50324

Proposed Rules Federal Register Vol. 82, No. 209

Tuesday, October 31, 2017

This section of the FEDERAL REGISTER possible, please submit all items on a procedure for distribution transformers contains notices to the public of the proposed compact disc (CD), in which case it is on September 22, 2017. 82 FR 44347. issuance of rules and regulations. The not necessary to include printed copies. The RFI initiated a data collection purpose of these notices is to give interested • Hand Delivery/Courier: Appliance process to consider whether to amend persons an opportunity to participate in the and Equipment Standards Program, U.S. DOE’s test procedures for distribution rule making prior to the adoption of the final Department of Energy, Building rules. transformers. DOE requested written Technologies Office, 950 L’Enfant Plaza comment, data, and information SW., 6th Floor, Washington, DC 20024. pertaining to these test procedures by DEPARTMENT OF ENERGY Telephone: (202) 287–1445. If possible, October 23, 2017. please submit all items on a CD, in The National Electrical Manufacturers 10 CFR Parts 429 and 431 which case it is not necessary to include Association (NEMA), an interested party printed copies. [EERE–2017–BT–TP–0055] in the matter, requested a two-week No telefacsimilies (faxes) will be extension of the public comment period Energy Conservation Program: Test accepted. For detailed instructions on for the RFI published in the Federal Procedure for Distribution submitting comments and additional Register on October 5, 2017. (NEMA, Transformers information on the rulemaking process, No. 4, at p. 1) see section III of the RFI published on DOE believes that re-opening the AGENCY: Office of Energy Efficiency and September 22, 2017. comment period to allow additional Renewable Energy, Department of Docket: The docket for this activity, time for interested parties to submit Energy. which includes Federal Register comments is appropriate. Therefore, ACTION: Request for information; re- notices, comments, and other DOE is re-opening the comment period opening of public comment period. supporting documents/materials, is until November 6, 2017 to provide available for review at http:// interested parties additional time to SUMMARY: On September 22, 2017, the www.regulations.gov. All documents in prepare and submit comments. U.S. Department of Energy (DOE) the docket are listed in the http:// Comments received between the published a request for information www.regulations.gov index. However, original October 23 closing date and the (RFI) pertaining to the test procedures some documents listed in the index, new November 6 closing date are for distribution transformers. The RFI such as those containing information considered timely filed. Therefore, provided an opportunity for submitting that is exempt from public disclosure, individuals who submitted late written comments, data, and may not be publicly available. comments during the original comment information by October 23, 2017. This The docket Web page can be found at period do not need to re-submit document announces that the period for http://www.regulations.gov/ comments. submitting comments on the RFI is to be #!docketDetail;D=EERE-2017-BT-TP- re-opened until November 6, 2017. 0055. The docket Web page will contain Issued in Washington, DC, on October 19, 2017. DATES: simple instructions on how to access all The comment period for the RFI, David Nemtzow, published on September 22, 2017 (82 FR documents, including public comments, in the docket. Director, Building Technologies Office, 44347), is re-opened until November 6, Energy Efficiency and Renewable Energy. 2017. DOE will accept written FOR FURTHER INFORMATION CONTACT: comments, data, and information in Mr. Jeremy Dommu, U.S. Department [FR Doc. 2017–23635 Filed 10–30–17; 8:45 am] response to the RFI received no later of Energy, Office of Energy Efficiency BILLING CODE 6450–01–P than November 6, 2017. and Renewable Energy, Building ADDRESSES: Interested persons are Technologies Program, EE–5B 1000 encouraged to submit comments by any Independence Avenue SW., DEPARTMENT OF HEALTH AND of the following methods: Washington, DC 20585–0121. HUMAN SERVICES • Telephone: (202) 586–9870. Email: Federal eRulemaking Portal: Food and Drug Administration www.regulations.gov. Follow the ApplianceStandardsQuestions@ ee.doe.gov. instructions for submitting comments. 21 CFR Part 101 • Email: Mary Greene, U.S. Department of DistributionTransformers2017TP055@ Energy, Office of the General Counsel, [Docket No. FDA–2017–N–0763] ee.doe.gov. Include docket number GC–33, 1000 Independence Avenue EERE–2017–BT–TP–0055 in the subject SW., Washington, DC 20585–0121. RIN 0910–AH43 line of the message. Submit electronic Telephone: (202) 586–1817. Email: [email protected]. Food Labeling: Health Claims; Soy comments in WordPerfect, Microsoft Protein and Coronary Heart Disease Word, PDF, or ASCII file format, and For further information on how to submit a comment, review other public avoid the use of special characters or AGENCY: Food and Drug Administration, any form of encryption. comments and the docket, contact the HHS. • Appliance and Equipment Standards Postal Mail: Appliance and ACTION: Proposed rule. Equipment Standards Program, U.S. Program staff at (202) 287–1445 or by Department of Energy, Building email: ApplianceStandardsQuestions@ SUMMARY: The Food and Drug Technologies Office, Mailstop EE–5B, ee.doe.gov. Administration (FDA, the Agency, or 1000 Independence Avenue SW., SUPPLEMENTARY INFORMATION: DOE we) is proposing to revoke its regulation Washington, DC 20585–0121. If published a RFI pertaining to the test authorizing the use of health claims on

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the relationship between soy protein • Mail/Hand delivery/Courier (for ‘‘Search’’ box and follow the prompts and coronary heart disease on the label written/paper submissions): Dockets and/or go to the Dockets Management or in the labeling of foods. We are taking Management Staff (HFA–305), Food and Staff, 5630 Fishers Lane, Rm. 1061, this action based on our review of the Drug Administration, 5630 Fishers Rockville, MD 20852. totality of publicly available scientific Lane, Rm. 1061, Rockville, MD 20852. FOR FURTHER INFORMATION CONTACT: • evidence currently available and our For written/paper comments Crystal Rivers, Center for Food Safety tentative conclusion that such evidence submitted to the Dockets Management and Applied Nutrition (HFS–830), Food does not support our previous Staff, FDA will post your comment, as and Drug Administration, 5001 Campus determination that there is significant well as any attachments, except for Dr., College Park, MD 20740, 240–402– scientific agreement (SSA) among information submitted, marked and 1444. qualified experts for a health claim identified, as confidential, if submitted SUPPLEMENTARY INFORMATION: regarding the relationship between soy as detailed in ‘‘Instructions.’’ protein and reduced risk of coronary Instructions: All submissions received Table of Contents heart disease. must include the Docket No. FDA– I. Executive Summary 2017–N–0763 for ‘‘Food Labeling: DATES: Submit either electronic or A. Purpose of the Proposed Rule Health Claims; Soy Protein and written comments on the proposed rule B. Summary of the Major Provisions of the Coronary Heart Disease.’’ Received by January 16, 2018. Proposed Rule comments, those received in a timely C. Legal Authority ADDRESSES: You may submit comments manner (see DATES and ADDRESSES), will D. Costs and Benefits as follows. Late, untimely filed be placed in the docket and, except for II. Table of Commonly Used Acronyms in comments will not be considered. those submitted as ‘‘Confidential This Document Electronic comments must be submitted Submissions,’’ publicly viewable at III. Background on or before January 16, 2018. The https://www.regulations.gov or at the IV. Legal Authority V. Scientific Evidence Regarding the https://www.regulations.gov electronic Dockets Management Staff between 9 filing system will accept comments Relationship Between Soy Protein and a.m. and 4 p.m., Monday through CHD until midnight Eastern Time at the end Friday. • A. Overview of Data and Eligibility for a of January 16, 2018. Comments received Confidential Submissions—To Health Claim by mail/hand delivery/courier (for submit a comment with confidential B. Reevaluation of the Health Claim for Soy written/paper submissions) will be information that you do not wish to be Protein Intake and CHD considered timely if they are made publicly available, submit your C. Assessment of Intervention Studies postmarked or the delivery service comments only as a written/paper D. Assessment of Observational Studies acceptance receipt is on or before that submission. You should submit two VI. Strength of the Scientific Evidence date. copies total. One copy will include the VII. Proposal To Revoke § 101.82 information you claim to be confidential VIII. Economic Analysis of Impacts Electronic Submissions IX. Proposed Effective Date with a heading or cover note that states Submit electronic comments in the X. Analysis of Environmental Impact ‘‘THIS DOCUMENT CONTAINS XI. Paperwork Reduction Act of 1995 following way: CONFIDENTIAL INFORMATION.’’ We • XII. Federalism Federal eRulemaking Portal: will review this copy, including the XIII. References https://www.regulations.gov. Follow the claimed confidential information, in our instructions for submitting comments. consideration of comments. The second I. Executive Summary Comments submitted electronically, copy, which will have the claimed including attachments, to https:// confidential information redacted/ A. Purpose of the Proposed Rule www.regulations.gov will be posted to blacked out, will be available for public The proposed rule would revoke the the docket unchanged. Because your viewing and posted on https:// regulation authorizing the use of a comment will be made public, you are www.regulations.gov. Submit both health claim regarding the relationship solely responsible for ensuring that your copies to the Dockets Management Staff. between soy protein and risk of comment does not include any If you do not wish your name and coronary heart disease (CHD) (§ 101.82 confidential information that you or a contact information to be made publicly (21 CFR 101.82)). In this proposed rule, third party may not wish to be posted, available, you can provide this we tentatively conclude, based on our such as medical information, your or information on the cover sheet and not reevaluation of the totality of the anyone else’s Social Security number, or in the body of your comments and you publicly available scientific evidence confidential business information, such must identify this information as now available, that the evidence does as a manufacturing process. Please note ‘‘confidential.’’ Any information marked not support our previous determination that if you include your name, contact as ‘‘confidential’’ will not be disclosed that there is SSA to support an information, or other information that except in accordance with 21 CFR 10.20 authorized health claim for the identifies you in the body of your and other applicable disclosure law. For relationship between soy protein and comments, that information will be more information about FDA’s posting reduced risk of CHD. posted on https://www.regulations.gov. of comments to public dockets, see 80 In 1999, we authorized a health claim • If you want to submit a comment FR 56469, September 18, 2015, or access about the relationship between soy with confidential information that you the information at: https://www.gpo.gov/ protein and a reduced risk of CHD do not wish to be made available to the fdsys/pkg/FR-2015-09-18/pdf/2015- (§ 101.82). In the Federal Register of public, submit the comment as a 23389.pdf. December 21, 2007, we announced our written/paper submission and in the Docket: For access to the docket to intention to reevaluate the scientific manner detailed (see ‘‘Written/Paper read background documents or the evidence for this health claim and Submissions’’ and ‘‘Instructions’’). electronic and written/paper comments provided the opportunity for public received, go to https:// comment (72 FR 72738). We explained Written/Paper Submissions www.regulations.gov and insert the that we were reevaluating the scientific Submit written/paper submissions as docket number, found in brackets in the basis for the soy protein and CHD health follows: heading of this document, into the claim because new studies yielded

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varied and inconsistent findings approach outlined in the ‘‘Evidence- 200 to 300 products currently making (beneficial effect, no effect) from one Based Review System for the Scientific the health claim. We estimate total trial to another. The results of these Evaluation of Health Claims’’ annualized costs of $35,000 to $81,000, studies called into question the (hereinafter the 2009 guidance) to when the relabeling costs are conclusions drawn from our prior evaluate the totality of publicly annualized over 20 years at a 7 percent review, which had served as the basis available scientific evidence to discount rate. The initial one-time costs for authorizing the soy protein and determine if the SSA standard in section are $370,000 to $860,000. reduced risk of CHD health claim. This 403(r)(3) of the Federal Food, Drug, and proposed rule is the next step in our Cosmetic Act (the FD&C Act) (21 U.S.C. The benefit of this rule is better reevaluation. (343(r)(3)) is met (Ref. 1). Our information for the consumers who are reevaluation of the totality of the considering purchasing products with B. Summary of the Major Provisions of publicly available scientific evidence soy protein. This may generate an the Proposed Rule indicates that, although some evidence unknown amount of increased The proposed rule would revoke the suggests a relationship between soy consumer surplus. Some consumers soy protein and CHD claim in § 101.82 protein intake and reduced risk of CHD, may react to this new information by because it does not meet the SSA the totality of the evidence is switching their consumption to standard. Our decision about whether to inconsistent and not conclusive. products that they enjoy more, or authorize a health claim represents Therefore, we have tentatively products that still have an authorized FDA’s determination as to whether there determined that the strength of the health claim. By basing their is ‘‘significant scientific agreement’’ totality of the publicly available data consumption decisions on more recent among qualified experts that the does not meet the SSA standard for a and accurate scientific information, they publicly available scientific evidence relationship between soy protein intake may get more consumer surplus, in the supports the substance/disease and CHD risk. form of enjoyment and/or potential relationship that is the subject of a health benefits, from the bundle of proposed health claim. In our C. Costs and Benefits products they consume. reevaluation of the scientific evidence The costs of this proposed rule, if in this proposed rule, we use our finalized, are relabeling the estimated

