This section of the FEDERAL REGISTER

contains notices to the public of the proposed

issuance of rules and regulations. The

purpose of these notices is to give interested

persons an opportunity to participate in the

rule making prior to the adoption of the final

rules.

Proposed Rules Federal Register

50324 

Vol. 82, No. 209 

Tuesday, October 31, 2017 

DEPARTMENT OF ENERGY 

10 CFR Parts 429 and 431 

[EERE–2017–BT–TP–0055] 

Energy Conservation Program: Test 

Procedure for Distribution 

Transformers 

AGENCY: Office of Energy Efficiency and 

Renewable Energy, Department of 

Energy. 

ACTION: Request for information; reopening of public comment period. 

SUMMARY: On September 22, 2017, the 

U.S. Department of Energy (DOE) 

published a request for information 

(RFI) pertaining to the test procedures 

for distribution transformers. The RFI 

provided an opportunity for submitting 

written comments, data, and 

information by October 23, 2017. This 

document announces that the period for 

submitting comments on the RFI is to be 

re-opened until November 6, 2017. 

DATES: The comment period for the RFI, 

published on September 22, 2017 (82 FR 

44347), is re-opened until November 6, 

2017. DOE will accept written 

comments, data, and information in 

response to the RFI received no later 

than November 6, 2017. 

ADDRESSES: Interested persons are 

encouraged to submit comments by any 

of the following methods: 

• Federal eRulemaking Portal: 

www.regulations.gov. Follow the 

instructions for submitting comments. 

• Email: 

DistributionTransformers2017TP055@

ee.doe.gov. Include docket number 

EERE–2017–BT–TP–0055 in the subject 

line of the message. Submit electronic 

comments in WordPerfect, Microsoft 

Word, PDF, or ASCII file format, and 

avoid the use of special characters or 

any form of encryption. 

• Postal Mail: Appliance and 

Equipment Standards Program, U.S. 

Department of Energy, Building 

Technologies Office, Mailstop EE–5B, 

1000 Independence Avenue SW., 

Washington, DC 20585–0121. If 

possible, please submit all items on a 

compact disc (CD), in which case it is 

not necessary to include printed copies. 

• Hand Delivery/Courier: Appliance 

and Equipment Standards Program, U.S. 

Department of Energy, Building 

Technologies Office, 950 L’Enfant Plaza 

SW., 6th Floor, Washington, DC 20024. 

Telephone: (202) 287–1445. If possible, 

please submit all items on a CD, in 

which case it is not necessary to include 

printed copies. 

No telefacsimilies (faxes) will be 

accepted. For detailed instructions on 

submitting comments and additional 

information on the rulemaking process, 

see section III of the RFI published on 

September 22, 2017. 

Docket: The docket for this activity, 

which includes Federal Register 

notices, comments, and other 

supporting documents/materials, is 

available for review at http://

www.regulations.gov. All documents in 

the docket are listed in the http://

www.regulations.gov index. However, 

some documents listed in the index, 

such as those containing information 

that is exempt from public disclosure, 

may not be publicly available. 

The docket Web page can be found at 

http://www.regulations.gov/ 

#!docketDetail;D=EERE-2017-BT-TP0055. The docket Web page will contain 

simple instructions on how to access all 

documents, including public comments, 

in the docket. 

FOR FURTHER INFORMATION CONTACT:

Mr. Jeremy Dommu, U.S. Department 

of Energy, Office of Energy Efficiency 

and Renewable Energy, Building 

Technologies Program, EE–5B 1000 

Independence Avenue SW., 

Washington, DC 20585–0121. 

Telephone: (202) 586–9870. Email: 

ApplianceStandardsQuestions@

ee.doe.gov. 

Mary Greene, U.S. Department of 

Energy, Office of the General Counsel, 

GC–33, 1000 Independence Avenue 

SW., Washington, DC 20585–0121. 

Telephone: (202) 586–1817. Email: 

mary.greene@hq.doe.gov. 

For further information on how to 

submit a comment, review other public 

comments and the docket, contact the 

Appliance and Equipment Standards 

Program staff at (202) 287–1445 or by 

email: ApplianceStandardsQuestions@

ee.doe.gov. 

SUPPLEMENTARY INFORMATION: DOE 

published a RFI pertaining to the test 

procedure for distribution transformers 

on September 22, 2017. 82 FR 44347. 

The RFI initiated a data collection 

process to consider whether to amend 

DOE’s test procedures for distribution 

transformers. DOE requested written 

comment, data, and information 

pertaining to these test procedures by 

October 23, 2017. 

The National Electrical Manufacturers 

Association (NEMA), an interested party 

in the matter, requested a two-week 

extension of the public comment period 

for the RFI published in the Federal 

Register on October 5, 2017. (NEMA, 

No. 4, at p. 1) 

DOE believes that re-opening the 

comment period to allow additional 

time for interested parties to submit 

comments is appropriate. Therefore, 

DOE is re-opening the comment period 

until November 6, 2017 to provide 

interested parties additional time to 

prepare and submit comments. 

Comments received between the 

original October 23 closing date and the 

new November 6 closing date are 

considered timely filed. Therefore, 

individuals who submitted late 

comments during the original comment 

period do not need to re-submit 

comments. 

Issued in Washington, DC, on October 19, 

2017. 

David Nemtzow, 

Director, Building Technologies Office, 

Energy Efficiency and Renewable Energy. 

[FR Doc. 2017–23635 Filed 10–30–17; 8:45 am] 

BILLING CODE 6450–01–P 

DEPARTMENT OF HEALTH AND 

HUMAN SERVICES 

Food and Drug Administration 

21 CFR Part 101 

[Docket No. FDA–2017–N–0763] 

RIN 0910–AH43 

Food Labeling: Health Claims; Soy 

Protein and Coronary Heart Disease 

AGENCY: Food and Drug Administration, 

HHS. 

ACTION: Proposed rule. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency, or 

we) is proposing to revoke its regulation 

authorizing the use of health claims on 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50325 

the relationship between soy protein 

and coronary heart disease on the label 

or in the labeling of foods. We are taking 

this action based on our review of the 

totality of publicly available scientific 

evidence currently available and our 

tentative conclusion that such evidence 

does not support our previous 

determination that there is significant 

scientific agreement (SSA) among 

qualified experts for a health claim 

regarding the relationship between soy 

protein and reduced risk of coronary 

heart disease. 

DATES: Submit either electronic or 

written comments on the proposed rule 

by January 16, 2018. 

ADDRESSES: You may submit comments 

as follows. Late, untimely filed 

comments will not be considered. 

