Trends in Food Science & Technology 36 (2014) 55e58

Letter to the Editor

DOI of original article: http://dx.doi.org/10.1016/j.tifs.2012.12.003.

0924-2244/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tifs.2013.12.003

Justification for soy

protein to still have a

category ‘A’ coronary

heart disease risk

reduction health

claim

Girgih et al. (2013) recently published a review inTrends in Food Science and Technology (Volume 30, pp.121e132) which challenges the justification for soy proteinto still have a category ‘A’ coronary heart disease riskreduction health claim as originally reviewed and approvedby the US Food and Drug Administration. The authorsfurther propose that the FDA use a modified ranking tran-sient scale that they introduce “could assist with otherpotential controversial health claims in the future”. Theauthors claim the motivation to write this review was basedon data on soy protein and cholesterol lowering generatedsince the soy protein heart health claim was approved in1999 which show modest to no effect and the fact thatthe FDA announced that it would re-evaluate the soy pro-tein and heart health claim in December 2007.

There are many concerns with this review, including:misinterpretation of laws, FDA guidance documents, andregulations pertaining to claims; misinterpretation of theoriginal FDA final rule on the soy protein health claim;omission of many studies that are supportive of the healthclaim published since 1999; and citing studies whichwere not designed to evaluate soy protein’s effect oncholesterol levels. Specific concerns are listed below:

1. The authors claim that the FDA “assessment of the soyprotein evidence excluded the isoflavone componentbecause of safety concerns such as altered menstrual cy-cle, male infertility and memory loss” (p. 122) is untrue

and misleading. In fact, in Section 3 of the FDA FinalRule (Federal Register of October 26, 1999) (FDA,1999) which the authors cite, the following reasons fornot including isoflavones is stated as: “Given the limitednumber of studies and the contradictory outcomes, FDAwas not persuaded that the isoflavone component of soyprotein was a relevant factor to the dietedisease relation-ship. Rather, FDA tentatively concluded that the evi-dence from a wide range of studies using differentlyprocessed soy protein was supportive of a relationshipbetween soy protein per se and reduced risk of CHD”.

2. As evidence of the need to demote the level of the FDAsoy protein health claim, the authors point out that theAHA challenged the heart health claim in 2006 (Sackset al., 2006) and that the European Food Safety Authorityfailed to approve the soy protein and reduction of LDL-Cclaim application on two occasions. With regard to theAHA challenge, one of the original authors of the AHAAdvisory conducted a more recent meta-analysis andre-evaluation of the studies cited by the AHA in their2006 Advisory and concluded that the studies overallshowed that soy protein provided significant LDL choles-terol (LDL-C) reduction (�0.17 mmol/L or �4.3%)through an intrinsic mechanism and also contributed tocholesterol lowering when displacing animal-derivedprotein (extrinsic mechanism) by an estimated3.6e6.0% (Jenkins et al., 2010). This level of LDL-Creduction is similar to that observed with other ingredi-ents which have health claims (barley beta-glucan(�0.26 to �0.27 mmol/L) (Abumweis, Jew, & Ames,2010; Talati, Baker, Pabilonia, White, & Coleman,2009), oat beta-glucan (�0.13 to �0.21 mmol/L)(Brown, Rosner, Willett, & Sacks, 1999; EFSA Panelon Dietetic Products: Nutrition and Allergies (NDA),2010; Ripsin et al., 1992) and viscous soluble fibers(�0.17 mmol/L) (Brown et al., 1999)). With regard tothe failure of soy protein to obtain health claim approvalby EFSA, it is among the greater than 93% of ingredientswhose applications for health claims were rejected bythis organization (Kupferschmidt, 2012). It is well recog-nized that health claims in the EU, particularly for com-plex ingredients such as soy protein which are mixturesand not single characterized molecular entities and forwhich there is not yet a single identified mechanism ofaction, will continue to be difficult to obtain under thecurrent paradigm.