TABLE 1—COST AND BENEFIT OVERVIEW, USD, ANNUALIZED OVER 20 YEARS

Low estimate Mean High estimate

Costs, 7 percent discount rate ...... $35,000 $55,000 $81,000 Costs, 3 percent discount rate ...... $25,000 $39,000 $58,000

Benefits ...... Consumer Enjoyment and/or potential Health Benefits

II. Table of Commonly Used Acronyms 1998–P–1154), we proposed to provide least 25 grams (g) of soy protein per day. in This Document for health claims on the relationship of Thus, we proposed to base the soy protein and reduced risk of CHD qualifying level of soy protein on a total TABLE 2—TABLE OF COMMONLY USED (hereinafter referred to as the 1998 soy daily intake of 25 g, as suggested by the ACRONYMS protein proposed rule). In the 1998 soy petitioner. For the purposes of health protein proposed rule, we considered claims, we assumed there are four eating Acronym What it means the relevant scientific studies and data occasions a day (i.e., three main meals presented in the petition as part of our and one snack). Therefore, in CHD ...... Coronary Heart Disease review of the scientific literature on soy § 101.82(c)(2)(iii)(A), we proposed the DASH ...... Dietary Approaches to Stop protein and CHD. We summarized these qualifying criterion for a food to bear the Hypertension DBP ...... Diastolic Blood Pressure studies in table 1 of the soy protein claim as 6.25 g of soy protein per FDA ...... Food and Drug Administration proposed rule (63 FR 62977 at 62998) reference amount customarily g ...... gram(s) and presented the rationale for a health consumed (RACC) (i.e., 25 g divided by kcal ...... kilocalorie(s) claim on this food/disease relationship four eating occasions per day). LDL ...... Low-Density Lipoprotein as provided for under the significant In the Federal Register of October 26, mg ...... milligram(s) scientific agreement standard in section NCEP ...... National Cholesterol Education 1999 (64 FR 57700), we authorized a 403(r)(3)(B)(i) of the FD&C Act and health claim for soy protein and risk of Program § 101.14(c). NHLBI ...... National Heart, Lung and coronary heart disease (21 CFR 101.82). Blood Institute In our 1998 evaluation of the As explained in the final rule, we oz ...... ounces scientific evidence for a relationship determined, based on our review of SBP ...... Systolic Blood Pressure between consumption of soy protein evidence submitted with comments to SSA ...... Significant Scientific Agree- and blood total and LDL-cholesterol the proposed rule, as well as evidence ment levels (two validated surrogate described in the proposed rule, that soy TC ...... Total Cholesterol endpoints for risk of CHD), we found protein included in a diet low in the data suggestive, but not sufficient, to saturated fat and cholesterol may reduce III. Background establish a dose-response for this the risk of CHD by lowering blood In the Federal Register of November relationship. However, we found cholesterol levels. FDA’s requirements 10, 1998 (63 FR 62977), and in response consistent, clinically significant for use of the health claim and model to a petition from Protein Technologies reductions of total- and LDL-cholesterol health claim language were codified at International, Inc. (see Docket No. FDA– levels in controlled trials that used at 21 CFR 101.82.

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FDA evaluates new scientific nutrient to a disease or health-related V. Scientific Evidence Regarding the information that becomes available to condition unless the claim is made in Relationship Between Soy Protein and determine whether it necessitates a accordance with section 403(r)(3) of the CHD change to an SSA health claim. On FD&C Act (for conventional foods) or A. Overview of Data and Eligibility for December 21, 2007, we published a 403(r)(5)(D) of the FD&C Act (for dietary a Health Claim notice in the Federal Register (72 FR supplements). 72738) (the 2007 reevaluation notice) Health claims characterize the The NLEA also directed FDA to issue announcing our intent to reevaluate the relationship between a substance and a regulations authorizing health claims scientific evidence for certain health reduction in risk of contracting a (i.e., labeling claims that characterize claims, including the authorized health particular disease or developing a claim for soy protein and risk of CHD the relationship of a nutrient to a health-related condition (Whitaker v. (§ 101.82). We stated that we were disease or health-related condition) for Thompson, 353 F.3d 947, 950–51 (D.C. reevaluating the scientific basis for the conventional foods if we determine, Cir.) (upholding FDA’s interpretation of soy protein and CHD health claim based upon the totality of publicly what constitutes a health claim), cert. because numerous studies published available scientific evidence (including denied, 125 S. Ct. 310 (2004)). The since we had authorized the health evidence from well-designed studies substance must be associated with a claim had evaluated the relationship conducted in a manner that is consistent disease or health-related condition for between soy protein and CHD, and the with generally recognized scientific which the general U.S. population, or an findings of these studies were procedures and principles), that there is identified U.S. population subgroup, is inconsistent from study to study. For SSA, among experts qualified by at risk (§ 101.14(b)(1)). We analyze the example, the Agency for Healthcare scientific training and experience to information and data related to a health Research and Quality (AHRQ) released evaluate such claims, that the claim is claim under the framework set out in a report in July 2005 outlining the supported by such evidence (see section our 2009 guidance titled, ‘‘Evidence- effects of soy products on health 403(r)(3)(B)(i) of the FD&C Act). FDA Based Review System for the Scientific outcomes, including cardiovascular may reevaluate the science related to an Evaluation of Health Claims’’ (Ref. 1). disease, and concluded that soy authorized health claim and may take The 2009 guidance discussed our products appear to exert a small benefit action to revoke the claim (see section process for evaluating the scientific on LDL cholesterol (Ref. 2). However, 403(r)(7)(B) of the FD&C Act (21 U.S.C. evidence for a health claim and the the AHRQ report included studies that 343(r)(7(B)). meaning of the significant scientific agreement (SSA) standard in section evaluated substances in addition to soy Additionally, our regulations, at 21 protein (e.g., isolated soy isoflavones). It 403(r)(3) of the FD&C Act (21 U.S.C. CFR 10.40(a), provide that we may was not clear from the AHRQ report 343(r)(3)) and 21 CFR 101.14(c). In a promulgate regulations necessary to whether the soy protein, or other review of a health claim, our first step enforce the FD&C Act as appropriate components of soy products such as is to identify the substance, the disease isoflavones, were responsible for and may initiate such action in any of or health-related condition that is the lowering LDL cholesterol. In addition, the ways specified in § 10.25 (21 CFR subject of the claim, and the population the AHRQ report used markers of 10.25). Specifically, § 10.25(b) provides to which the claim is targeted (Ref. 1). cardiac function (e.g., triglycerides, that the Commissioner may initiate a Next, we consider the totality of endothelial function, and oxidized low- proceeding to revoke a regulation. publicly available data and information density lipoprotein) that are not Accordingly, we are acting within our to determine whether the scientific surrogate endpoints recognized by FDA statutory and regulatory authorities to evidence could support a relationship for CHD risk. propose to revoke the authorized health between the substance and the disease Subsequently, we received a citizen claim for soy protein and a reduced risk or health-related condition. We begin petition dated August 8, 2008 (Docket of CHD. If this proposed rule is this process by organizing the evidence Number FDA–2008–P–0452–001) finalized, the use of an authorized into categories, such as human studies, (hereinafter ‘‘the 2008 citizen petition’’), health claim would be prohibited and a meta-analyses, review articles, animal requesting that the Commissioner of food that bears the health claim on the studies, and in vitro studies, so we can Food and Drugs revoke § 101.82. On label or in labeling would misbrand the thoroughly and systematically assess the January 4, 2016, we denied the food (see section 403(r)(1)(B) of the evidence during the evaluation process. petitioner’s request because the limited FD&C Act). Each category of evidence may offer us relevant evidence submitted in the helpful information and a better In situations where we determine that understanding of the topic; however, petition and a supplement to the the totality of the publicly available petition did not provide sufficient only well-designed, well-conducted scientific evidence does not meet the grounds for us to revoke the soy protein human studies provide both the level of statutory SSA standard, we may and CHD health claim. However, as scientific rigor and generalizability to consider whether there is credible noted in the response to the citizen human populations needed to evidence to support a ‘‘qualified’’ health petition, we considered the relevant potentially support a health claim studies included in the petition as part claim and what qualifying statements relationship. We focus our review on of our reevaluation. and other information should reports of human intervention studies accompany the claim to ensure that it is and observational studies. Of the two IV. Legal Authority truthful and not misleading. If, when we types of studies, well-conducted The Nutrition Labeling and Education finalize this rule, we conclude there is intervention studies provide the Act of 1990 (NLEA) (Pub. L. 101–535) not SSA, but there is some credible strongest evidence of an effect and are amended the FD&C Act by, among other evidence for the use of a qualified the most reliable category of studies for things, adding section 403(r) to the health claim about the relationship determining a cause-and-effect FD&C Act. This section specifies, in between soy protein and a reduced risk relationship (Ref. 1). In an intervention part, that a food is misbranded if it bears of CHD, we intend to issue a statement study, subjects similar to each other are a claim that expressly or by implication of enforcement discretion for the use of randomly assigned to either receive the characterizes the relationship of a a qualified health claim. intervention or not to receive the

