer Korde, 2009 (102) Epidemiological study of the early intake of soya and protective effect against breast cancer Guest, 2009 (103) Health economics model of treatment for CMPA; safety parameters on soya not evaluated Palmer, 2009 (104) Urogenital effects of in utero exposure to diethylstilbestrol in males; does not include studies on infant formulas Cederroth, 2009 (105) Effects of soya on male reproductive function; animal studies; does not include paediatric studies on soya infant formulas Vandenplas, 2011 (106) Narrative review on the safety of soya infant formulas; some papers cited are analysed in this review Dias, 2010 (107) Persistence of CMPA and use of different infant formulas; no safety parameters on soya reported Bolca, 2010 (108) Soya isoflavones in breast tissue of women under breast resection Cheng, 2010 (109) Cohort study of soya ingestion during adolescence; not related to infant formulas Terracciano, 2010 (110) Analysis of soya allergy; no other safety parameters reported Tillet, 2010 (111) Informative letter of toxicology classification Nacmias, 2010 (112) Paper related to allergy to soya in neonates; no other safety parameters reported Sladkevicius, 2010 (113) Health economics analysis of soya use Katz, 2010 (114) Paper related to allergy to soya; no other safety parameters reported Patisaul, 2010 (115) Narrative description of biochemical, basic, clinical and epidemiological studies of soya; includes analysis of papers related to soya infant formulas, already considered in this review Donovan, 2010 (116) Description of soya effects on intestinal cell proliferation and antirotavirus effect; no safety parameters on soya reported Dinsdale, 2010 (117) Narrative review focused on animal and human studies on potential soya toxicity; non-systematic analysis concludes that there is no evidence of soya infant formula toxicity in children Wada, 2011 (118) Cross-sectional study of the correlationship between soya in diet and urinary level of sex hormones in boys/girls aged 4 –6 years; no history about soya infant formulas is recorded McCarver, 2011 (119) Exhaustive narrative review focused on animal and human studies; non-systematic analysis concludes that there is no evidence of soya infant formula toxicity in children Kim, 2011 (120) Case – control study in 7–10·2-year-old girls to establish a correlationship between isoflavones in serum and precocious puberty; no diet history analysed; does not include a discussion on soya infant formulas Kattan, 2011 (121) Narrative review of soya allergy; no safety parameters on soya reported Dabeka, 2011 (122) Comparative analysis of aluminium in different food products for children; no safety parameters reported Degen, 2011 (123) Measurements of isoflavones in urine of 6–18-year-old children; no history about soya infant formulas reported Nguyen, 2011 (124) US measurements of different organs in children fed soya, cows' milk or HM; no mathematical data reported; only graphs and P values reported Jefferson, 2011 (125) Narrative review of basic, clinical and epidemiological studies of the effects of soya in animal models and human subjects; describes some important papers included in this review Durham, 2011 (126) Analysis of food allergy; no safety parameters on soya reported Levi, 2012 (127) Utility of atopy patch in atopic dermatitis; no safety parameters on soya reported Jefferson, 2012 (128) Narrative review of basic, clinical and epidemiological studies of the effects of soya in animal models and human subjects; describes some important papers included in this review Blom, 2012 (129) Analysis of allergy to soya; no other safety parameters reported Crinella, 2012 (130) Narrative review of different hypotheses related to ADHD, with focus on manganese toxicity; brief description of possible association of soya, manganese and ADHD CMPA, cows' milk protein allergy; RCT, randomised controlled trial; HM, human milk; ADHD, attention deficit hyperactivity disorder. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Soya-based infant formulas (SIF) containing soya flour were introduced almost 100 years ago. Modern soya formulas are used in allergy/intolerance to cows' milk-based formulas (CMF), post-infectious diarrhoea, lactose intolerance and galactosaemia, as a vegan human milk (HM) substitute, etc. The safety of SIF is still debated. In the present study, we reviewed the safety of SIF in relation to anthropometric growth, bone health (bone mineral content), immunity, cognition, and reproductive and endocrine functions. The present review includes cross-sectional, case-control, cohort studies or clinical trials that were carried out in children fed SIF compared with those fed other types of infant formulas and that measured safety. The databases that were searched included PubMed (1909 to July 2013), Embase (1988 to May 2013), LILACS (1990 to May 2011), ARTEMISA (13th edition, December 2012), Cochrane controlled trials register, Bandolier and DARE using the Cochrane methodology. Wherever possible, a meta-analysis was carried out. We found that the anthropometric patterns of children fed SIF were similar to those of children fed CMF or HM. Despite the high levels of phytates and aluminium in SIF, Hb, serum protein, Zn and Ca concentrations and bone mineral content were found to be similar to those of children fed CMF or HM. We also found the levels of genistein and daidzein to be higher in children fed SIF; however, we did not find strong evidence of a negative effect on reproductive and endocrine functions. Immune measurements and neurocognitive parameters were similar in all the feeding groups. In conclusion, modern SIF are evidence-based safety options to feed children requiring them. The patterns of growth, bone health and metabolic, reproductive, endocrine, immune and neurological functions are similar to those observed in children fed CMF or HM.