56 Letter to the Editor / Trends in Food Science & Technology 36 (2014) 55e58

3. The authors also present an argument that the isofla-vones may be responsible for the cholesterol loweringeffect of soy protein when this argument has largelybeen abandoned recently in light of many studies con-ducted since the health claim was issued that show thatisolated isoflavones do not lower cholesterol (studiesare summarized in Harland, Krul, Mukherjea, &Maki, 2013) (Harland et al., 2013). Moreover, the au-thors cite Taku, Umegaki, Sato, Endoh, & Watanabe,2007 (Taku et al., 2007) as support for the role ofisoflavones as being responsible for the cholesterollowering effect of soy protein, however, the authorsfailed to cite a subsequent meta-analysis by Taku,Umegaki, Ishimi, & Watanabe, 2008 (Taku et al.,2008) that showed that isolated isoflavones, in theabsence of soy protein, do not demonstrate a choles-terol lowering effect.

4. The authors compiled a table of studies of emerging clin-ical trials and meta-analyses showing moderate to no ef-fect of soy protein on CVD risk (Table 2); the authors cite5 meta-analyses conducted after 1999 (Balk et al., 2005;Reynolds et al., 2006; Taku et al., 2007; Weggemans &Trautwein, 2003; Zhan & Ho, 2005) but fail to cite addi-tional relevant meta-analyses (Zhou, 2004 (Zhou, Melby,& Watanabe, 2004); Harland, 2008 (Harland & Haffner,2008); Hooper, 2008 (Hooper et al., 2008); Anderson,2011 (Anderson&Bush, 2011)) that have been publishedsince 1999. The authors do not provide a justification orcriteria for the selection of the studies listed in Table 2.Of the studies listed, two examined the effects of isofla-vones with little or no soy protein consumption(Atteritano et al., 2007; Clerici et al., 2007) and one studywas included that was not a cholesterol lowering studybut a report of lipid changes in a study designed to inves-tigate the role of soy protein on bone density in post-menopausal women (Campbell, Khalil, Payton, &Arjmandi, 2010). The authors failed to cite 21 clinicalstudies that were conducted between 1999 and 2010 onsoy protein and cholesterol lowering (Allen, 2007(Allen, Becker, Kwiterovich, Lindenstruth, & Curtis,2007); Ashton, 2000 (Ashton & Ball, 2000); Azadbakht,2007 (Azadbakht et al., 2007); Borodin, 2000 (Borodinet al., 2009); Dent, 2001 (Dent et al., 2001); Evans,2007 (Evans, Mjike, Hoxley, Pearson, & Katz, 2007);Greany, 2004 (Greany, Nettleton, Wangen, Thomas, &Kurzer, 2004); Hoie, 2005a (Hoie, Graubaum, Harde,Gruenwald, & Wernecke, 2005); Hoie 2005b (Hoie,Morgenstern, et al., 2005); Hoie, 2007 (Hoie et al.,2007); Maki, 2010 (Maki et al., 2010); McVeigh, 2006(McVeigh, Dillingham, Lampe, & Duncan, 2006);Meyer, 2004 (Meyer et al., 2004); Pipe, 2009 (Pipeet al., 2009); Radhakrishnan, 2009 (Radhakrishnan,Rashmi, & Vaid, 2009); Takatsuka, 2000 (Takatsukaet al., 2000); Van Horn, 2001 (Van Horn et al., 2001);Welty, 2007 (Welty, Lee, Lew, & Zhou, 2007); West,2005 (West et al., 2005); Wong, 2010 (Wong et al.,

2010)) (all cited in Harland et al., 2010) (Harlandet al., 2013). Overall it can be concluded that the authorsdid not conduct a comprehensive and fair review of thesoy protein and cholesterol lowering literature.

5. The authors’ attempts to establish a relationshipbetween the quantity of clinical studies included in ahealth claim petition and the strength of the relationshipbetween a substance and disease risk are faulty andillogical. A smaller number of clinical trials used tosuccessfully establish SSA does not necessarily indi-cate the substance/disease relationship is stronger thanfor a substance that included a larger number of clinicaltrials in a health claim submission, particularly if thehealth claim with a larger number of clinical trialsshows a consistently positive relationship between thesubstance and disease risk. In addition, the authorsincorrectly state that “the soy protein CHD claimrequired 41 reviewed clinical trials to pass FDA scru-tiny for approval”. In fact, the FDA gave particularweight to only 14 trials when reviewing the healthclaim submission (FDA, 1999). If there was an attemptto imply that clinical trials were initiated solely for thepurpose of winning regulatory approval for the soyhealth claim, it should be noted that eight of the 14 clin-ical trials given the greatest weight by FDA in their re-view of the soy protein/CHD submission werepublished well before the passage of the Nutrition La-beling and Education Act of 1990 (Nutrition Labelingand Education Act, 1990), which sets forth the require-ments for permitting health claims.