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intervention, whereas in an a relationship between the substance the statistical analysis, the type of observational study, the subjects (or and the disease. outcome measured, and study their medical records) are observed for We evaluate the individual reports of population characteristics other than a certain outcome (i.e., disease). human studies to determine whether relevance to the U.S. population (e.g., Observational studies lack the any scientific conclusions can be drawn selection bias and the provision of controlled setting of intervention from each study. The absence of critical important subject information [e.g., age, studies. In contrast to intervention factors, such as a control group or a smokers]). (Ref. 1). We would not use studies, observational studies cannot statistical analysis, means that scientific studies that are so deficient that determine whether an observed conclusions cannot be drawn from the scientific conclusions cannot be drawn relationship represents a relationship in study (Ref. 5–6). Studies from which we from them to support the health claim which the substance caused a reduction cannot draw any scientific conclusions relationship, and we eliminate such in disease risk or if other factors or do not support the health claim studies from further review. variables may have contributed to an relationship, and we eliminate such We then evaluate the results of the studies from further review. remaining human studies and then rate outcome (Ref. 3). In addition to Because health claims involve the overall strength of the total body of individual reports of human studies, we reducing the risk of a disease in people publicly available evidence (Ref. 1). We also consider other types of data and who do not already have the disease consider the study type (e.g., information such as meta-analyses, that is the subject of the claim, we intervention, prospective cohort, case- review articles, and animal and in vitro consider evidence from studies in control, cross-sectional), the studies. These other types of data and individuals diagnosed with the disease methodological quality rating information may be useful to help us that is the subject of the health claim previously assigned, the quantity of understand the scientific issues about only if it is scientifically appropriate to evidence (number of studies of each the substance, the disease, or both, but extrapolate to individuals who do not type and study sample sizes), whether cannot by themselves support a health have the disease. The available the body of scientific evidence supports claim relationship. Reports that discuss scientific evidence should demonstrate a health claim relationship for the U.S. a number of different studies, such as that: (1) The mechanism(s) for the population or target subgroup, whether meta-analyses and review articles do not mitigation or treatment effects measured study results supporting the proposed provide sufficient information on the in the diseased populations are the same claim have been replicated (Ref. 7), and individual studies reviewed in order for as the mechanism(s) for risk reduction the overall consistency (Ref. 8–9) of the us to determine critical elements such effects in non-diseased populations; and total body of evidence (Ref. 1). Based on as the study population characteristics (2) the substance affects these the totality of the publicly available and the composition of the products mechanisms in the same way in both scientific evidence, we determine used. Similarly, the lack of detailed diseased and healthy people. If such whether such evidence meets that SSA information on studies summarized in evidence is not available, then we standard to support an authorized review articles and meta-analyses cannot draw any scientific conclusions health claim (also referred to as ‘‘SSA prevents us from determining whether from studies that use diseased subjects health claim’’) for the substance/disease the studies are flawed in critical to evaluate the substance/disease relationship. If the evidence does not elements such as design, conduct of relationship. Next, we rate the meet the SSA standard, then we may studies, and data analysis. We must be remaining human intervention and consider whether such evidence is able to review the critical elements of a observational studies for methodological credible to support a qualified health study to determine whether any quality. This quality rating is based on claim. If there is credible evidence to scientific conclusions can be drawn several criteria related to study design support a qualified health claim, then from it. We use meta-analyses, review (e.g., use of a placebo-control group we consider what qualifying language articles, and similar publications to versus a non-placebo-control group), should be included to convey the limits identify reports of additional studies data collection (e.g., type of dietary on the level of scientific evidence that may be useful to the health claim assessment method), the quality of the supporting the relationship or to review and as background about the statistical analysis, the type of outcome prevent the claim from being misleading substance-disease relationship. If measured (e.g., disease incidence versus in other ways. validated surrogate endpoint), and study additional studies are identified, we B. Reevaluation of the Health Claim for evaluate them individually. population characteristics other than relevance to the U.S. population (e.g., Soy Protein Intake and CHD We use animal and in vitro studies as age, smoker versus non-smoker) to In our reevaluation of the scientific background information regarding evaluate factors such as selection bias evidence for a relationship between soy mechanisms of action that might be and whether important information protein and reduced risk of CHD, we involved in any relationship between about the study subjects was gathered have used the approach outlined in the the substance and the disease. In vitro and reported. For example, if the 2009 guidance to evaluate the totality of studies are conducted in an artificial scientific study adequately addressed all the current publicly available scientific environment and cannot account for a or most of the criteria related to study evidence regarding this relationship (see multitude of normal physiological design, we would assign a high section 403(r)(3)(B) of the FD&C Act). In processes, such as digestion, absorption, methodological quality rating to the this section, we present our reevaluation distribution, and metabolism, which study. We would assign moderate or of the totality of the publicly available affect how humans respond to the low quality ratings based on the extent scientific evidence, including the consumption of foods and dietary of the deficiencies or uncertainties in studies we previously reviewed in substances (Ref. 4). Further, the the quality criteria. As noted in our promulgating the regulation that physiology of animals is different than guidance (Evidence-Based Review authorized the 1999 soy protein and that of humans. Animal and in vitro System for the Scientific Evaluation of CHD health claim (64 FR 57700), as well studies can be used to generate Health Claims), this quality rating is as studies published after we authorized hypotheses or to explore a mechanism based on several factors related to study the health claim in 1999. The 2009 of action but cannot adequately support design, data collection, the quality of guidance represents FDA’s current

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thinking on the evaluation of health design, conduct of studies, and data disease relationships (§ 101.75, claims as well as the interpretation and analysis. We need to be able to review § 101.81). Therefore, to determine the meaning of SSA. Because the 1999 final the critical elements of a study to independent effect of soy protein intake rule predates that guidance, we determine whether any scientific on blood cholesterol levels, total fat, acknowledge that our reevaluation of conclusions can be drawn from it. As a saturated fat, cholesterol, and dietary studies previously considered in the result, while the review articles, meta- fiber need to be controlled for in the 1999 rulemaking may differ in certain analyses, book chapters, letters, and studies. Studies that substituted soy respects from the previous evaluation. government reports we identified protein for animal protein or feeding For the purposes of this review, we have provided useful background studies that did not properly control for identified the following disease information, they did not provide these nutrients and/or did not report endpoints for use in identifying CHD sufficient information from which these nutrients were eliminated from risk reduction for the purposes of a scientific conclusions could be drawn further review. For studies in which soy health claim evaluation: The incidence regarding soy protein consumption and protein was added to the usual diet, the of coronary events (e.g., myocardial risk of CHD. addition of soy protein should not result infarction, ischemia), cardiovascular in significant changes in the total fat, 2. Assessment of Animal and In Vitro death, coronary artery disease, saturated fat, cholesterol, and dietary Studies atherosclerosis, and CHD (Ref. 1). We fiber in the diet (because soy protein consider high blood pressure, blood We use animal and in vitro studies as does not have significant amounts of (serum or plasma) total cholesterol (TC), background information regarding these nutrients) (Ref. 13–15). Therefore, and blood LDL cholesterol levels to be mechanisms of action that might be we did not eliminate these types of surrogate endpoints for CHD risk (Ref. involved in any relationship between studies that did not control for and/or 1). We use these disease and surrogate the substance and the disease; these did not report these nutrients. endpoints to evaluate the potential studies also can be used to generate To determine the independent effects effects of soy protein on CHD risk. hypotheses or to explore a mechanism of soy protein on blood pressure, studies For the purposes of the reevaluation, of action, but they cannot adequately need to control for the amount of we identified a total of 709 publications, support a relationship between a sodium and potassium, because both drawn from studies included in the substance and a disease in humans (Ref. nutrients influence blood pressure (Ref. 1999 final rule, comments submitted to 1, 4). Such studies cannot mimic the 16). Studies that substituted soy protein the 2007 notice of reevaluation, the normal human physiology that may be for animal protein or feeding studies 2008 citizen petition, and searches of involved in the risk reduction of CHD, where subjects were provided soy the more recent literature. These nor can the studies mimic the human protein in test diets that did not publications consisted of 30 in vitro body’s response to the consumption of properly control for these nutrients and/ studies; 85 animal studies; 27 soy protein. Therefore, we cannot draw or did not report these nutrients were government documents; 163 review any scientific conclusions from the eliminated from further review. For articles, meta-analyses, letters, abstracts, animal or in vitro studies regarding soy studies that added soy protein to the and books or book chapters; 11 Web protein and the risk of CHD in humans, diet, the addition of soy protein should sites; 3 articles written in a foreign and they provide insufficient data to not result in significant changes in the language; and 141 publications that did support a health claim. In accordance amount of sodium and potassium in the not evaluate the substance/disease with these principles, in our review we diet; therefore, we did not eliminate relationship. The publications also considered animal and in vitro studies these types of studies that did not included 11 observational studies that but determined that they did not control for and/or did not report these evaluated the substance/disease provide useful supportive information nutrients (Ref. 13–15). Furthermore, relationship and 238 publications about the relationship between soy because the nutrients that affect blood describing intervention studies that protein consumption and risk of CHD. pressure (sodium and potassium) and evaluated the relationship between soy C. Assessment of Intervention Studies cholesterol (saturated fat, dietary fiber, protein intake and CHD risk. and cholesterol) are different, some For the purposes of this review, we studies might be appropriate for 1. Assessment of Review Articles, Meta- categorized the intervention studies supporting one surrogate endpoint, but Analyses, Book Chapters, Letters, and based on whether the subjects: (1) not the other. Thus, for the purposes of Government Reports Added soy protein to the diet this assessment, we discuss some Although useful for background (supplement) in addition to the subjects’ studies twice. information, review articles, meta- usual diet; (2) were instructed to Of the 238 total publications analyses, book chapters, letters, and substitute soy protein for animal protein describing intervention studies that government reports do not contain in their diet; and (3) were provided test evaluated the relationship between soy sufficient information on the individual diets (feeding studies) with soy protein protein intake and CHD risk, 9 studies which they reviewed and, for animal protein (usually casein) in publications did not report data on a therefore, we could not draw any the control diet. In studies where soy FDA-recognized surrogate endpoint of scientific conclusions from this proteins were used as a substitute for CHD risk (i.e., blood total cholesterol, information. For example, we could not animal proteins, changes in the total fat, blood LDL cholesterol, blood pressure) determine factors such as the study saturated fat, cholesterol, and dietary (Ref. 17–25). Because these publications population characteristics or the fiber content of the diet can occur. A did not report data on one or more composition of the products used (e.g., reduced intake of total fat (Ref. 10), surrogate endpoints, we could not draw food, dietary supplements). Similarly, saturated fat ((Ref. 10), or cholesterol scientific conclusions about the the lack of detailed information on (Ref. 11) has been shown to lower blood relationship between soy protein studies summarized in review articles, cholesterol, and an increased intake of consumption and risk of CHD from meta-analyses, book chapters, letters, dietary fiber (Ref. 12) has shown the these studies (Ref. 1). and government reports prevents us same (Ref. 10), and we have authorized The remaining 229 publications from determining whether the studies SSA health claims for reduced risk of described 212 intervention studies that are flawed in critical elements such as CHD based on these substance and evaluated soy protein intake and CHD

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risk. Of these 212 intervention studies, 145). Such large differences in nutrient criteria established by the National scientific conclusions could not be intakes of dietary fiber, saturated fat, or Heart, Lung and Blood Institute (NHLBI) drawn from 154 studies due to dietary cholesterol make it difficult to to sort studies that measured blood significant flaws. These studies are clearly delineate what may be causing a cholesterol into 3 categories: (1) Studies discussed in sections V.C. 1. and V.C. 2. change in serum cholesterol levels. that had subjects with desirable or Such studies may have other flaws in Therefore, the results of these studies borderline blood cholesterol (TC <240 addition to those specifically could not be interpreted, and we could mg/dL or LDL-cholesterol less than 160 mentioned. This left 58 well-designed, not draw scientific conclusions about mg/dL); (2) studies that had subjects well-conducted intervention studies to the relationship between soy protein with high blood cholesterol (TC >240 or include in our evaluation of the totality consumption and risk of CHD from LDL cholesterol >160 mg/dL); and (3) of the publicly available scientific these studies (Ref. 1). studies that had some subjects with evidence. One study, Zittermann et al. (2004) desirable or borderline cholesterol level was a randomized, crossover study (Ref. and other subjects with high cholesterol 1. Intervention Studies That Examined 1) in which 14 German women levels (Ref. 156). Additionally, studies Soy Protein Intake and Blood consumed 5 cookies made with soy that measured blood pressure were Cholesterol flour or 5 cookies made with wheat sorted based on criteria established by As stated previously in this section, flour while they remained on their usual NHLBI into three categories: (1) Normal we could not draw scientific diet for one menstrual cycle (30.8 ± 0.9 (Systolic Blood Pressure (SBP) <120 conclusions about the relationship days). The composition of the test mmHg or Diastolic Blood Pressure between soy protein consumption and cookies and of the amount of soy (DBP) <80 mmHg); (2) pre-hypertension risk of CHD from 154 intervention protein in the cookies was not (SBP 120 to 139 mmHg or DBP 80 to 89 studies due to significant design flaws. adequately described. Furthermore, mmHg); and (3) hypertension (SBP ≥140 These studies include 17 studies that while the study reported that subjects mmHg or DBP ≥90 mmHg) (Ref. 157– did not include a control group or were to consume the cookies while they 158). Studies were further sorted by provide an appropriate control for the remained on their usual diet, the study whether the studies added comparison to the relative effects of soy reported significantly higher intake of (supplemented) soy protein to the diet, protein (Ref. 26–42). Without an dietary fiber (P <0.0001) in the soy were feeding studies, or were appropriate control group, we could not period (cookies made with soy flour) substitution studies. Because some determine if the changes in LDL than in the control period. When an studies measured both blood cholesterol cholesterol were due to soy protein intervention study involves providing a and blood pressure, we discussed these intake or uncontrolled extraneous whole food rather than a food studies twice (see tables 4–8 in Ref. factors (Ref. 1). Therefore, we could not component, the experimental and 230). draw scientific conclusions about the control diets should be similar enough a. Studies in subjects with desirable or relationship between soy protein that the relationship between the borderline cholesterol levels that added consumption and risk of CHD from substance and disease can be evaluated isolated soy protein to the diet. these studies (Ref. 1). Because the composition of the Carmignani et al. (2014) was a 16- Ten studies did not conduct statistical test cookies were not adequately week, randomized, double-blind, analyses between the control group and described, it is not clear why there are placebo-controlled, parallel trial of treatment group. The statistical analysis differences in dietary fiber intake moderate quality in which 40 of the substance/disease relationship is between the two groups. Thus, we could postmenopausal Brazilian women a critical factor because it provides the not draw scientific conclusions about consumed daily 40 g/day placebo comparison between subjects that the relationship between soy protein powder of maltrodextrin (n=20) or 40 g/ consumed soy protein and those that and CHD when the amounts of other day protein powder containing 24 g/day did not consume soy protein (i.e., substances that are known to affect the isolated soy protein (90 mg/day control) to determine whether there is a risk of CHD (e.g. dietary fiber) are naturally occurring isoflavones) (n=20) reduction in CHD risk (Ref. 43–52). different between the control and in addition to their usual diet (Ref. 159). Therefore, we could not draw scientific experimental diets (Ref. 1, 146). There was no significant difference in conclusions about the relationship Nine studies, described in 11 blood TC and LDL cholesterol between between soy protein consumption and publications that evaluated soy protein the soy protein group and the control risk of CHD from these studies. intake and blood cholesterol, contained group. In eight studies (Ref. 53–60), the added phytosterols in the treatment Liu et al. (2012) was a 6-month, duration of the study intervention was group (Ref. 131–132, 147–155). We have randomized, double-blind, placebo- too short (less than 3 weeks) to an existing regulation for a SSA health controlled, parallel trial of moderate adequately determine if changes in claim for the relationship between plant quality in which 120 postmenopausal serum cholesterol levels were due to the sterol/stanol esters and reduced risk of Chinese women consumed daily 15 g/ consumption of soy protein (Ref. 1, 61). CHD; however, because plant sterol/ day milk protein plus 100 mg/day Therefore, we could not draw scientific stanol esters can reduce blood isoflavone supplement (control) (n=60) conclusions about the relationship cholesterol, it is not possible to clearly or 15 g/day isolated soy protein plus between soy protein consumption and delineate what may be causing a change 100 mg/day isoflavone supplement risk of CHD from these studies. in serum cholesterol levels (Ref. 1). (n=60) in addition to their usual diet Seventy-six studies, described in 84 Therefore, the results of these studies (Ref. 160). There was no significant publications, that substituted soy could not be interpreted, and we could difference in the change in blood TC protein for animal protein or were not draw scientific conclusions about and LDL cholesterol between the milk feeding studies reported large the relationship between soy protein protein and isoflavone group (control) differences in or did not report consumption and risk of CHD from and the soy protein and isoflavone information on other dietary these studies. group. components that have an effect on blood For the remaining 58 intervention Santo et al. (2008) was a 28-day, cholesterol (e.g., dietary fiber, saturated studies from which we could draw randomized, double-blind, controlled fat, dietary cholesterol) (Ref. 56, 62– scientific conclusions, we used the parallel trial of moderate quality in