    The British journal of nutrition 02/2014; 111(8):1-21. DOI:10.1017/S0007114513003942 · 3.34 Impact Factor
  • Source
    • "Narrative review of soya infant formulas; includes studies considered in this review Pedrosa, 2006 (79) Analysis of palatability of soya and other infant formulas D'Auria, 2006 (80) Letter to editor related to paper by Seppo on the impact of soya formulas on growth Osbron, 2006 (81) Systematic review of the efficacy of soya in preventing allergy Ostrom, 2006 (82) RCT on soya infant formula efficacy for regurgitation treatment Ballmer-Weber, 2007 (83) Clinical characteristics of allergy to soya Fortres, 2007 (84) Portuguese paper on phyto-oestrogen intake and thelarche Halm, 2007 (85) Comparison of phyto-oestrogen levels in urine between children and adults eating soya nuts Turck, 2007 (86) Narrative review of indications of soya and safety issues Song, 2007 (87) Narrative review of the positive and negative effects of soya; studies on soya formula already considered Agostoni, 2007 (88) Effects of soya on weight/age and length/age in children aged 6– 12 months; does not include reports on the basal and final measurements of weight-only and height-only differences Wolff, 2008 (89) Cohort study related to puberty in girls analysing exposure to soya, but not to a soya infant formula Zuidmeer, 2008 (90) Prevalence of plant allergies, including allergy to soya, across countries; no safety parameters on infant formulas reported Johnson, 2008 (91) Narrative review of some articles that describe safety issues regarding soya infant formulas, already considered in this review Ngamphaiboon, 2008 (92) Description of CMPA in Thai children Mehr, 2008 (93) Food choices for CMPA; no safety parameters on soya analysed Boucher, 2008 (94) Epidemiological study of the early intake of soya and protective effect against breast cancer Kemp, 2008 (95) Consensus about the best treatment for CMPA; no safety parameters on soya analysed Bernbaum, 2008 (96) Pilot study to evaluate the validity of different techniques to measure breast bud, testicular volume and breast adipose tissue in children; no correlationship study between soya intake and maturation abnormalities Koplin, 2008 (97) Use of soya and allergy to peanuts; no other safety parameters analysed Caminiti, 2009 (98) Analysis of cross-reaction to soya; no other safety parameters analysed Antunes, 2009 (99) Analysis of allergy to soya and extensively hydrolysed formulas; no other safety parameters reported Badger, 2009 (100) Narrative review of some basic and clinical studies of the effects of soya on health; includes some papers considered in this review Lee, 2009 (101) Epidemiological study of the intake of soya during adolescence and protective effect against breast cancer Korde, 2009 (102) Epidemiological study of the early intake of soya and protective effect against breast cancer Guest, 2009 (103) Health economics model of treatment for CMPA; safety parameters on soya not evaluated Palmer, 2009 (104) Urogenital effects of in utero exposure to diethylstilbestrol in males; does not include studies on infant formulas Cederroth, 2009 (105) Effects of soya on male reproductive function; animal studies; does not include paediatric studies on soya infant formulas Vandenplas, 2011 (106) Narrative review on the safety of soya infant formulas; some papers cited are analysed in this review Dias, 2010 (107) Persistence of CMPA and use of different infant formulas; no safety parameters on soya reported Bolca, 2010 (108) Soya isoflavones in breast tissue of women under breast resection Cheng, 2010 (109) Cohort study of soya ingestion during adolescence; not related to infant formulas Terracciano, 2010 (110) Analysis of soya allergy; no other safety parameters reported Tillet, 2010 (111) Informative letter of toxicology classification Nacmias, 2010 (112) Paper related to allergy to soya in neonates; no other safety parameters reported Sladkevicius, 2010 (113) Health economics analysis of soya use Katz, 2010 (114) Paper related to allergy to soya; no other safety parameters reported Patisaul, 2010 (115) Narrative description of biochemical, basic, clinical and epidemiological studies of soya; includes analysis of papers related to soya infant formulas, already considered in this review Donovan, 2010 (116) Description of soya effects on intestinal cell proliferation and antirotavirus effect; no safety parameters on soya reported Dinsdale, 2010 (117) Narrative review focused on animal and human studies on potential soya toxicity; non-systematic analysis concludes that there is no evidence of soya infant formula toxicity in children Wada, 2011 (118) Cross-sectional study of the correlationship between soya in diet and urinary level of sex hormones in boys/girls aged 4 –6 years; no history about soya infant formulas is recorded McCarver, 2011 (119) Exhaustive narrative review focused on animal and human studies; non-systematic analysis concludes that there is no evidence of soya infant formula toxicity in children Kim, 2011 (120) Case – control study in 7–10·2-year-old girls to establish a correlationship between isoflavones in serum and precocious puberty; no diet history analysed; does not include a discussion on soya infant