Electronic comments must be submitted 

on or before January 16, 2018. The 

https://www.regulations.gov electronic 

filing system will accept comments 

until midnight Eastern Time at the end 

of January 16, 2018. Comments received 

by mail/hand delivery/courier (for 

written/paper submissions) will be 

considered timely if they are 

postmarked or the delivery service 

acceptance receipt is on or before that 

date. 

Electronic Submissions 

Submit electronic comments in the 

following way: 

• Federal eRulemaking Portal: 

https://www.regulations.gov. Follow the 

instructions for submitting comments. 

Comments submitted electronically, 

including attachments, to https://

www.regulations.gov will be posted to 

the docket unchanged. Because your 

comment will be made public, you are 

solely responsible for ensuring that your 

comment does not include any 

confidential information that you or a 

third party may not wish to be posted, 

such as medical information, your or 

anyone else’s Social Security number, or 

confidential business information, such 

as a manufacturing process. Please note 

that if you include your name, contact 

information, or other information that 

identifies you in the body of your 

comments, that information will be 

posted on https://www.regulations.gov. 

• If you want to submit a comment 

with confidential information that you 

do not wish to be made available to the 

public, submit the comment as a 

written/paper submission and in the 

manner detailed (see ‘‘Written/Paper 

Submissions’’ and ‘‘Instructions’’). 

Written/Paper Submissions 

Submit written/paper submissions as 

follows: 

• Mail/Hand delivery/Courier (for 

written/paper submissions): Dockets 

Management Staff (HFA–305), Food and 

Drug Administration, 5630 Fishers 

Lane, Rm. 1061, Rockville, MD 20852. 

• For written/paper comments 

submitted to the Dockets Management 

Staff, FDA will post your comment, as 

well as any attachments, except for 

information submitted, marked and 

identified, as confidential, if submitted 

as detailed in ‘‘Instructions.’’ 

Instructions: All submissions received 

must include the Docket No. FDA– 

2017–N–0763 for ‘‘Food Labeling: 

Health Claims; Soy Protein and 

Coronary Heart Disease.’’ Received 

comments, those received in a timely 

manner (see DATES and ADDRESSES), will 

be placed in the docket and, except for 

those submitted as ‘‘Confidential 

Submissions,’’ publicly viewable at 

https://www.regulations.gov or at the 

Dockets Management Staff between 9 

a.m. and 4 p.m., Monday through 

Friday. 

• Confidential Submissions—To 

submit a comment with confidential 

information that you do not wish to be 

made publicly available, submit your 

comments only as a written/paper 

submission. You should submit two 

copies total. One copy will include the 

information you claim to be confidential 

with a heading or cover note that states 

‘‘THIS DOCUMENT CONTAINS 

CONFIDENTIAL INFORMATION.’’ We 

will review this copy, including the 

claimed confidential information, in our 

consideration of comments. The second 

copy, which will have the claimed 

confidential information redacted/ 

blacked out, will be available for public 

viewing and posted on https://

www.regulations.gov. Submit both 

copies to the Dockets Management Staff. 

If you do not wish your name and 

contact information to be made publicly 

available, you can provide this 

information on the cover sheet and not 

in the body of your comments and you 

must identify this information as 

‘‘confidential.’’ Any information marked 

as ‘‘confidential’’ will not be disclosed 

except in accordance with 21 CFR 10.20 

and other applicable disclosure law. For 

more information about FDA’s posting 

of comments to public dockets, see 80 

FR 56469, September 18, 2015, or access 

the information at: https://www.gpo.gov/ 

fdsys/pkg/FR-2015-09-18/pdf/2015- 

23389.pdf. 

Docket: For access to the docket to 

read background documents or the 

electronic and written/paper comments 

received, go to https://

www.regulations.gov and insert the 

docket number, found in brackets in the 

heading of this document, into the 

‘‘Search’’ box and follow the prompts 

and/or go to the Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852. 

FOR FURTHER INFORMATION CONTACT: 

Crystal Rivers, Center for Food Safety 

and Applied Nutrition (HFS–830), Food 

and Drug Administration, 5001 Campus 

Dr., College Park, MD 20740, 240–402– 

1444. 

SUPPLEMENTARY INFORMATION: 

Table of Contents 

I. Executive Summary 

A. Purpose of the Proposed Rule 

B. Summary of the Major Provisions of the 

Proposed Rule 

C. Legal Authority 

D. Costs and Benefits 

II. Table of Commonly Used Acronyms in 

This Document 

III. Background 

IV. Legal Authority 

V. Scientific Evidence Regarding the 

Relationship Between Soy Protein and 

CHD 

A. Overview of Data and Eligibility for a 

Health Claim 

B. Reevaluation of the Health Claim for Soy 

Protein Intake and CHD 

C. Assessment of Intervention Studies 

D. Assessment of Observational Studies 

VI. Strength of the Scientific Evidence 

VII. Proposal To Revoke § 101.82 

VIII. Economic Analysis of Impacts 

IX. Proposed Effective Date 

X. Analysis of Environmental Impact 

XI. Paperwork Reduction Act of 1995 

XII. Federalism 

XIII. References 

I. Executive Summary 

A. Purpose of the Proposed Rule 

The proposed rule would revoke the 

regulation authorizing the use of a 

health claim regarding the relationship 

between soy protein and risk of 

coronary heart disease (CHD) (§ 101.82 

(21 CFR 101.82)). In this proposed rule, 

we tentatively conclude, based on our 

reevaluation of the totality of the 

publicly available scientific evidence 

now available, that the evidence does 

not support our previous determination 

that there is SSA to support an 

authorized health claim for the 

relationship between soy protein and 

reduced risk of CHD. 

In 1999, we authorized a health claim 

about the relationship between soy 

protein and a reduced risk of CHD 

(§ 101.82). In the Federal Register of 

December 21, 2007, we announced our 

intention to reevaluate the scientific 

evidence for this health claim and 

provided the opportunity for public 

comment (72 FR 72738). We explained 

that we were reevaluating the scientific 

basis for the soy protein and CHD health 

claim because new studies yielded 


ethrower on DSK3G9T082PROD with PROPOSALS
50326 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

varied and inconsistent findings 

(beneficial effect, no effect) from one 

trial to another. The results of these 

studies called into question the 

conclusions drawn from our prior 

review, which had served as the basis 

for authorizing the soy protein and 

reduced risk of CHD health claim. This 

proposed rule is the next step in our 

reevaluation. 