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which 30 American men consumed: (1) significant difference between the two cholesterol levels were similar and 25 g/day isoflavone-poor soy protein diets for blood TC or LDL cholesterol. conclusions could be drawn. However, isolate (1.9 mg/day isoflavones) (n=11); McVeigh et al. (2006) was a there was no significant difference in (2) 25 g/day isoflavone-rich soy protein randomized, single-blind, controlled, blood TC and LDL cholesterol between isolate (97 mg/day naturally occurring crossover trial of moderate quality in the soy protein group plus 0.5 mg isoflavones) (n=10); or (3) 25 g/day of which 35 Canadian men consumed 32 estradiol and the textured milk protein milk protein (n=9) (control) mixed with g/day soy protein isolate depleted of plus 0.5 mg estradiol control group. a beverage of their choice in addition to isoflavones (1.64 mg/day), 32 g/day soy Jayagopal et al. (2002) was a their usual diet (Ref. 161). There were protein isolate (62 mg/day isoflavones), randomized, double-blind, placebo- no significant differences in blood TC or 32 g/day milk protein isolate for a controlled, crossover trial of moderate and LDL cholesterol between the two duration of 57 days each (Ref. 165). quality in which 32 postmenopausal soy protein isolate treatment groups and There was no significant difference British women with type 2 diabetes the casein control group. between blood TC and LDL cholesterol consumed 30 g/day of isolated soy Evans et al. (2007) was a randomized, between the soy protein and casein protein or 30 g/day of cellulose (control) double-blind, placebo-controlled, groups. in addition to their usual diet for a crossover trial of moderate quality in Sagara et al. (2004) was a 5-week, duration of 12 weeks each (Ref. 169). which 22 postmenopausal American randomized, double-blind, placebo- Blood TC and LDL cholesterol was women consumed: (1) 25 g/day isolated controlled parallel trial of moderate significantly lower (P <0.05) in soy soy protein plus 20 g/day soy lecithin; quality in which 50 Scottish men protein period compared to the (2) 25 g/day isolated soy protein plus consumed 20 g/day of isolated soy cellulose period. placebo lecithin; (3) placebo protein protein powder in biscuits, cereal bars, Higashi et al. (2001) (trial one) was a (50:50 calcium/sodium caseinate) and and bread rolls (n=25) or biscuits, cereal randomized, controlled, crossover trial 20 g/day soy lecithin; and (4) double bars, and bread rolls without added soy of moderate quality in which 14 placebo (protein placebo and soy protein in addition to their usual diets Japanese men consumed daily milk or (n=25) (Ref. 166). There was no yogurt only (no placebo) and 20 g/day lecithin) in addition to their usual diet, significant difference in blood TC soy protein isolate mixed in milk or for a duration of 4 weeks each (Ref. between the two groups. yogurt in addition to their usual diet for 162). There was no significant Teixeira et al. (2004) was a a duration of 4 weeks each (Ref. 26). difference in blood TC and LDL randomized, controlled, crossover trial There was no significant difference in cholesterol between the isolated soy of moderate quality in which 14 men blood TC and LDL cholesterol between protein plus soy lecithin and placebo American men with type 2 diabetes the soy protein period and the control protein plus soy lecithin treatment with nephropathy consumed an period (milk or yogurt only). period (control). There was also no estimated 35 g/day of soy protein isolate Teede et al. (2001) and Dalais et al., significant difference in blood TC and and casein (control) in addition to their (2003) was a 3-month randomized, LDL between the isolated soy protein usual diets for a duration of 8 weeks double-blind, placebo-controlled, plus placebo lecithin and double each (Ref. 167). There was no significant parallel trial of moderate quality in placebo period (control). difference in blood TC and LDL which 179 Australian men and Maesta et al. (2007) was a 16-week, cholesterol between the soy protein and postmenopausal women consumed a randomized, single-blind, placebo- casein group. casein placebo (n=93) or 40 g/day soy controlled, parallel trial of moderate Murray et al. (2003) was a 6-month, protein isolate (n=86) mixed with a quality in which 46 postmenopausal randomized, double-blind, placebo- beverage twice a day in addition to their Brazilian women consumed: (1) 25 g/ controlled, parallel trial of moderate usual diet (Ref. 170–171). There was no day isolated soy protein (n=10); (2) 25 quality in which 30 American significant difference in blood TC and g/day isolated soy protein, plus postmenopausal women consumed: (1) LDL cholesterol between the casein resistance exercise (n=14); (3) 25 g/day 38 g/day soy protein isolate containing control group and soy protein isolate maltodextrin (control) (n=11); or (4) 25 (25 g soy protein) plus 1.0 mg estradiol group. In a subgroup analysis of the g/day maltodextrin plus resistance (n=8); (2) 38 g textured milk protein postmenopausal women (n=55 casein exercise (n=11) (control) in addition to plus 1.0 mg estradiol (n=7) (control); (3) and n=51 soy protein) by Dalais et al. their usual diet (Ref. 163). There was no 38 g/day soy protein isolate containing (2003), there was no significant significant difference in blood TC and (25 g soy protein) plus 0.5 mg estradiol difference in blood TC between the LDL cholesterol between the soy protein (n=8); or (4) 38 g/day textured milk casein control group and soy protein and control groups. protein plus 0.5 mg estradiol(control) isolate group. However, blood LDL Kohno et al. (2006) was a two-part, (n=7) in addition to their usual diet (Ref. cholesterol was significantly (P <0.05) randomized, double-blind, placebo- 168). The baseline TC levels in the 38 lower in the soy protein isolate group controlled, parallel trial of moderate g/day textured milk protein plus 1.0 mg compared to the casein control group. quality (Ref. 164). In the first part of the estradiol group were significantly higher Washburn et al. (1999) was a trial, 126 Japanese men and women, in than the (25 g soy protein) plus 1.0 mg randomized, double-blind, placebo- addition to their usual diet, consumed estradiol group. If the baseline controlled, crossover trial of moderate daily 5 g casein (control) (n=61) or 5 g cholesterol values between groups are quality in which 42 perimenopausal of soybean b-conglycinin (storage significantly different, then it is difficult American women consumed daily: (1) protein component of soy protein to determine if differences at the end of 20 g/day complex carbohydrate isolate) in the form of a candy (n=65) for the study were due to the intervention supplement mixed with a beverage 12 weeks. There was no significant or to differences observed at the (control); (2) 20 g/day isolated soy difference between the two diets for beginning of the study (Ref. 1). Thus, we protein (34 mg/day naturally occurring blood TC or LDL cholesterol. In the could not draw scientific conclusions phytoestrogens) supplement mixed with second part of the trial, 95 Japanese men from this arm of the study. For the soy a beverage as a single dose; and (3) 20 and women consumed daily 5 g casein protein group plus 0.5 mg estradiol and g/day soy protein supplement (34 mg/ (n=50) or 5g soybean b-conglycinin the textured milk protein plus 0.5 mg day naturally occurring phytoestrogens) (n=45) for 20 weeks. There was no estradiol (control) groups, the baseline mixed with beverages split into two