formulas Kattan, 2011 (121) Narrative review of soya allergy; no safety parameters on soya reported Dabeka, 2011 (122) Comparative analysis of aluminium in different food products for children; no safety parameters reported Degen, 2011 (123) Measurements of isoflavones in urine of 6–18-year-old children; no history about soya infant formulas reported Nguyen, 2011 (124) US measurements of different organs in children fed soya, cows' milk or HM; no mathematical data reported; only graphs and P values reported Jefferson, 2011 (125) Narrative review of basic, clinical and epidemiological studies of the effects of soya in animal models and human subjects; describes some important papers included in this review Durham, 2011 (126) Analysis of food allergy; no safety parameters on soya reported Levi, 2012 (127) Utility of atopy patch in atopic dermatitis; no safety parameters on soya reported Jefferson, 2012 (128) Narrative review of basic, clinical and epidemiological studies of the effects of soya in animal models and human subjects; describes some important papers included in this review Blom, 2012 (129) Analysis of allergy to soya; no other safety parameters reported Crinella, 2012 (130) Narrative review of different hypotheses related to ADHD, with focus on manganese toxicity; brief description of possible association of soya, manganese and ADHD CMPA, cows' milk protein allergy; RCT, randomised controlled trial; HM, human milk; ADHD, attention deficit hyperactivity disorder. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Soya-based infant formulas (SIF) containing soya flour were introduced almost 100 years ago. Modern soya formulas are used in allergy/intolerance to cows' milk-based formulas (CMF), post-infectious diarrhoea, lactose intolerance and galactosaemia, as a vegan human milk (HM) substitute, etc. The safety of SIF is still debated. In the present study, we reviewed the safety of SIF in relation to anthropometric growth, bone health (bone mineral content), immunity, cognition, and reproductive and endocrine functions. The present review includes cross-sectional, case-control, cohort studies or clinical trials that were carried out in children fed SIF compared with those fed other types of infant formulas and that measured safety. The databases that were searched included PubMed (1909 to July 2013), Embase (1988 to May 2013), LILACS (1990 to May 2011), ARTEMISA (13th edition, December 2012), Cochrane controlled trials register, Bandolier and DARE using the Cochrane methodology. Wherever possible, a meta-analysis was carried out. We found that the anthropometric patterns of children fed SIF were similar to those of children fed CMF or HM. Despite the high levels of phytates and aluminium in SIF, Hb, serum protein, Zn and Ca concentrations and bone mineral content were found to be similar to those of children fed CMF or HM. We also found the levels of genistein and daidzein to be higher in children fed SIF; however, we did not find strong evidence of a negative effect on reproductive and endocrine functions. Immune measurements and neurocognitive parameters were similar in all the feeding groups. In conclusion, modern SIF are evidence-based safety options to feed children requiring them. The patterns of growth, bone health and metabolic, reproductive, endocrine, immune and neurological functions are similar to those observed in children fed CMF or HM.
    British Journal Of Nutrition 02/2014; · 3.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In mice, exposure to isoflavones (ISO), abundant in soy infant formula, during the first 5 d of life alters structural and functional development of reproductive organs. Effects of longer exposures are unknown. The study objective was to evaluate whether exposure to a combination of daidzein and genistein in the first 10 compared to 5 d of life results in greater adverse effects on ovarian and uterine structure in adult mice. Thirteen litters of 8-12 pups were cross-fostered and randomized to corn oil or ISO (2 mg daidzein + 5 mg genistein/kg body weight/d) for the first 5 or 10 d of life. The 10-d protocol mimicked the period when infants are fed soy protein formula (SPF) but avoids the time when suckling pups can consume mother's diet. Body and organ weights, and histology of ovaries and uteri were analyzed. There were no differences in the ovary or uterus weight, number of ovarian follicles, number of multiple oocyte follicles, or percent of ovarian cysts with 5 or 10 d ISO intervention compared to respective controls. The 10-d ISO group had higher body weights from 6 d to 4 mo of age and a higher percent of hyperplasia in the oviduct than the respective control. Lower number of ovarian corpus lutea and a higher incidence of abnormal changes were reported in the uteri of both ISO groups compared to their respective controls. Five and 10-d exposure to ISO had similar long-lasting adverse effects on the structure of ovaries and uterus in adult mice. Only the 10-d ISO exposure resulted in greater body weight gain at adulthood.
    Journal of Toxicology and Environmental Health Part A 06/2012; 75(11):649-60. DOI:10.1080/15287394.2012.688482 · 1.83 Impact Factor
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