B. Summary of the Major Provisions of 

the Proposed Rule 

The proposed rule would revoke the 

soy protein and CHD claim in § 101.82 

because it does not meet the SSA 

standard. Our decision about whether to 

authorize a health claim represents 

FDA’s determination as to whether there 

is ‘‘significant scientific agreement’’ 

among qualified experts that the 

publicly available scientific evidence 

supports the substance/disease 

relationship that is the subject of a 

proposed health claim. In our 

reevaluation of the scientific evidence 

in this proposed rule, we use our 

approach outlined in the ‘‘EvidenceBased Review System for the Scientific 

Evaluation of Health Claims’’ 

(hereinafter the 2009 guidance) to 

evaluate the totality of publicly 

available scientific evidence to 

determine if the SSA standard in section 

403(r)(3) of the Federal Food, Drug, and 

Cosmetic Act (the FD&C Act) (21 U.S.C. 

(343(r)(3)) is met (Ref. 1). Our 

reevaluation of the totality of the 

publicly available scientific evidence 

indicates that, although some evidence 

suggests a relationship between soy 

protein intake and reduced risk of CHD, 

the totality of the evidence is 

inconsistent and not conclusive. 

Therefore, we have tentatively 

determined that the strength of the 

totality of the publicly available data 

does not meet the SSA standard for a 

relationship between soy protein intake 

and CHD risk. 

C. Costs and Benefits 

The costs of this proposed rule, if 

finalized, are relabeling the estimated 

200 to 300 products currently making 

the health claim. We estimate total 

annualized costs of $35,000 to $81,000, 

when the relabeling costs are 

annualized over 20 years at a 7 percent 

discount rate. The initial one-time costs 

are $370,000 to $860,000. 

The benefit of this rule is better 

information for the consumers who are 

considering purchasing products with 

soy protein. This may generate an 

unknown amount of increased 

consumer surplus. Some consumers 

may react to this new information by 

switching their consumption to 

products that they enjoy more, or 

products that still have an authorized 

health claim. By basing their 

consumption decisions on more recent 

and accurate scientific information, they 

may get more consumer surplus, in the 

form of enjoyment and/or potential 

health benefits, from the bundle of 

products they consume. 

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 

in This Document 

TABLE 2—TABLE OF COMMONLY USED

ACRONYMS

Acronym What it means 

CHD ............ Coronary Heart Disease 

DASH ......... Dietary Approaches to Stop 

Hypertension 

DBP ............ Diastolic Blood Pressure 

FDA ............ Food and Drug Administration 

g ................. gram(s) 

kcal ............. kilocalorie(s) 

LDL ............. Low-Density Lipoprotein 

mg .............. milligram(s) 

NCEP ......... National Cholesterol Education 

Program 

NHLBI ......... National Heart, Lung and 

Blood Institute 

oz ................ ounces 

SBP ............ Systolic Blood Pressure 

SSA ............ Significant Scientific Agreement 

TC ............... Total Cholesterol 

III. Background 

In the Federal Register of November 

10, 1998 (63 FR 62977), and in response 

to a petition from Protein Technologies 

International, Inc. (see Docket No. FDA– 

1998–P–1154), we proposed to provide 

for health claims on the relationship of 

soy protein and reduced risk of CHD 

(hereinafter referred to as the 1998 soy 

protein proposed rule). In the 1998 soy 

protein proposed rule, we considered 

the relevant scientific studies and data 

presented in the petition as part of our 

review of the scientific literature on soy 

protein and CHD. We summarized these 

studies in table 1 of the soy protein 

proposed rule (63 FR 62977 at 62998) 

and presented the rationale for a health 

claim on this food/disease relationship 

as provided for under the significant 

scientific agreement standard in section 

403(r)(3)(B)(i) of the FD&C Act and 

§ 101.14(c). 

In our 1998 evaluation of the 

scientific evidence for a relationship 

between consumption of soy protein 

and blood total and LDL-cholesterol 

levels (two validated surrogate 

endpoints for risk of CHD), we found 

the data suggestive, but not sufficient, to 

establish a dose-response for this 

relationship. However, we found 

consistent, clinically significant 

reductions of total- and LDL-cholesterol 

levels in controlled trials that used at 

least 25 grams (g) of soy protein per day. 

Thus, we proposed to base the 

qualifying level of soy protein on a total 

daily intake of 25 g, as suggested by the 

petitioner. For the purposes of health 

claims, we assumed there are four eating 

occasions a day (i.e., three main meals 

and one snack). Therefore, in 

§ 101.82(c)(2)(iii)(A), we proposed the 

qualifying criterion for a food to bear the 

claim as 6.25 g of soy protein per 

reference amount customarily 

consumed (RACC) (i.e., 25 g divided by 

four eating occasions per day). 

In the Federal Register of October 26, 

1999 (64 FR 57700), we authorized a 

health claim for soy protein and risk of 

coronary heart disease (21 CFR 101.82). 

As explained in the final rule, we 

determined, based on our review of 

evidence submitted with comments to 

the proposed rule, as well as evidence 

described in the proposed rule, that soy 

protein included in a diet low in 

saturated fat and cholesterol may reduce 

the risk of CHD by lowering blood 

cholesterol levels. FDA’s requirements 

for use of the health claim and model 

health claim language were codified at 

21 CFR 101.82. 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50327 

FDA evaluates new scientific 

information that becomes available to 

determine whether it necessitates a 

change to an SSA health claim. On 

December 21, 2007, we published a 

notice in the Federal Register (72 FR 

72738) (the 2007 reevaluation notice) 

announcing our intent to reevaluate the 

scientific evidence for certain health 

claims, including the authorized health 

claim for soy protein and risk of CHD 

(§ 101.82). We stated that we were 

reevaluating the scientific basis for the 

soy protein and CHD health claim 

because numerous studies published 

since we had authorized the health 

claim had evaluated the relationship 

between soy protein and CHD, and the 

findings of these studies were 

inconsistent from study to study. For 

example, the Agency for Healthcare 

Research and Quality (AHRQ) released 

a report in July 2005 outlining the 

effects of soy products on health 

outcomes, including cardiovascular 

disease, and concluded that soy 

products appear to exert a small benefit 

on LDL cholesterol (Ref. 2). However, 

the AHRQ report included studies that 

evaluated substances in addition to soy 

protein (e.g., isolated soy isoflavones). It 

was not clear from the AHRQ report 

whether the soy protein, or other 

components of soy products such as 

isoflavones, were responsible for 

lowering LDL cholesterol. In addition, 

the AHRQ report used markers of 

cardiac function (e.g., triglycerides, 

endothelial function, and oxidized lowdensity lipoprotein) that are not 

surrogate endpoints recognized by FDA 

for CHD risk. 