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equal doses in addition to their usual day isolated soy protein plus 20 g/day flour with an estimated 4.6 g/day wheat diets for 6 weeks each (Ref. 172). Blood of soybean cotyledon fiber; (3) 25 g/day protein (control) (n=24) or 45 g/day soy TC and LDL cholesterol were casein plus 20 g/day soybean cotyledon flour with an estimated 15 g/day of soy significantly (P <0.05) lower in the soy fiber (control); and (4) 25 g/day casein protein (n=23) in addition to their usual protein groups compared to the control plus 20 g/day of dietary fiber from diet (Ref. 180). There was no significant group. cellulose (control) for a duration of 4 difference in blood TC between the two Gooderham et al. (1996) was a 28-day weeks each (Ref. 176). Subjects were groups. randomized, controlled, parallel trial of counseled to incorporate the muffins d. Studies in subjects with desirable moderate quality in which 20 Canadian into a low-fat, low-cholesterol diet. or borderline cholesterol levels that were men consumed daily a supplement There were no significant differences feeding studies or substitution studies containing 60 g/day of soy protein between isolated soy protein groups and with soy foods. isolate (n=10) or a supplement control groups for blood TC and LDL Matthan et al. (2007) was a containing 60 g/day of casein (control) cholesterol. randomized, controlled, crossover trial (n=10) in addition to their usual diet van Raaji et al. (1981) was a 4-week, of moderate quality in which 28 (Ref. 173). There was no significant controlled, parallel trial of moderate American subjects were fed four diets: difference in blood TC and LDL quality in which 69 Dutch men and (1) Animal protein (control), (2) soybean cholesterol between the soy protein women were fed an average Western diet (∼37.5 g/day soy protein), (3) soy isolate group and casein group. diet with different types of dietary flour (∼37.5 g/day soy protein), and (4) b. Studies in subjects with desirable or protein incorporated into specifically and soy milk (∼37.5 g/day soy protein) borderline cholesterol levels that were developed products. The dietary protein for a duration of 6 weeks each (Ref. feeding studies or substitution studies groups were: (1) 54 g/day of isolated soy 181). Blood LDL cholesterol was with isolated soy protein. protein (n=24); (2) 17 g/day soy significantly lower (P <0.05) in the Mangano et al. (2013) was a 1-year, (approximately a 2:1 mixture of soymilk diet period compared to the randomized, double-blind, placebo- casein:soy) (n=20); or (3) 55 g/day animal protein diet period (control). controlled, parallel trial of moderate casein (control) (n=25) (Ref. 177). However, there was no significant quality in which 97 postmenopausal Participants were matched for initial American women consumed: (1) 18 g/ difference in blood TC between the serum cholesterol, energy intake, and soymilk diet period and the animal day isolated soy protein plus 105 mg/ sex. There was no significant difference day isoflavone tablets (n=25); (2) 18 g/ protein diet period. Furthermore, there in blood TC between the isolated soy was no significant difference in blood day isolated soy protein plus placebo protein groups and casein control group. TC or LDL cholesterol between the tablets (n=24); (3) 18 g/day control However, blood LDL was significantly animal protein diet period (control) and protein (casein, whey, and egg protein) lower (P <0.05) in the isolated soy the soybean diet period or the soy flour plus 105 mg/day isoflavone tablets protein group compared to the casein diet period. (n=26); or (4) control protein and control group. placebo tablets (n=22) in a beverage or c. Studies in subjects with desirable or Jenkins et al. (1989) was a controlled, food. Subjects were counseled to reduce borderline cholesterol levels that added crossover trial of moderate quality in animal protein foods by approximately soy foods to the diet. which 11 obese Canadian women who 3 oz/day, which is an amount Takatsuka et al. (2000) was a 60-day, consumed a low calorie diet (1,000 kcal) equivalent to the protein powder randomized, controlled, parallel trial of had 2 meals replaced by soy-based provided in the study (Ref. 174). There moderate quality in which 52 liquid formula made from soy flour and was no significant difference in blood premenopausal Japanese women soy protein isolate, and a milk-based TC or LDL cholesterol between any of consumed approximately 16 g/day of liquid formula for a duration of 4 weeks the soy protein groups and the control soy protein from soy milk (n=27) in each. The soy formula provided groups. addition to their usual diet or followed approximately 17 g/day soy protein, and Steinberg et al. (2003) was a their usual diet as a control diet (n=25) the cow’s milk formula provided 18 g/ randomized, double-blind, controlled, (Ref. 178). The control diet was a usual day milk protein (control) (Ref. 182). crossover trial of moderate quality in diet and therefore not a true placebo. There was no significant difference in which 28 postmenopausal American The change in blood TC was blood TC and LDL cholesterol between women consumed: (1) 25 g/day of significantly lower (P = 0.022) in the soy the soy formula and the cow’s milk isolated soy protein (107 mg/day milk group compared to the control formula groups. naturally occurring isoflavones); (2) 25 group. However, there was no Bosello et al. (1988) was a 75-day, g/day of isolated soy protein depleted of significant difference in the change in controlled, parallel trial of moderate isoflavones (2 mg/day isoflavones); and blood LDL cholesterol between the two quality in which 24 obese Italian (3) 25 g/day total milk protein (control) groups. subjects were fed a very low calorie diet for a duration of 6 weeks each (Ref. Mitchell and Collins (1999) was a 4- (375 kcal/day) for 15 days (Ref. 183). 175). Subjects mixed the protein week, randomized, controlled, parallel The very low calorie diets were then powders with a beverage and were trial of moderate quality in which 10 integrated with a commercial textured instructed to incorporate the protein British men consumed: (1) One liter of preparation that provided into their diet without increasing soy milk (n=4); (2) one liter of rice milk approximately 27 g/day of casein protein or energy intake. There was no (control) (n=3); or (3) one liter of semi (control) or approximately 28 g/day soy significant difference in blood TC and skimmed cow’s milk (control) (n=3) in protein that was consumed daily for 60 LDL cholesterol between soy protein addition to their usual diets. There was days. The 60-day hypocaloric diet groups and milk protein control group. no significant difference in blood TC provided a total of 800 kcal/day (375 Bakhit et al. (1994) was a randomized, between groups (Ref. 179). kcal/day from the very low calorie diet controlled, crossover trial of moderate Murkies et al., (1995) was a 12-week and 425 kcal/day from commercial quality in which 21 American men randomized, double-blind, controlled textured preparation). Blood TC and consumed muffins containing: (1) 25 g/ parallel trial of moderate quality in LDL cholesterol was significantly lower day isolated soy protein plus 20 g/day which 47 postmenopausal Australian (P <0.01) after consuming the soy of dietary fiber from cellulose; (2) 25 g/ women consumed 45 g/day of wheat protein diet compared to the casein diet.

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e. Studies that include subjects with f. Studies in subjects with high Hoie et al. (2005b) was an 8-week, normal, borderline, and high cholesterol cholesterol levels that added isolated randomized, double-blind, placebo- that were fed or substituted isolated soy soy protein to the diet. controlled, parallel trial of moderate protein in the diet. Hoie et al. (2007) was an 8-week, quality in which 117 German subjects Greany et al. (2004) was a randomized, double-blind, placebo- consumed: (1) 25 g/day soy protein randomized, controlled, crossover trial controlled, parallel trial of moderate (n=39); (2) 15 g/day soy protein plus 10 of moderate quality in which 33 quality in which 88 German subjects g/day milk protein (derived from postmenopausal American women consumed: (1) 25 g/day of isolated soy caseinate and skimmed milk powder) consumed: (1) 26 g/day of soy protein protein in its native, non-denatured (n=39); or (3) 25 g/day milk protein isolate; (2) 26 g/day soy protein isolate form (n=28); (2) 25 g/day of isolated soy (derived from caseinate and skimmed plus probiotic capsules; (3) 26 g/day protein (n=32); or (3) 25 g/day of milk milk powder) (control) (n=39) in milk protein; and (4) 26 g/day milk protein (derived from caseinate and addition to their usual diets (Ref. 190). protein plus probiotic capsules for a skimmed milk powder) (n=28) (control) Blood LDL cholesterol was significantly duration of 6 weeks each (Ref. 184). in addition to their usual diets (Ref. lower (P = 0.002) after consumption of Subjects were counseled to substitute 187). Blood TC and LDL cholesterol was 25 g/day soy protein compared to the 25 the protein powders in two divided significantly lower (P <0.001 and P = g/day casein group. TC was also doses for other protein containing foods 0.002, respectively) after consuming the significantly lower (P = 0.002) after in their diet. For the analysis, the soy non-denatured isolated soy protein consumption of 25 g/day soy protein protein and milk protein diets (control), compared to milk protein group. Blood compared to the 25 g/day casein group. with or without probiotics, were TC cholesterol was also significantly In the 15 g/day soy protein plus 10 g/ combined. Blood TC and LDL lower (P = 0.008) after consuming day casein group blood LDL cholesterol cholesterol was significantly lower (P isolated soy protein compared to milk was significantly lower (P = 0.011) <0.05) after consuming the soy protein protein group. However, there was no compared to 25 g/day casein control isolate compared to the milk protein significant difference for blood LDL group. TC was also significantly lower control period. cholesterol after consuming isolated soy (P = 0.001) after consumption of 15 g/ Wong et al. (1998) was a randomized, protein compared to milk protein group. day soy protein plus 10 g/day casein controlled, crossover trial of high Hoie et al. (2006) was a 4-week, compared to 25 g/day casein control quality in which 13 American subjects randomized, double-blind, placebo- group. with normal or borderline high Teede et al. (2005) was a 3-month, controlled, parallel trial of moderate cholesterol and 13 American subjects randomized, double-blind, placebo- quality in which 80 German subjects with high cholesterol consumed a controlled, parallel trial of moderate consumed daily: (1) Ultra-heat-treated National Cholesterol Education Program quality in which 40 postmenopausal chocolate-flavored milk containing 24.4 (NCEP) Step 1 soy protein diet that Australian women consumed 40 g/day g/day isolated soy protein and 30.4 g/ provided approximately 50 g/day isolated soy protein (n=19) or a casein isolated soy protein or an NCEP Step 1 day milk protein (n=20); (2) 43.3 g/day placebo in addition to their usual diet animal protein diet that provided milk protein (control) (n=20); (3) ultra- (n=21) (Ref. 191). There was no approximately 50 g/day animal protein heat-treated chocolate flavored milk significant difference in blood TC or (control) for a duration of 5 weeks each containing 12.2 g/day isolated soy LDL cholesterol between the soy protein (Ref. 185). Blood LDL cholesterol was protein and 15.2 g/day milk protein and casein group. significantly lower (P <0.05) after the (n=20); or (4) 21.7 g/day milk protein Harrison et al. (2004) was a 5-week, soy protein period compared to the (control) (n=20) (Ref. 188). There was no randomized, double-blind, placebo- animal protein period for both the significant difference in blood TC or controlled, parallel trial of moderate normal and borderline high subjects and LDL cholesterol between the group that quality in which 112 British men and high cholesterol subjects. However, consumed the ultra-heat-treated women consumed foods (bread, cracker there was no significant difference in chocolate-flavored milk containing 24.4 biscuits, and snack bars) that provided blood TC between the soy protein diet g/day isolated soy protein and 30.4 g/ 25 g/day isolated soy protein (n=59) or and the control diet for both the normal day milk protein group and the control the same foods without soy protein as and borderline high subjects and high milk protein group. There was also no a control (n=53) in addition to their cholesterol subjects. significant difference in blood TC and usual diet (Ref. 192). There was no Goldberg et al. (1982) was a LDL cholesterol between the group that significant difference in blood TC and randomized, controlled, crossover trial consumed ultra-heat-treated chocolate- LDL cholesterol between the soy protein of moderate quality in which 12 flavored milk containing 12.2 g/day soy and control groups. American subjects with high cholesterol protein and 15.2 g/day milk protein per Blum et al. (2003) was a randomized, and 4 American subjects with normal or day (n=20) or the control milk protein double-blind, placebo-controlled, borderline high cholesterol consumed group. crossover trial of moderate quality in daily: (1) An animal protein diet Hoie et al. (2005a) was an 8-week, which 24 postmenopausal Israeli (control); and (2) an isolated soy protein randomized, double-blind, placebo- women consumed 25 g/day milk protein diet for a duration of 6 weeks each. The controlled, parallel trial of moderate (control) and 25 g/day isolated soy soy protein diet contained an estimated quality in which 77 German subjects protein in addition to their usual diets 99 g/day of isolated soy protein (Ref. consumed 25 g/day soy protein (n=39) for a duration of 6 weeks each (Ref. 186). Blood TC and LDL cholesterol in or 25 g/day milk protein (derived from 193). Blood TC and LDL cholesterol was the 12 subjects with high cholesterol caseinate and skimmed milk powder) significantly lower (P <0.05) after was significantly lower (P <0.025) after (control) (n=38) in addition to their consuming soy protein isolate compared the soy protein diet compared to the usual diets (Ref. 189). Blood LDL to milk protein period. animal protein diet. However, there was cholesterol was significantly lower (P Cuevas et al. (2003) was a no significant difference in blood TC <0.05) in the soy protein group when randomized, double-blind, controlled, and LDL between the two diets in the compared to the casein group. There crossover trial of moderate quality in four subjects with normal or borderline was no difference in blood TC between which 18 postmenopausal Chilean high cholesterol. the soy protein group and casein group. women consumed diets providing 40 g/