6. There are several incorrect statements regarding regula-tory and labeling matters. The authors state that “The UScurrently allows three main types of claims on the labelsfor food and dietary supplement: nutrient content, struc-ture/function, and health claims, which are collectivelyreferred to as qualified health claims”. This is incorrect;“health claims” are subdivided into two subcategories:“Qualified Health Claims” and “Health Claims ThatMeet Significant Scientific Agreement” (Food & DrugAdministration, 2009). The authors also state that bothnutrient content claims and structure/function claimsmust be “accompanied by a disclaimer statement thatthe claim has not been evaluated by the FDA, and isnot intended to diagnose, treat, cure or prevent any dis-ease”. This is incorrect; the disclaimer statement is notrequired for nutrient content claims, nor is it requiredfor structure/function claims made on conventionalfoods (it is only required for structure/function claimsmade on dietary supplements) (Food & DrugAdministration, 2006). Finally, the authors state that“the commencement of a relook/review of the soy pro-tein health claim stems from the fact that the soy proteinhealth claim no longer meets significant scientificagreement,.”. The FDA is the ultimate arbiter of deter-mining whether or not a claim meets SSA; the soy pro-tein/CHD claim still meets SSA and, as per Title 21 of

57Letter to the Editor / Trends in Food Science & Technology 36 (2014) 55e58

theUSCode of Federal Regulations, Part 101.82, is still apermitted health claim.

7. The authors make a proposal for the FDA to adopt a“transient scale ranking” of health claims in the futureas a way to apparently avoid the ongoing re-evaluationof the soy health claim by the FDA. The authors state“.no matter the quality and quantity of the scientificevidence (SSA) that a claim has, it should initially beassigned a lower ranking category (e.g. a “C” or “B”)but not an “A” until it passes the scrutiny test of the sci-entific community and experts in the field during awaiting period that could range from between 2 and 5years”. It is not clear what the advantage of such anew ranking system would offer in view of the factthat the FDA is already empowered to re-review healthclaims, per section 403(r) of the Federal Foods, Drug,and Cosmetic Act (as evidenced by their decision tore-review 4 health claims in 2007). Decisions on thesehave not yet been made to date, so it seems as though asystem requiring “ongoing” review would only be moredemanding of resources which are extremely limitedunder the current system. Other dietary recommenda-tions such as the Dietary Guidelines and/or establish-ment of the DRIs are subject to periodic review sothat new data or evidence may be taken into consider-ation to determine whether any necessary updates orcorrections need to be made. Health claims can beconsidered in a similar light. Having a system, as pro-posed by the authors, of having graded health claimsthat change over time, is not only resource intensive,but would be confusing to the consumer and health pro-fessionals alike, requiring constant referral and under-mining the credibility of established, scientificallysound health claims.

In summary, we feel that the review by Girgih AT et al.is not objective and some of the statements are misleadingand/or incorrect and that an erratum should be issued tocorrect the errors. The soy protein heart health claim isone of several health claims under re-evaluation by theFDA, which has the authority to review decisions basedon new data or information. While the opinions and recom-mendations of the authors may be of interest, any change inregulations by which health claims are reviewed should bedone according to the established rulemaking process, withinput from regulatory bodies, scientific experts and industrystakeholders.

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Elaine S. Krul*Nutrition Discovery, Protein Solutions, DuPont Nutrition & Health,

4300 Duncan Avenue, St. Louis, MO 63110, USAE-mail: ekrul@solae.com

Lulu MauroRegulatory and Scientific Affairs, DuPont Nutrition & Health,

4300 Duncan Avenue, St. Louis, MO 63110, USA

Ratna MukherjeaGlobal Nutrition, DuPont Nutrition & Health,

4300 Duncan Avenue, St. Louis, MO 63110, USA

*Corresponding author.