Subsequently, we received a citizen 

petition dated August 8, 2008 (Docket 

Number FDA–2008–P–0452–001) 

(hereinafter ‘‘the 2008 citizen petition’’), 

requesting that the Commissioner of 

Food and Drugs revoke § 101.82. On 

January 4, 2016, we denied the 

petitioner’s request because the limited 

relevant evidence submitted in the 

petition and a supplement to the 

petition did not provide sufficient 

grounds for us to revoke the soy protein 

and CHD health claim. However, as 

noted in the response to the citizen 

petition, we considered the relevant 

studies included in the petition as part 

of our reevaluation. 

IV. Legal Authority 

The Nutrition Labeling and Education 

Act of 1990 (NLEA) (Pub. L. 101–535) 

amended the FD&C Act by, among other 

things, adding section 403(r) to the 

FD&C Act. This section specifies, in 

part, that a food is misbranded if it bears 

a claim that expressly or by implication 

characterizes the relationship of a 

nutrient to a disease or health-related 

condition unless the claim is made in 

accordance with section 403(r)(3) of the 

FD&C Act (for conventional foods) or 

403(r)(5)(D) of the FD&C Act (for dietary 

supplements). 

The NLEA also directed FDA to issue 

regulations authorizing health claims 

(i.e., labeling claims that characterize 

the relationship of a nutrient to a 

disease or health-related condition) for 

conventional foods if we determine, 

based upon the totality of publicly 

available scientific evidence (including 

evidence from well-designed studies 

conducted in a manner that is consistent 

with generally recognized scientific 

procedures and principles), that there is 

SSA, among experts qualified by 

scientific training and experience to 

evaluate such claims, that the claim is 

supported by such evidence (see section 

403(r)(3)(B)(i) of the FD&C Act). FDA 

may reevaluate the science related to an 

authorized health claim and may take 

action to revoke the claim (see section 

403(r)(7)(B) of the FD&C Act (21 U.S.C. 

343(r)(7(B)). 

Additionally, our regulations, at 21 

CFR 10.40(a), provide that we may 

promulgate regulations necessary to 

enforce the FD&C Act as appropriate 

and may initiate such action in any of 

the ways specified in § 10.25 (21 CFR 

10.25). Specifically, § 10.25(b) provides 

that the Commissioner may initiate a 

proceeding to revoke a regulation. 

Accordingly, we are acting within our 

statutory and regulatory authorities to 

propose to revoke the authorized health 

claim for soy protein and a reduced risk 

of CHD. If this proposed rule is 

finalized, the use of an authorized 

health claim would be prohibited and a 

food that bears the health claim on the 

label or in labeling would misbrand the 

food (see section 403(r)(1)(B) of the 

FD&C Act). 

In situations where we determine that 

the totality of the publicly available 

scientific evidence does not meet the 

statutory SSA standard, we may 

consider whether there is credible 

evidence to support a ‘‘qualified’’ health 

claim and what qualifying statements 

and other information should 

accompany the claim to ensure that it is 

truthful and not misleading. If, when we 

finalize this rule, we conclude there is 

not SSA, but there is some credible 

evidence for the use of a qualified 

health claim about the relationship 

between soy protein and a reduced risk 

of CHD, we intend to issue a statement 

of enforcement discretion for the use of 

a qualified health claim. 

V. Scientific Evidence Regarding the 

Relationship Between Soy Protein and 

CHD 

A. Overview of Data and Eligibility for 

a Health Claim 

Health claims characterize the 

relationship between a substance and a 

reduction in risk of contracting a 

particular disease or developing a 

health-related condition (Whitaker v. 

Thompson, 353 F.3d 947, 950–51 (D.C. 

Cir.) (upholding FDA’s interpretation of 

what constitutes a health claim), cert. 

denied, 125 S. Ct. 310 (2004)). The 

substance must be associated with a 

disease or health-related condition for 

which the general U.S. population, or an 

identified U.S. population subgroup, is 

at risk (§ 101.14(b)(1)). We analyze the 

information and data related to a health 

claim under the framework set out in 

our 2009 guidance titled, ‘‘EvidenceBased Review System for the Scientific 

Evaluation of Health Claims’’ (Ref. 1). 

The 2009 guidance discussed our 

process for evaluating the scientific 

evidence for a health claim and the 

meaning of the significant scientific 

agreement (SSA) standard in section 

403(r)(3) of the FD&C Act (21 U.S.C. 

343(r)(3)) and 21 CFR 101.14(c). In a 

review of a health claim, our first step 

is to identify the substance, the disease 

or health-related condition that is the 

subject of the claim, and the population 

to which the claim is targeted (Ref. 1). 

Next, we consider the totality of 

publicly available data and information 

to determine whether the scientific 

evidence could support a relationship 

between the substance and the disease 

or health-related condition. We begin 

this process by organizing the evidence 

into categories, such as human studies, 

meta-analyses, review articles, animal 

studies, and in vitro studies, so we can 

thoroughly and systematically assess the 

evidence during the evaluation process. 

Each category of evidence may offer us 

helpful information and a better 

understanding of the topic; however, 

only well-designed, well-conducted 

human studies provide both the level of 

scientific rigor and generalizability to 

human populations needed to 

potentially support a health claim 

relationship. We focus our review on 

reports of human intervention studies 

and observational studies. Of the two 

types of studies, well-conducted 

intervention studies provide the 

strongest evidence of an effect and are 

the most reliable category of studies for 

determining a cause-and-effect 

relationship (Ref. 1). In an intervention 

study, subjects similar to each other are 

randomly assigned to either receive the 

intervention or not to receive the 


ethrower on DSK3G9T082PROD with PROPOSALS
50328 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

intervention, whereas in an 

observational study, the subjects (or 

their medical records) are observed for 

a certain outcome (i.e., disease). 

Observational studies lack the 

controlled setting of intervention 

studies. In contrast to intervention 

studies, observational studies cannot 

determine whether an observed 

relationship represents a relationship in 

which the substance caused a reduction 

in disease risk or if other factors or 

variables may have contributed to an 

outcome (Ref. 3). In addition to 

individual reports of human studies, we 

also consider other types of data and 

information such as meta-analyses, 

review articles, and animal and in vitro 

studies. These other types of data and 

information may be useful to help us 

understand the scientific issues about 

the substance, the disease, or both, but 

cannot by themselves support a health 

claim relationship. Reports that discuss 

a number of different studies, such as 

meta-analyses and review articles do not 

provide sufficient information on the 

individual studies reviewed in order for 

us to determine critical elements such 

as the study population characteristics 

and the composition of the products 

used. Similarly, the lack of detailed 

information on studies summarized in 

review articles and meta-analyses 

prevents us from determining whether 

the studies are flawed in critical 

elements such as design, conduct of 

studies, and data analysis. We must be 

able to review the critical elements of a 

study to determine whether any 

scientific conclusions can be drawn 

from it. We use meta-analyses, review 

articles, and similar publications to 

identify reports of additional studies 

that may be useful to the health claim 

review and as background about the 

substance-disease relationship. If 

additional studies are identified, we 

evaluate them individually. 