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day caseinate (control) and 40 g/day blood LDL cholesterol between the milk g/day for men. The treatment effects for isolated soy protein in addition to an protein control and isolated soy protein blood TC and LDL cholesterol were NCEP Step 1 diet for a duration of 4 diet. significantly lower (P = 0.017 and P = weeks each (Ref. 194). There was no Ma et al. (2005) was a 5-week, 0.042, respectively) after consuming the significant difference in blood TC and randomized, double-blind, controlled, soy protein diets compared to the LDL cholesterol between the caseinate parallel trial of moderate quality in animal protein diets. For 20 subjects control diet and soy protein diet. which 159 American subjects consumed with LCL–C >160 mg/dL, the treatment Gardner et al. (2001) was a 12-week, daily 28 g/day milk protein supplement effects for blood TC and LDL–C were randomized, double-blind, placebo- (n=78) (control) or a 32 g/day isolated significantly lower (P <0.001 and P = controlled, parallel trial of moderate soy protein supplement (n=81) in a 0.003) after consuming the soy protein quality in which 94 postmenopausal beverage. Subjects were counseled to diets compared to the animal protein American women consumed: (1) 42 g/ modify their protein and carbohydrate diets. These data were also reported in day total milk protein (control) (n=30); intake to account for the protein Wang et al., (2004) and Desroches et al., (2) 42 g/day isolated soy protein with supplement intake. There was no (2004) (Ref. 204–205). isoflavones depleted (3 mg/day) (n=33); significant difference in blood TC and Van Horn et al. (2001) was a 6-week, or (3) 42 g/day isolated soy protein (80 LDL cholesterol between the two diets randomized, controlled, parallel trial of mg/day naturally occurring isoflavones) (Ref. 198). high quality in which 126 (n=31) in addition to their usual diet West et al. (2005) and Hilpert et al. postmenopausal American women (Ref. 195). There was no significant (2005) both discuss a randomized, consumed an NCEP Step 1 diet in which difference in blood TC or LDL double-blind, controlled, crossover trial they isocalorically substituted: (1) Oats cholesterol between the isolated soy of high quality in which 32 American and 29 g/day milk protein (n=31) protein groups and the total milk subjects were fed an NCEP Step 1 diet (control); (2) wheat and 29 g/day protein control group. that incorporated 25 g/day milk protein isolated soy protein (n=31); (3) oats and Hori et al. (2001) was a 3-month, or 25 g/day soy protein isolate for a 29 g/day isolated soy protein (n=31); or randomized, double-blind, placebo- duration of 6 weeks each (Ref. 199–200). (4) wheat and 29 g/day milk protein controlled, parallel trial of moderate On each diet, 15 g of the protein (n=32) (control) for other carbohydrates quality in which 21 Taiwanese men supplement was consumed in a muffin and dairy type foods (Ref. 206). There consumed: (1) Casein hydrolysate (n=7); while the remaining protein supplement was no significant difference in blood (2) 3 g/day of a crude type of soy protein was provided to the subjects to integrate TC or LDL cholesterol between the two hydrolysate (n=7); or (3) 6 g/day of a into the meals provided. There was no control and the two soy protein diets. crude type of soy protein hydrolysate significant difference in blood TC and h. Studies in subjects with high (n=7) in addition to their usual diet. LDL cholesterol between the milk cholesterol that added soy foods to the Blood TC was significantly lower (P protein and soy protein isolate diets. diet. <0.05) after consuming 3 g/day of a Jenkins et al. (2002 a and b) was a Gardner et al. (2007) was a 4-week, crude type of soy protein hydrolysate randomized, single-blind, controlled, randomized, single-blind, controlled, group for 3 months compared to the crossover trial of moderate quality in crossover trial of high quality in which casein hydrolysate control (Ref. 196). which 41 Canadian men and women 28 American men and women Blood TC was also significantly lower were fed an NCEP Step 2 diet in which consumed daily: (1) 1 percent cow’s after consuming 6 g/day crude type of the main protein containing foods were milk (control); (2) whole bean soy milk; soy protein hydrolysate group after 2 replaced with test foods made with: (1) and (3) soy protein isolate milk, in and 3 months compared to the casein Approximately 60 g/day dairy and egg addition to an American Heart hydrolysate control. Blood LDL protein; (2) 50 g/day of soy protein Association diet (Ref. 207). The whole cholesterol was significantly lower (P isolate (10 mg/day naturally occurring bean soy milk and the soy protein <0.05) after consuming 3 g/day of a isoflavones); and (3) 50 g/day soy isolate milk provided 25 g/day of soy crude type of soy protein hydrolysate protein isolate (73 mg/day naturally protein, and the 1 percent cow’s milk group after 2 and 3 months compared to occurring isoflavones) for a duration of provided 25 g/day of milk protein. the casein hydrolysate control. Blood 1 month each (Ref. 201–202). The Blood LDL cholesterol was a LDL cholesterol was also significantly percent change in blood TC and LDL significantly lower (P = 0.02) after lower (P <0.05) after consuming 6 g/day cholesterol was significantly lower (P consuming whole bean soy milk when a crude type of soy protein hydrolysate <0.01) after consuming the soy protein compared to 1 percent cow’s milk. group after 1, 2, and 3 months compared diets compared to the dairy and egg Blood LDL cholesterol was also to the casein hydrolysate group. protein diet (control). significantly lower (P = 0.02) after g. Studies in subjects with high Lichtenstein et al. (2002) was a consuming the soy protein diet cholesterol levels that were feeding or randomized, double-blind, controlled, compared to the 1 percent cow’s milk substitution studies with isolated soy crossover, feeding trial of moderate diet. protein. quality in which 42 American men and i. Study in subjects with high Chen et al. (2006) was a 12-week, women consumed diets of: (1) Isolated cholesterol that were fed soy foods. randomized, double-blind, placebo- soy protein depleted of isoflavones (25 Jenkins et al. (2000) was a controlled, parallel trial of high quality g soy protein/1,000 kcal); (2) isolated randomized, controlled, crossover trial in which 26 Taiwanese subjects on soy protein enriched with isoflavones of moderate quality in which 25 dialysis consumed daily their usual (25 g soy protein plus 50 mg Canadian men and women consumed dialysis diet that incorporated 30 g/day isoflavones/1,000 kcal); (3) animal daily an NCEP Step 2 diet that milk protein (control) (n=13) or an protein with no added isoflavones (25 g incorporated: (1) A commercial isolated soy protein diet containing 30 animal protein/1,000 kcal); and (4) breakfast cereal containing 8 g/day g/day soy protein (n=13) (Ref. 197). animal protein with added isoflavones wheat protein (control); and (2) a Blood TC was significantly lower (P (25 g animal protein and 50 mg breakfast cereal made with 70 percent <0.05) in the isolated soy protein diet isoflavones/1,000 kcal) for a duration of soy flour that provided 36 g/day soy compared to the milk protein control. 6 weeks each (Ref. 203). The mean soy protein for a duration of 3 weeks each There was no significant difference in intake for women was 55 g/day and 71 (Ref. 208). There was no significant

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difference between the wheat protein protein in the diets), the study measured controlled, parallel trial of moderate cereal (control) period and soy flour biomarkers (SBP or DBP) instead of quality in which 112 British men and cereal diet period for blood TC and LDL clinical outcomes (e.g., incidence of women with pre-hypertension (SBP 120 cholesterol. CHD). Therefore, this study is so to 139 mmHg or DBP 80 to 89 mmHg) deficient in methodological quality that consumed foods (bread, cracker biscuits, 2. Intervention Studies That Examined it is considered to be of low-quality and snack bars) that provided 25 g/day Soy Protein Intake and Systolic Blood design (Ref. 1) and, as a result, we could isolated soy protein (n=59) or the same Pressure (SBP) or Diastolic Blood not draw scientific conclusions foods without soy protein as a control Pressure (DBP) regarding the relationship between soy (n=53) in addition to their usual diet Twenty-eight studies, described in 30 protein intake and reduced risk of CHD. (Ref. 192). There was no significant publications, either substituted soy a. Studies in subjects with normal or difference in SBP and DBP between the protein in the diet or were feeding pre-hypertension (SBP <139 mmHg or soy protein and control groups. studies. These studies did not control DBP <89 mmHg). Cuevas et al. (2003) was a for or provide information on sodium Anderson et al. (2007) was a 16-week, randomized, double-blind, controlled, and potassium intake in the diet (Ref. randomized, single-blind, controlled, crossover trial of moderate quality in 44, 55, 66, 74, 77, 84, 91, 96–97, 99, 114, parallel trial of moderate quality in which 18 pre-hypertensive (SBP 120 to 116, 123, 125–126, 131–132, 139–140, which 35 obese American women with 139 mmHg or DBP 80 to 89 mmHg) 144, 149–151, 153–154, 181, 201–202, pre-hypertension (SBP 120 to 139 postmenopausal Chilean women 208–209). Because sodium and mmHg or DBP 80 to 89 mmHg) were fed consumed diets providing 40 g/day potassium intake also influence blood daily 3 meal replacement shakes caseinate (control) or 40 g/day isolated pressure, the independent effects of soy containing approximately 22 g/day of soy protein in addition to an NCEP Step protein intake and blood pressure could casein (control) (n=18) or 21 g/day 1 diet for a duration of 4 weeks each not be determined. Therefore, we could isolated soy protein (n=17) each (Ref. (Ref. 194). There was no significant not draw scientific conclusions about 89). There was no significant difference difference in SBP or DBP between the the relationship between soy protein in SBP or DBP between the casein and soy protein diet and caseinate control consumption and risk of CHD from soy protein diet. diet. these studies. Azadbakht et al. (2007) was a Teede et al. (2001) was a 3-month Four studies did not include an randomized, controlled, crossover trial randomized, double-blind, placebo- appropriate control protein for a of moderate quality in which 42 controlled, parallel trial of moderate comparison of the relative effects of soy postmenopausal Iranian women with quality in which 179 pre-hypertensive protein (Ref. 40, 42, 210–211). Without pre-hypertension (SBP 120 to 139 (SBP 120 to 139 mmHg or DBP 80 to 89 an appropriate control group, it cannot mmHg or DBP 80 to 89 mmHg) mmHg) Australian men and be determined if the changes in SBP or consumed daily: (1) A Dietary postmenopausal women consumed a DBP were due to soy protein intake or Approaches to Stop Hypertension casein placebo (n=93) or 40 g/day soy uncontrolled, extraneous factors. (DASH) control diet; (2) a 30 g/day soy protein isolate mixed with a beverage Therefore, we could not draw scientific protein diet; and (3) a 30 g/day soy nut twice a day (n=86) in addition to their conclusions about the relationship diet for a duration of 8 weeks each (Ref. usual diet (Ref. 170). SBP was between soy protein consumption and 65). The soy protein and soy nut diets significantly lower (P <0.05) in the soy risk of CHD from these studies. were the same as the DASH diet with protein isolate group compared to Chiechi et al. (2002) was a 6-month, soy protein and soy nuts being casein control group. However, there randomized, parallel trial in which 67 substituted for red meat for the control was no significant difference in DBP subjects with pre-hypertension (SBP 120 diet. There was no significant difference between the casein control group and to 139 mmHg or DBP 80 to 89 mmHg) in SBP or DBP between the DASH soy protein isolate group. consumed their usual diet (n=43) or control diet and the soy protein and soy Washburn et al. (1999) was a their usual diet plus a soy food serving nut diets. randomized, double-blind, placebo- each day (e.g. soy milk, miso soup, tofu, Evans et al. (2007) was a randomized, controlled, crossover trial of moderate tempeh, or soy beans) (n=34) (Ref. 142). double-blind, placebo-controlled, quality in which 42 pre-hypertensive Subjects in the soy group also crossover trial of moderate quality in (SBP 120 to 139 mmHg or DBP 80 to 89 exchanged two meals twice a week with which 22 pre-hypertensive (SBP 120 to mmHg), perimenopausal American two meals from a study menu that was 139 mmHg or DBP 80 to 89 mmHg), women consumed: (1) A complex based on traditional Mediterranean postmenopausal American women carbohydrate supplement (20 g/day) recipes and soy or soy products. consumed: (1) 25 g/day isolated soy mixed with a beverage (control); (2) 20 Approximately 50 percent of subjects in protein plus 20 g/day soy lecithin; (2) 25 g/day isolated soy protein supplement the soy group dropped out of the study g/day isolated soy protein plus placebo mixed with a beverage as a single dose; compared to 20 percent in the control lecithin; (3) placebo protein (50:50 and (3) 20 g/day soy protein supplement group. Therefore, the dropout rate in the calcium/sodium caseinate) and 20 g/day mixed with beverages split into two treatment group makes the results of soy lecithin; and (4) double placebo equal doses in addition to their usual this study difficult to interpret. A high (protein placebo and soy lecithin) in diet for a duration of 6 weeks each (Ref. dropout rate can introduce bias because addition to their usual diet for a 172). There was no difference in SBP or it changed the number of subjects in the duration of 4 weeks each (Ref. 162). DBP between the soy protein treatment group and may also have There was no significant difference in supplement mixed with a beverage as a changed the group’s composition SBP or DBP between the soy protein single dose period and the complex compared to the control group. In plus placebo lecithin group and the carbohydrate control period. However, addition to a high dropout rate, the double placebo group (control) or SBP and DBP were significantly lower study had other quality issues (e.g., between the soy protein plus soy (P <0.05) after consuming the 20 g/day information on study blinding was not lecithin group and the placebo protein soy protein supplement mixed with reported, adequate descriptions were plus soy lecithin period (control). beverages split into two equal doses not provided for the composition of the Harrison et al. (2004) was a 5-week, compared to the complex carbohydrate background diets or the amount of soy randomized, double-blind, placebo- supplement.

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b. Studies in normotensive or pre- Rivas et al. (2002) was a 3-month respect to a disease; however, it is hypertensive (SBP <39 mmHg or DBP randomized, double-blind, placebo- subsequently demonstrated in an <89 mmHg) and hypertensive subjects controlled, parallel trial of moderate intervention study that the nutrient- (SBP ≥140 mmHg or DBP ≥90 mmHg). quality in which 40 hypertensive (SBP containing dietary supplement does not He et al. (2005) was a 12-week, ≥140 mmHg or DBP ≥90 mmHg) Spanish confer a benefit or actually increases randomized, double-blind, parallel trial men and women consumed daily 1 liter risk of the disease (Ref. 226). For of moderate quality in which 276 of soy milk (18 g/day soy protein) or 1 example, previous epidemiological Chinese men and women with pre- liter of cow’s milk (15.5 g/day protein) studies reported an association between hypertension (SBP 120 to 139 mmHg or in addition to their usual diet (Ref. 213). fruits and vegetables high in beta- DBP 80 to 89 mmHg) or hypertension SBP and DBP was significantly lower (P carotene and a reduced risk of lung (SBP ≥140 mmHg or DBP ≥90 mmHg) <0.0001) in the soy milk group cancer (Ref. 227). However, subsequent consumed cookies containing 40 g/day compared to the cow’s milk group. intervention studies, the Alpha- Tocopherol and Beta Carotene complex carbohydrates from wheat D. Assessment of Observational Studies (n=139) (control) or cookies with 40 g/ Prevention Study (ATBC) and the day isolated soy protein (n=137) (Ref. FDA identified 11 observational Carotene and Retinol Efficiency Trial 212). Subjects were instructed to reduce studies that evaluated soy protein and (CARET), demonstrated that beta- other food intake to keep total energy CHD risk (Ref. 214–224). All of these carotene supplements increase the risk intake constant. Most subjects observational studies calculated soy of lung cancer in smokers and asbestos- consumed the cookies in place of their protein intake from estimated dietary exposed workers, respectively (Ref. usual breakfast or usual lunch. SBP and intake. In observational studies that 228–229). These studies illustrate that DBP were significantly (P <0.001) lower calculated nutrient intake from the effect of a nutrient provided as a for those who consumed the soy protein conventional foods, measures of soy dietary supplement exhibits different cookies compared to the wheat cookies protein intake were based on recorded health effects compared to when it is (control). dietary intake methods such as food consumed as part of a usual diet among frequency questionnaires, diet recalls, or Sagara et al. (2004) was a 5-week many other food components. diet records, in which the type and randomized, double-blind, placebo- Furthermore, these studies demonstrate amount of foods consumed were controlled, parallel trial of moderate the potential public health risk of estimated. A common weakness of quality in which 50 Scottish men with relying on results from epidemiological observational studies is the limited pre-hypertension (SBP 120 to 139 studies in which the effect of a nutrient ability to ascertain the actual food or is based on recorded dietary intake of mmHg or DBP 80 to 89 mmHg) or nutrient intake for the population hypertension (SBP ≥140 mmHg or DBP conventional foods as the sole source for ≥ studied as a result of poor memory, concluding that a relationship exists 90 mmHg) consumed 20 g/day of over- or underestimation of portion isolated soy protein powder in biscuits, between a specific nutrient and disease sizes, and recall bias (Ref. 225). risk (i.e., the effect could actually be cereal bars, and bread rolls (n=25) or Furthermore, the nutrient content of biscuits, cereal bars, and bread rolls harmful). foods can vary due to a number of For the reasons provided in this without added soy protein in addition factors, including soil composition, food section, scientific conclusions cannot be to their usual diets (n=25) (Ref. 166). processing and cooking procedures, and drawn from observational studies on There was no significant difference in storage conditions (e.g., duration, foods for soy protein as a food SBP or DBP between the soy protein and temperature). Thus, we cannot ascertain ingredient or component of food. control group. an accurate amount of soy protein c. Studies in hypertensive subjects consumed based merely on subjects’ VI. Strength of the Scientific Evidence ≥ ≥ (SBP 140 mmHg or DBP 90 mmHg). reports of dietary intake of foods. In evaluating the scientific evidence Webb et al. (2008) was a 5-day, In addition, soy foods contain not using our evidence-based review system randomized, double-blind, placebo- only soy protein, but also other (Ref. 1), we considered the strength of controlled, parallel trial of moderate nutrients that may be associated with evidence for a relationship between soy quality in which 25 hypertensive (SBP the metabolism of soy protein or the protein intake and reduced risk of CHD. ≥140 mmHg or DBP ≥90 mmHg) British pathogenesis of CHD. Therefore, When evaluating the strength of the men and women with CHD consumed because soy protein containing foods evidence, we consider study types, 25.7 g/day soy protein isolate (n=13) or consist of many nutrients and methodological quality, quantity of 25.7 g/day milk protein isolate (n=12) in substances, it is difficult to study the evidence for and against the claim addition to their usual diets (Ref. 60). nutrient or food components in isolation (taking into account the numbers of There was no significant difference in (Ref. 3). For studies based on recorded various types of studies and study SBP or DBP between the soy protein dietary intake of such foods, it is not sample sizes), relevance to the U.S. isolate group and the control milk possible to accurately determine population or target subgroup, protein isolate group. whether any observed effects of soy replication of study results supporting Jayagopal et al. (2002) was a protein on coronary heart disease risk the claim, and overall consistency of the randomized, double-blind, placebo- were due to: (1) Soy protein alone; (2) evidence (beneficial effect, no effect) controlled, crossover trial of moderate interactions between soy protein and (Ref. 1). For the outcome of an quality in which 32 hypertensive (SBP other nutrients; (3) other nutrients intervention study to demonstrate an ≥140 mmHg or DBP ≥90 mmHg) acting alone or together; or (4) decreased effect, the validated surrogate or clinical postmenopausal British women with consumption of other nutrients or endpoint evaluated in the intervention type 2 diabetes consumed 30 g/day of substances contained in foods displaced group should be statistically isolated soy protein or 30 g/day of from the diet by the increased intake of significantly different from the same cellulose (control) in addition to their soy protein containing foods. In some validated surrogate or clinical endpoint usual diet for a duration of 12 weeks instances, epidemiological studies based evaluated in the control group (P <0.05). each (Ref. 169). There was no significant on the recorded dietary intake of After assessing the totality of the difference in SBP and DBP between the conventional foods may indicate a scientific evidence, we then determine control diet and the soy protein diet. benefit for a particular nutrient with whether there is SSA to support an

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authorized health claim, or credible reducing the risk of CHD, while the agreement, among experts qualified by evidence to support a qualified health other 27 intervention studies did not. scientific training and experience to claim. Study findings also were inconsistent evaluate such claims, that the claim is Our decision about whether to regardless of whether soy protein was supported. Therefore, we have authorize a health claim represents our added to diet as a supplement or tentatively concluded that, currently, determination as to whether there is whether the studies were substitution or there is not significant scientific significant scientific agreement among feeding studies. The study findings also agreement among experts, under section qualified experts that the publicly were inconsistent regardless of the 403(r)(3)(B)(i) of the FD&C Act, that a available scientific evidence supports study size (10 subjects to 179 subjects) health claim about a relationship the substance/disease relationship that or the dose of soy protein (3 g to 92 g/ between soy protein intake and CHD is the subject of a proposed health day). Of the 12 high or moderate quality risk is supported by the evidence. We claim. The SSA standard is intended to intervention studies that measured SBP request comment and any supporting be a strong standard that provides a high or DBP from which a conclusion could data and information concerning this level of confidence in the validity of the be drawn, only 4 showed a benefit in tentative conclusion. However, while substance/disease relationship. SSA lowering SBP or DBP with soy protein the totality of the publicly available occurs well after the stage of emerging consumption, while the other 8 studies scientific evidence does not support a science, where data and information did not show a benefit. Again, the study finding of SSA, if, when we finalize this permit an inference, but does not findings were inconsistent regardless of rule, we conclude there is not SSA, but require consensus based on unanimous baseline SBP or DBP, study size (18 there is some credible evidence for the and incontrovertible scientific opinion. subjects to 276 subjects), or dose (18 g use of a qualified health claim about the We explained in our 2009 guidance to 60 g/day). Consistency of findings relationship between soy protein and a (Ref. 1) that we may evaluate new among similar and different study reduced risk of CHD, we intend to issue information that becomes available to designs is important for evaluating a statement of enforcement discretion determine whether it necessitates a causation and the strength of scientific for the use of a qualified health claim. change to an existing SSA claim to evidence (Ref. 1). The totality of the In the 1999 soy protein final rule maximize the public health benefit of evidence does not provide a basis on authorizing the use of a health claim our health claims review. The 2009 which experts would find SSA because regarding soy protein and the risk of guidance represents our current of the high degree of inconsistency of CHD (64 FR 57700) (now codified at thinking on the meaning of the SSA findings across similar and different § 101.82) (the 1999 authorized soy standard in section 403(r)(3) of the studies with high or moderate protein health claim), the petitioner FD&C Act and § 101.14(c) and the methodological quality. This degree of determined that use of soy as a dietary process for evaluating the scientific inconsistency would not be seen when protein is generally recognized as safe. evidence for a health claim pursuant to SSA exists because, when there is SSA, Under the health claim petition process, these authorities. we would find most of the studies to we evaluate whether the proponent of As noted in section V, we reevaluated, consistently find a beneficial the claim demonstrates, to FDA’s consistent with the 2009 guidance (Ref. relationship between a substance and a satisfaction, that the food ingredient is 1), the studies included in the 1999 final disease risk. ‘‘safe and lawful’’ under the applicable rule as well as new studies that were food safety provisions of the FD&C Act. published since the original review. As Although there is some evidence that In the 1999 soy protein final rule, we discussed in section V.C and D, the suggests a relationship between soy concluded that there was not sufficient totality of the scientific evidence protein intake and reduced risk of CHD, evidence to challenge the petitioner’s includes 58 well-designed, well- the strength of the totality of the current, assertion that soy protein ingredients executed intervention studies. Of these publicly available scientific evidence, are GRAS. The petitioner met the 58 studies, 46 are intervention studies of discussed in sections V and VI and the showing required by § 101.14(b)(3)(ii) high or moderate quality that measured references cited therein, which includes that the substance be ‘‘safe and lawful.’’ blood TC or LDL cholesterol, and 12 are many studies that post-date the We have reviewed the scientific intervention studies of high or moderate publication of our 1999 rule, is evidence relative to the safety of soy quality that measured SBP or DBP. The inconsistent and not conclusive. See protein as a food ingredient and the results of these studies were also tables 4–8 in Ref. 230. The evidence does not change our previous inconsistent and not conclusive. additional evidence now available to us conclusion that the use of soy protein at Of the 46 studies intervention studies includes a number of new studies that the levels necessary to justify a claim of high or moderate quality that do not support the relationship, and a has been demonstrated, to our measured blood TC or LDL cholesterol, number of studies that are inconclusive satisfaction, to be safe and lawful under 25 studies were conducted on subjects that also do not support a relationship. the applicable food safety provisions of with desirable or borderline cholesterol This combined body of evidence the FD&C Act. levels, defined as a blood TC less than represents the totality of the scientific 240 mg/dL or LDL cholesterol less than evidence that is currently available. We VII. Proposal To Revoke § 101.82 160 mg/dL; 18 were conducted on have now evaluated this entire body of As discussed above, FDA may subjects with high TC levels, defined as evidence, which consists of the studies reevaluate the science related to an TC levels less than 240 mg/dL or LDL in the 1999 rule as well as new evidence authorized health claim and may take cholesterol greater than or equal to 160 published since that time, using the action to revoke the claim (see section mg/dL; and 3 studies included subjects evidence based process described in our 403(r)(7)(B) of the FD&C Act (21 U.S.C. with desirable or borderline TC levels 2009 guidance. The totality of the 343(r)(7)(B)). Based on our review of the and subjects with high TC levels. Of the evidence, which includes the new, non- totality of the publicly available 46 intervention studies that looked at supportive studies, does not support the scientific evidence, we have tentatively the relationship between blood TC and/ statutory standard for authorizing a concluded that the SSA standard is not or LCL cholesterol and soy protein health claim. We have determined that met for a relationship between soy intake, only 19 intervention studies the totality of the scientific evidence protein and reduced risk of CHD. showed a benefit in significantly does not provide significant scientific Therefore, we are proposing to revoke