We use animal and in vitro studies as 

background information regarding 

mechanisms of action that might be 

involved in any relationship between 

the substance and the disease. In vitro 

studies are conducted in an artificial 

environment and cannot account for a 

multitude of normal physiological 

processes, such as digestion, absorption, 

distribution, and metabolism, which 

affect how humans respond to the 

consumption of foods and dietary 

substances (Ref. 4). Further, the 

physiology of animals is different than 

that of humans. Animal and in vitro 

studies can be used to generate 

hypotheses or to explore a mechanism 

of action but cannot adequately support 

a relationship between the substance 

and the disease. 

We evaluate the individual reports of 

human studies to determine whether 

any scientific conclusions can be drawn 

from each study. The absence of critical 

factors, such as a control group or a 

statistical analysis, means that scientific 

conclusions cannot be drawn from the 

study (Ref. 5–6). Studies from which we 

cannot draw any scientific conclusions 

do not support the health claim 

relationship, and we eliminate such 

studies from further review. 

Because health claims involve 

reducing the risk of a disease in people 

who do not already have the disease 

that is the subject of the claim, we 

consider evidence from studies in 

individuals diagnosed with the disease 

that is the subject of the health claim 

only if it is scientifically appropriate to 

extrapolate to individuals who do not 

have the disease. The available 

scientific evidence should demonstrate 

that: (1) The mechanism(s) for the 

mitigation or treatment effects measured 

in the diseased populations are the same 

as the mechanism(s) for risk reduction 

effects in non-diseased populations; and 

(2) the substance affects these 

mechanisms in the same way in both 

diseased and healthy people. If such 

evidence is not available, then we 

cannot draw any scientific conclusions 

from studies that use diseased subjects 

to evaluate the substance/disease 

relationship. Next, we rate the 

remaining human intervention and 

observational studies for methodological 

quality. This quality rating is based on 

several criteria related to study design 

(e.g., use of a placebo-control group 

versus a non-placebo-control group), 

data collection (e.g., type of dietary 

assessment method), the quality of the 

statistical analysis, the type of outcome 

measured (e.g., disease incidence versus 

validated surrogate endpoint), and study 

population characteristics other than 

relevance to the U.S. population (e.g., 

age, smoker versus non-smoker) to 

evaluate factors such as selection bias 

and whether important information 

about the study subjects was gathered 

and reported. For example, if the 

scientific study adequately addressed all 

or most of the criteria related to study 

design, we would assign a high 

methodological quality rating to the 

study. We would assign moderate or 

low quality ratings based on the extent 

of the deficiencies or uncertainties in 

the quality criteria. As noted in our 

guidance (Evidence-Based Review 

System for the Scientific Evaluation of 

Health Claims), this quality rating is 

based on several factors related to study 

design, data collection, the quality of 

the statistical analysis, the type of 

outcome measured, and study 

population characteristics other than 

relevance to the U.S. population (e.g., 

selection bias and the provision of 

important subject information [e.g., age, 

smokers]). (Ref. 1). We would not use 

studies that are so deficient that 

scientific conclusions cannot be drawn 

from them to support the health claim 

relationship, and we eliminate such 

studies from further review. 

We then evaluate the results of the 

remaining human studies and then rate 

the overall strength of the total body of 

publicly available evidence (Ref. 1). We 

consider the study type (e.g., 

intervention, prospective cohort, casecontrol, cross-sectional), the 

methodological quality rating 

previously assigned, the quantity of 

evidence (number of studies of each 

type and study sample sizes), whether 

the body of scientific evidence supports 

a health claim relationship for the U.S. 

population or target subgroup, whether 

study results supporting the proposed 

claim have been replicated (Ref. 7), and 

the overall consistency (Ref. 8–9) of the 

total body of evidence (Ref. 1). Based on 

the totality of the publicly available 

scientific evidence, we determine 

whether such evidence meets that SSA 

standard to support an authorized 

health claim (also referred to as ‘‘SSA 

health claim’’) for the substance/disease 

relationship. If the evidence does not 

meet the SSA standard, then we may 

consider whether such evidence is 

credible to support a qualified health 

claim. If there is credible evidence to 

support a qualified health claim, then 

we consider what qualifying language 

should be included to convey the limits 

on the level of scientific evidence 

supporting the relationship or to 

prevent the claim from being misleading 

in other ways. 

B. Reevaluation of the Health Claim for 

Soy Protein Intake and CHD 

In our reevaluation of the scientific 

evidence for a relationship between soy 

protein and reduced risk of CHD, we 

have used the approach outlined in the 

2009 guidance to evaluate the totality of 

the current publicly available scientific 

evidence regarding this relationship (see 

section 403(r)(3)(B) of the FD&C Act). In 

this section, we present our reevaluation 

of the totality of the publicly available 

scientific evidence, including the 

studies we previously reviewed in 

promulgating the regulation that 

authorized the 1999 soy protein and 

CHD health claim (64 FR 57700), as well 

as studies published after we authorized 

the health claim in 1999. The 2009 

guidance represents FDA’s current 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50329 

thinking on the evaluation of health 

claims as well as the interpretation and 

meaning of SSA. Because the 1999 final 

rule predates that guidance, we 

acknowledge that our reevaluation of 

studies previously considered in the 

1999 rulemaking may differ in certain 

respects from the previous evaluation. 

For the purposes of this review, we have 

identified the following disease 

endpoints for use in identifying CHD 

risk reduction for the purposes of a 

health claim evaluation: The incidence 

of coronary events (e.g., myocardial 

infarction, ischemia), cardiovascular 

death, coronary artery disease, 

atherosclerosis, and CHD (Ref. 1). We 

consider high blood pressure, blood 

(serum or plasma) total cholesterol (TC), 

and blood LDL cholesterol levels to be 

surrogate endpoints for CHD risk (Ref. 

1). We use these disease and surrogate 

endpoints to evaluate the potential 

effects of soy protein on CHD risk. 