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the soy protein and reduced risk of CHD rule is a significant regulatory action The costs of this rule are relabeling health claim in § 101.82. under Executive Order 12866. the estimated 200 to 300 products The Regulatory Flexibility Act VIII. Economic Analysis of Impacts currently making the health claim. We requires Agencies to analyze regulatory estimate total annualized costs of We have examined the impacts of the options that would minimize any $35,000 to $81,000, when the relabeling proposed rule under Executive Order significant impact of a rule on small costs are annualized over 20 years at a 12866, Executive Order 13563, entities. Because up to 40 small 7-percent discount rate. The initial, one- Executive Order 13771, the Regulatory businesses could be required to relabel time costs are $370,000 to $860,000. Flexibility Act (5 U.S.C. 601–612), and one or more products, we find that the the Unfunded Mandates Reform Act of proposed rule may have a significant The benefit of this rule is better 1995 (Pub. L. 104–4). Executive Orders economic impact on a substantial information for the consumers who are 12866 and 13563 direct Agencies to number of small entities. considering purchasing products with assess all costs and benefits of available Section 202(a) of the Unfunded soy protein. This may generate an regulatory alternatives and, when Mandates Reform Act of 1995 requires unknown amount of increased regulation is necessary, to select that Agencies prepare a written consumer surplus. Some consumers regulatory approaches that maximize statement, which includes an may react to this new information by net benefits (including potential assessment of anticipated costs and switching their consumption to economic, environmental, public health benefits, before proposing ‘‘any rule that products that they enjoy more, or and safety, and other advantages; includes any Federal mandate that may products that still have an authorized distributive impacts; and equity). result in the expenditure by State, local, health claim. We request public Executive Order 13771 requires that the and tribal governments, in the aggregate, comment on how many consumers are costs associated with new regulations or by the private sector, of $100,000,000 likely to react to the changes in health shall ‘‘be offset by the elimination of or more (adjusted annually for inflation) claims caused by this proposed rule, existing costs associated with at least in any one year.’’ The current threshold and what the nature of their reaction two prior regulations.’’ It has been after adjustment for inflation is $148 will be. By basing their consumption determined that this proposed rule is an million, using the most current (2016) decisions on more recent and accurate action that does not impose more than Implicit Price Deflator for the Gross scientific information, they will get de minimis costs as described below Domestic Product. This proposed rule more consumer surplus, in the form of and thus is not a regulatory or would not result in any year enjoyment and/or potential health deregulatory action for purposes of expenditure that meets or exceeds this benefits, from the bundle of products Executive Order 13771. This proposed amount. they consume.

TABLE 3—COST AND BENEFIT OVERVIEW, USD, ANNUALIZED OVER 20 YEARS

Low estimate Mean High estimate

Costs, 7 percent discount rate ...... $35,000 $55,000 $81,000 Costs, 3 percent discount rate ...... 25,000 39,000 58,000

Benefits ...... Consumer Health Benefits and/or Enjoyment

The Economic Analysis of Impacts of X. Analysis of Environmental Impact with the exercise of Federal authority the proposed rule performed in We have determined under 21 CFR under the Federal statute.’’ Federal law accordance with Executive Order 12866, 25.32(p) that this action, revoking a includes an express preemption Executive Order 13563, the Regulatory health claim, is categorically excluded provision that preempts ‘‘any Flexibility Act, and the Unfunded from an environmental assessment or an requirement respecting any claims of Mandates Reform Act is available at environmental impact statement. the type described in [21 U.S.C. https://www.regulations.gov under the 343(r)(1)] made in the label or labeling docket number for this proposed rule XI. Paperwork Reduction Act of 1995 of food that is not identical to the and at: https://www.fda.gov/AboutFDA/ FDA tentatively concludes that this requirement of [21 U.S.C. 343(r)] ReportsManualsForms/Reports/ proposed rule contains no collection of * * *.’’ 21 U.S.C. 343–1(a)(5). However, EconomicAnalyses/default.htm. information. Therefore, clearance by the the statutory provision does not preempt any State requirement IX. Proposed Effective Date Office of Management and Budget under the Paperwork Reduction Act of 1995 is respecting a statement in the labeling of We intend that the effective date for not required. food that provides for a warning a final rule resulting from this concerning the safety of the food or rulemaking be 30 days after the final XII. Federalism component of the food (Pub. L. 101–535, rule’s date of publication in the Federal FDA has analyzed this proposed rule section 6, 104 Stat. 2353 (1990)). If this Register. in accordance with the principles set proposed rule is made final, the final With respect to a compliance date, we forth in Executive Order 13132. Section rule would revoke the health claim intend that any adjustments to a 4(a) of the Executive order requires related to soy protein and coronary product’s labeling occur in a manner Agencies to ‘‘construe * * * a Federal heart disease in the label or labeling of consistent with our uniform compliance statute to preempt State law only where food under 21 U.S.C. 343(r). date (see 81 FR 85156, November 25, the statute contains an express XIII. References 2016). Thus, if we issue a final rule preemption provision or there is some before December 31, 2018, then the other clear evidence that the Congress The following references are on compliance date would be January 1, intended preemption of State law, or display in the Dockets Management 2020. where the exercise of State law conflicts Staff (see ADDRESSES) and are available

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Chinese Women’’. Journal of Nutrition. POSTAL SERVICE 553(b), (c)) regarding proposed 2003;133:2874–2878. rulemaking by 39 U.S.C. 410(a), we 225. Flegal K.M. ‘‘Evaluating Epidemiologic 39 CFR Part 111 invite public comments on the Evidence of the Effects of Food and following proposed revisions to Mailing Nutrient Exposures’’. American Journal eInduction Option, Seamless Standards of the United States Postal of Clinical Nutrition. 1999;69:1339S– Acceptance Program, and Full-Service Service, Domestic Mail Manual (DMM), 1344S. Automation Option, Verification incorporated by reference in the Code of 226. Lichtenstein A.H., Russell R.M. Standards Federal Regulations. See 39 CFR 111.1. ‘‘Essential Nutrients: Food or AGENCY: Postal ServiceTM. Accordingly, 39 CFR part 111 is Supplements? Where Should the proposed to be amended as follows: Emphasis Be?’’. Journal of the American ACTION: Proposed rule. Medical Association. 2005;294:351–358. PART 111—[AMENDED] SUMMARY: The Postal Service is 227. Peto R., Doll R., Buckley J.D., Sporn proposing to amend Mailing Standards M.B. ‘‘Can Dietary Beta-Carotene ■ 1. The authority citation for 39 CFR of the United States Postal Service, Materially Reduce Human Cancer part 111 continues to read as follows: Domestic Mail Manual (DMM®), Rates?’’. Nature. 1981;290:201–208. sections 705.20, eInduction Option, Authority: 5 U.S.C. 552(a); 13 U.S.C. 301– 228. ‘‘The Effect of Vitamin E and Beta 307; 18 U.S.C. 1692–1737; 39 U.S.C. 101, Carotene on the Incidence of Lung 705.22, Seamless Acceptance Program, 401, 403, 404, 414, 416, 3001–3011, 3201– Cancer and Other Cancers in Male and 705.23, Full-Service Automation 3219, 3403–3406, 3621, 3622, 3626, 3632, Smokers. The Alpha-Tocopherol, Beta Option, to add the verification 3633, and 5001. standards. Carotene Cancer Prevention Study ■ 2. Revise the following sections of Group’’. New England Journal of DATES: Submit comments on or before Mailing Standards of the United States Medicine. 1994;330:1029–1035. November 30, 2017. Postal Service, Domestic Mail Manual 229. Omenn G.S., Goodman G.E., Thornquist ADDRESSES: Mail or deliver written (DMM), as follows: M.D., Balmes J., Cullen M.R., Glass A., comments to the manager, Product Mailing Standards of the United States Keogh J.P., Meyskens F.L., Valanis B., Classification, U.S. Postal Service, 475 Williams J.H., Barnhart S., Hammar S. Postal Service, Domestic Mail Manual L’Enfant Plaza SW., Room 4446, (DMM) ‘‘Effects of a Combination of Beta Washington, DC 20260–5015. If sending Carotene and Vitamin a on Lung Cancer comments by email, include the name * * * * * and Cardiovascular Disease’’. New and address of the commenter and send 700 Special Standards England Journal of Medicine. to [email protected], with 1996;334:1150–1155. a subject line of ‘‘Verification * * * * * 230. Food and Drug Administration, ‘‘Tables Standards’’. Faxed comments are not of Scientific Evidence Regarding the 705 Advanced Preparation and accepted. You may inspect and Relationship Between Soy Protein and Special Postage Payment Systems photocopy all written comments, by CHD’’ appointment only, at USPS® * * * * * List of Subjects in 21 CFR Part 101 Headquarters Library, 475 L’Enfant 705.20.0 eInduction Option Plaza SW., 11th Floor North, 20.1 Description Food labeling, Nutrition, Reporting Washington, DC 20260. These records and recordkeeping requirements. are available for review on Monday [Revise the fourth sentence of 20.1 to read as follows:] Therefore, under the Federal Food, through Friday, 9 a.m.–4 p.m., by calling 202–268–2906. * * * For additional information on Drug, and Cosmetic Act and under the eInduction Option see Publication FOR FURTHER INFORMATION CONTACT: authority delegated to the Commissioner 6850, Publication for Streamlined Mail Heather Dyer at (207) 482–7217, or of Food and Drugs, it is proposed that Acceptance for Letters and Flats, Garry Rodriguez at (202) 268–7281. 21 CFR part 101 be amended as follows: available at https://postalpro.usps.com. SUPPLEMENTARY INFORMATION: The Postal PART 101—FOOD LABELING * * * * * Service is proposing to amend DMM [Add new subsection 20.5, sections 705.20, eInduction Option, Verifications, to read as follows:] ■ 1. The authority citation for part 101 705.22, Seamless Acceptance Program, continues to read as follows: and 705.23, Full-Service Automation 20.5 Verifications Option, to add the applicable Authority: 15 U.S.C. 1453, 1454, 1455; 21 The six eInduction option verification verification descriptions, error U.S.C. 321, 331, 342, 343, 348, 371; 42 U.S.C. descriptions, error thresholds, and thresholds, and postage assessments, 243, 264, 271. postage assessments, are provided in standards. These standards have been 20.5.1 through 20.5.6. § 101.82 [Removed] made available to the public via Publication 6850, Publication for 20.5.1 Undocumented (Extra) ■ 2. Remove § 101.82. Streamlined Mail Acceptance for Letters Containers Verification Dated: October 26, 2017. and Flats, available at https:// An Undocumented Container error Anna K. Abram, postalpro.usps.com, which also occurs when a scanned IMcb is not Deputy Commissioner for Policy, Planning, contains additional information on the found in an eDoc, or is included in an Legislation, and Analysis. verification processes. eDoc and associated to a postage statement in estimated (EST) status. [FR Doc. 2017–23629 Filed 10–30–17; 8:45 am] List of Subjects in 39 CFR Part 111 Containers will be flagged as BILLING CODE 4164–01–P Administrative practice and Undocumented 10 days after the scan procedure, Postal Service. unload date/time if no eDoc has been Although we are exempt from the uploaded or if the postage statement is notice and comment requirements of the still in EST status. The threshold is 0%. Administrative Procedure Act (5 U.S.C. All errors will be subject to an

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