For the purposes of the reevaluation, 

we identified a total of 709 publications, 

drawn from studies included in the 

1999 final rule, comments submitted to 

the 2007 notice of reevaluation, the 

2008 citizen petition, and searches of 

the more recent literature. These 

publications consisted of 30 in vitro 

studies; 85 animal studies; 27 

government documents; 163 review 

articles, meta-analyses, letters, abstracts, 

and books or book chapters; 11 Web 

sites; 3 articles written in a foreign 

language; and 141 publications that did 

not evaluate the substance/disease 

relationship. The publications also 

included 11 observational studies that 

evaluated the substance/disease 

relationship and 238 publications 

describing intervention studies that 

evaluated the relationship between soy 

protein intake and CHD risk. 

1. Assessment of Review Articles, MetaAnalyses, Book Chapters, Letters, and 

Government Reports 

Although useful for background 

information, review articles, metaanalyses, book chapters, letters, and 

government reports do not contain 

sufficient information on the individual 

studies which they reviewed and, 

therefore, we could not draw any 

scientific conclusions from this 

information. For example, we could not 

determine factors such as the study 

population characteristics or the 

composition of the products used (e.g., 

food, dietary supplements). Similarly, 

the lack of detailed information on 

studies summarized in review articles, 

meta-analyses, book chapters, letters, 

and government reports prevents us 

from determining whether the studies 

are flawed in critical elements such as 

design, conduct of studies, and data 

analysis. We need to be able to review 

the critical elements of a study to 

determine whether any scientific 

conclusions can be drawn from it. As a 

result, while the review articles, metaanalyses, book chapters, letters, and 

government reports we identified 

provided useful background 

information, they did not provide 

sufficient information from which 

scientific conclusions could be drawn 

regarding soy protein consumption and 

risk of CHD. 

2. Assessment of Animal and In Vitro 

Studies 

We use animal and in vitro studies as 

background information regarding 

mechanisms of action that might be 

involved in any relationship between 

the substance and the disease; these 

studies also can be used to generate 

hypotheses or to explore a mechanism 

of action, but they cannot adequately 

support a relationship between a 

substance and a disease in humans (Ref. 

1, 4). Such studies cannot mimic the 

normal human physiology that may be 

involved in the risk reduction of CHD, 

nor can the studies mimic the human 

body’s response to the consumption of 

soy protein. Therefore, we cannot draw 

any scientific conclusions from the 

animal or in vitro studies regarding soy 

protein and the risk of CHD in humans, 

and they provide insufficient data to 

support a health claim. In accordance 

with these principles, in our review we 

considered animal and in vitro studies 

but determined that they did not 

provide useful supportive information 

about the relationship between soy 

protein consumption and risk of CHD. 

C. Assessment of Intervention Studies 

For the purposes of this review, we 

categorized the intervention studies 

based on whether the subjects: (1) 

Added soy protein to the diet 

(supplement) in addition to the subjects’ 

usual diet; (2) were instructed to 

substitute soy protein for animal protein 

in their diet; and (3) were provided test 

diets (feeding studies) with soy protein 

for animal protein (usually casein) in 

the control diet. In studies where soy 

proteins were used as a substitute for 

animal proteins, changes in the total fat, 

saturated fat, cholesterol, and dietary 

fiber content of the diet can occur. A 

reduced intake of total fat (Ref. 10), 

saturated fat ((Ref. 10), or cholesterol 

(Ref. 11) has been shown to lower blood 

cholesterol, and an increased intake of 

dietary fiber (Ref. 12) has shown the 

same (Ref. 10), and we have authorized 

SSA health claims for reduced risk of 

CHD based on these substance and 

disease relationships (§ 101.75, 

§ 101.81). Therefore, to determine the 

independent effect of soy protein intake 

on blood cholesterol levels, total fat, 

saturated fat, cholesterol, and dietary 

fiber need to be controlled for in the 

studies. Studies that substituted soy 

protein for animal protein or feeding 

studies that did not properly control for 

these nutrients and/or did not report 

these nutrients were eliminated from 

further review. For studies in which soy 

protein was added to the usual diet, the 

addition of soy protein should not result 

in significant changes in the total fat, 

saturated fat, cholesterol, and dietary 

fiber in the diet (because soy protein 

does not have significant amounts of 

these nutrients) (Ref. 13–15). Therefore, 

we did not eliminate these types of 

studies that did not control for and/or 

did not report these nutrients. 

To determine the independent effects 

of soy protein on blood pressure, studies 

need to control for the amount of 

sodium and potassium, because both 

nutrients influence blood pressure (Ref. 

16). Studies that substituted soy protein 

for animal protein or feeding studies 

where subjects were provided soy 

protein in test diets that did not 

properly control for these nutrients and/ 

or did not report these nutrients were 

eliminated from further review. For 

studies that added soy protein to the 

diet, the addition of soy protein should 

not result in significant changes in the 

amount of sodium and potassium in the 

diet; therefore, we did not eliminate 

these types of studies that did not 

control for and/or did not report these 

nutrients (Ref. 13–15). Furthermore, 

because the nutrients that affect blood 

pressure (sodium and potassium) and 

cholesterol (saturated fat, dietary fiber, 

and cholesterol) are different, some 

studies might be appropriate for 

supporting one surrogate endpoint, but 

not the other. Thus, for the purposes of 

this assessment, we discuss some 

studies twice. 

Of the 238 total publications 

describing intervention studies that 

evaluated the relationship between soy 

protein intake and CHD risk, 9 

publications did not report data on a 

FDA-recognized surrogate endpoint of 

CHD risk (i.e., blood total cholesterol, 

blood LDL cholesterol, blood pressure) 

(Ref. 17–25). Because these publications 

did not report data on one or more 

surrogate endpoints, we could not draw 

scientific conclusions about the 

relationship between soy protein 

consumption and risk of CHD from 

these studies (Ref. 1). 

The remaining 229 publications 

described 212 intervention studies that 

evaluated soy protein intake and CHD 


ethrower on DSK3G9T082PROD with PROPOSALS
50330 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

risk. Of these 212 intervention studies, 

scientific conclusions could not be 

drawn from 154 studies due to 

significant flaws. These studies are 

discussed in sections V.C. 1. and V.C. 2. 

Such studies may have other flaws in 

addition to those specifically 

mentioned. This left 58 well-designed, 

well-conducted intervention studies to 

include in our evaluation of the totality 

of the publicly available scientific 

evidence. 

1. Intervention Studies That Examined 

Soy Protein Intake and Blood 

Cholesterol 

As stated previously in this section, 

we could not draw scientific 

conclusions about the relationship 

between soy protein consumption and 

risk of CHD from 154 intervention 

studies due to significant design flaws. 

These studies include 17 studies that 

did not include a control group or 

provide an appropriate control for the 

comparison to the relative effects of soy 

protein (Ref. 26–42). Without an 

appropriate control group, we could not 

determine if the changes in LDL 

cholesterol were due to soy protein 

intake or uncontrolled extraneous 

factors (Ref. 1). Therefore, we could not 

draw scientific conclusions about the 

relationship between soy protein 

consumption and risk of CHD from 

these studies 

Ten studies did not conduct statistical 

analyses between the control group and 

treatment group. The statistical analysis 

of the substance/disease relationship is 

a critical factor because it provides the 

comparison between subjects that 

consumed soy protein and those that 

did not consume soy protein (i.e., 

control) to determine whether there is a 

reduction in CHD risk (Ref. 43–52). 

Therefore, we could not draw scientific 

conclusions about the relationship 

between soy protein consumption and 

risk of CHD from these studies. 

In eight studies (Ref. 53–60), the 

duration of the study intervention was 

too short (less than 3 weeks) to 

adequately determine if changes in 

serum cholesterol levels were due to the 

consumption of soy protein (Ref. 1, 61). 

Therefore, we could not draw scientific 

conclusions about the relationship 

between soy protein consumption and 

risk of CHD from these studies. 

Seventy-six studies, described in 84 

publications, that substituted soy 

protein for animal protein or were 

feeding studies reported large 

differences in or did not report 

information on other dietary 

components that have an effect on blood 

cholesterol (e.g., dietary fiber, saturated 

fat, dietary cholesterol) (Ref. 56, 62– 

145). Such large differences in nutrient 

intakes of dietary fiber, saturated fat, or 

dietary cholesterol make it difficult to 

clearly delineate what may be causing a 

change in serum cholesterol levels. 

Therefore, the results of these studies 

could not be interpreted, and we could 

not draw scientific conclusions about 

the relationship between soy protein 

consumption and risk of CHD from 

these studies (Ref. 1). 

One study, Zittermann et al. (2004) 

was a randomized, crossover study (Ref. 

1) in which 14 German women 

consumed 5 cookies made with soy 

flour or 5 cookies made with wheat 

flour while they remained on their usual 

diet for one menstrual cycle (30.8 ± 0.9 

days). The composition of the test 

cookies and of the amount of soy 

protein in the cookies was not 

adequately described. Furthermore, 

while the study reported that subjects 

were to consume the cookies while they 

remained on their usual diet, the study 

reported significantly higher intake of 

dietary fiber (P <0.0001) in the soy 

period (cookies made with soy flour) 

than in the control period. When an 

intervention study involves providing a 

whole food rather than a food 

component, the experimental and 

control diets should be similar enough 

that the relationship between the 

substance and disease can be evaluated 

(Ref. 1). Because the composition of the 

test cookies were not adequately 

described, it is not clear why there are 

differences in dietary fiber intake 

between the two groups. Thus, we could 

not draw scientific conclusions about 

the relationship between soy protein 

and CHD when the amounts of other 

substances that are known to affect the 

risk of CHD (e.g. dietary fiber) are 

different between the control and 

experimental diets (Ref. 1, 146). 

Nine studies, described in 11 

publications that evaluated soy protein 

intake and blood cholesterol, contained 

added phytosterols in the treatment 

group (Ref. 131–132, 147–155). We have 

an existing regulation for a SSA health 

claim for the relationship between plant 

sterol/stanol esters and reduced risk of 

CHD; however, because plant sterol/ 

stanol esters can reduce blood 

cholesterol, it is not possible to clearly 

delineate what may be causing a change 

in serum cholesterol levels (Ref. 1). 

Therefore, the results of these studies 

could not be interpreted, and we could 

not draw scientific conclusions about 

the relationship between soy protein 

consumption and risk of CHD from 

these studies. 

For the remaining 58 intervention 

studies from which we could draw 

scientific conclusions, we used the 

criteria established by the National 

Heart, Lung and Blood Institute (NHLBI) 

to sort studies that measured blood 

cholesterol into 3 categories: (1) Studies 

that had subjects with desirable or 

borderline blood cholesterol (TC <240 

mg/dL or LDL-cholesterol less than 160 

mg/dL); (2) studies that had subjects 

with high blood cholesterol (TC >240 or 

LDL cholesterol >160 mg/dL); and (3) 

studies that had some subjects with 

desirable or borderline cholesterol level 

and other subjects with high cholesterol 

levels (Ref. 156). Additionally, studies 

that measured blood pressure were 

sorted based on criteria established by 

NHLBI into three categories: (1) Normal 

(Systolic Blood Pressure (SBP) <120 

mmHg or Diastolic Blood Pressure 

(DBP) <80 mmHg); (2) pre-hypertension 

(SBP 120 to 139 mmHg or DBP 80 to 89 

mmHg); and (3) hypertension (SBP ≥140 

mmHg or DBP ≥90 mmHg) (Ref. 157– 

158). Studies were further sorted by 

whether the studies added 

(supplemented) soy protein to the diet, 

were feeding studies, or were 

substitution studies. Because some 

studies measured both blood cholesterol 

and blood pressure, we discussed these 

studies twice (see tables 4–8 in Ref. 

230). 

a. Studies in subjects with desirable or 

borderline cholesterol levels that added 

isolated soy protein to the diet. 

Carmignani et al. (2014) was a 16- 

week, randomized, double-blind, 

placebo-controlled, parallel trial of 

moderate quality in which 40 

postmenopausal Brazilian women 

consumed daily 40 g/day placebo 

powder of maltrodextrin (n=20) or 40 g/ 

day protein powder containing 24 g/day 

isolated soy protein (90 mg/day 

naturally occurring isoflavones) (n=20) 

in addition to their usual diet (Ref. 159). 

There was no significant difference in 

blood TC and LDL cholesterol between 

the soy protein group and the control 

group. 

Liu et al. (2012) was a 6-month, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 120 postmenopausal 

Chinese women consumed daily 15 g/ 

day milk protein plus 100 mg/day 

isoflavone supplement (control) (n=60) 

or 15 g/day isolated soy protein plus 

100 mg/day isoflavone supplement 

(n=60) in addition to their usual diet 

(Ref. 160). There was no significant 

difference in the change in blood TC 

and LDL cholesterol between the milk 

protein and isoflavone group (control) 

and the soy protein and isoflavone 

group. 

Santo et al. (2008) was a 28-day, 

randomized, double-blind, controlled 

parallel trial of moderate quality in 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50331 

which 30 American men consumed: (1) 

25 g/day isoflavone-poor soy protein 

isolate (1.9 mg/day isoflavones) (n=11); 

(2) 25 g/day isoflavone-rich soy protein 

isolate (97 mg/day naturally occurring 

isoflavones) (n=10); or (3) 25 g/day of 

milk protein (n=9) (control) mixed with 

a beverage of their choice in addition to 

their usual diet (Ref. 161). There were 

no significant differences in blood TC 

and LDL cholesterol between the two 

soy protein isolate treatment groups and 

the casein control group. 

Evans et al. (2007) was a randomized, 

double-blind, placebo-controlled, 

crossover trial of moderate quality in 

which 22 postmenopausal American 

women consumed: (1) 25 g/day isolated 

soy protein plus 20 g/day soy lecithin; 

(2) 25 g/day isolated soy protein plus 

placebo lecithin; (3) placebo protein 

(50:50 calcium/sodium caseinate) and 

20 g/day soy lecithin; and (4) double 

placebo (protein placebo and soy 

lecithin) in addition to their usual diet, 

for a duration of 4 weeks each (Ref. 

162). There was no significant 

difference in blood TC and LDL 

cholesterol between the isolated soy 

protein plus soy lecithin and placebo 

protein plus soy lecithin treatment 

period (control). There was also no 

significant difference in blood TC and 

LDL between the isolated soy protein 

plus placebo lecithin and double 

placebo period (control). 

Maesta et al. (2007) was a 16-week, 

randomized, single-blind, placebocontrolled, parallel trial of moderate 

quality in which 46 postmenopausal 

Brazilian women consumed: (1) 25 g/ 

day isolated soy protein (n=10); (2) 25 

g/day isolated soy protein, plus 

resistance exercise (n=14); (3) 25 g/day 

maltodextrin (control) (n=11); or (4) 25 

g/day maltodextrin plus resistance 

exercise (n=11) (control) in addition to 

their usual diet (Ref. 163). There was no 

significant difference in blood TC and 

LDL cholesterol between the soy protein 

and control groups. 

Kohno et al. (2006) was a two-part, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality (Ref. 164). In the first part of the 

trial, 126 Japanese men and women, in 

addition to their usual diet, consumed 

daily 5 g casein (control) (n=61) or 5 g 

of soybean b-conglycinin (storage 

protein component of soy protein 

isolate) in the form of a candy (n=65) for 

12 weeks. There was no significant 

difference between the two diets for 

blood TC or LDL cholesterol. In the 

second part of the trial, 95 Japanese men 

and women consumed daily 5 g casein 

(n=50) or 5g soybean b-conglycinin 

(n=45) for 20 weeks. There was no 

significant difference between the two 

diets for blood TC or LDL cholesterol. 

McVeigh et al. (2006) was a 

randomized, single-blind, controlled, 

crossover trial of moderate quality in 

which 35 Canadian men consumed 32 

g/day soy protein isolate depleted of 

isoflavones (1.64 mg/day), 32 g/day soy 

protein isolate (62 mg/day isoflavones), 

or 32 g/day milk protein isolate for a 

duration of 57 days each (Ref. 165). 

There was no significant difference 

between blood TC and LDL cholesterol 

between the soy protein and casein 

groups. 

Sagara et al. (2004) was a 5-week, 

randomized, double-blind, placebocontrolled parallel trial of moderate 

quality in which 50 Scottish men 

consumed 20 g/day of isolated soy 

protein powder in biscuits, cereal bars, 

and bread rolls (n=25) or biscuits, cereal 

bars, and bread rolls without added soy 

protein in addition to their usual diets 

(n=25) (Ref. 166). There was no 

significant difference in blood TC 

between the two groups. 

Teixeira et al. (2004) was a 

randomized, controlled, crossover trial 

of moderate quality in which 14 men 

American men with type 2 diabetes 

with nephropathy consumed an 

estimated 35 g/day of soy protein isolate 

and casein (control) in addition to their 

usual diets for a duration of 8 weeks 

each (Ref. 167). There was no significant 

difference in blood TC and LDL 

cholesterol between the soy protein and 

casein group. 

Murray et al. (2003) was a 6-month, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 30 American 

postmenopausal women consumed: (1) 

38 g/day soy protein isolate containing 

(25 g soy protein) plus 1.0 mg estradiol 

(n=8); (2) 38 g textured milk protein 

plus 1.0 mg estradiol (n=7) (control); (3) 

38 g/day soy protein isolate containing 

(25 g soy protein) plus 0.5 mg estradiol 

(n=8); or (4) 38 g/day textured milk 

protein plus 0.5 mg estradiol(control) 

(n=7) in addition to their usual diet (Ref. 

168). The baseline TC levels in the 38 

g/day textured milk protein plus 1.0 mg 

estradiol group were significantly higher 

than the (25 g soy protein) plus 1.0 mg 

estradiol group. If the baseline 

cholesterol values between groups are 

significantly different, then it is difficult 

to determine if differences at the end of 

the study were due to the intervention 

or to differences observed at the 

beginning of the study (Ref. 1). Thus, we 

could not draw scientific conclusions 

from this arm of the study. For the soy 

protein group plus 0.5 mg estradiol and 

the textured milk protein plus 0.5 mg 

estradiol (control) groups, the baseline 

cholesterol levels were similar and 

conclusions could be drawn. However, 

there was no significant difference in 

blood TC and LDL cholesterol between 

the soy protein group plus 0.5 mg 

estradiol and the textured milk protein 

plus 0.5 mg estradiol control group. 

Jayagopal et al. (2002) was a 

randomized, double-blind, placebocontrolled, crossover trial of moderate 

quality in which 32 postmenopausal 

British women with type 2 diabetes 

consumed 30 g/day of isolated soy 

protein or 30 g/day of cellulose (control) 

in addition to their usual diet for a 

duration of 12 weeks each (Ref. 169). 

Blood TC and LDL cholesterol was 

significantly lower (P <0.05) in soy 

protein period compared to the 

cellulose period. 

Higashi et al. (2001) (trial one) was a 

randomized, controlled, crossover trial 

of moderate quality in which 14 

Japanese men consumed daily milk or 

yogurt only (no placebo) and 20 g/day 

soy protein isolate mixed in milk or 

yogurt in addition to their usual diet for 

a duration of 4 weeks each (Ref. 26). 

There was no significant difference in 

blood TC and LDL cholesterol between 

the soy protein period and the control 

period (milk or yogurt only). 

Teede et al. (2001) and Dalais et al., 

(2003) was a 3-month randomized, 

double-blind, placebo-controlled, 

parallel trial of moderate quality in 

which 179 Australian men and 

postmenopausal women consumed a 

casein placebo (n=93) or 40 g/day soy 

protein isolate (n=86) mixed with a 

beverage twice a day in addition to their 

usual diet (Ref. 170–171). There was no 

significant difference in blood TC and 

LDL cholesterol between the casein 

control group and soy protein isolate 

group. In a subgroup analysis of the 

postmenopausal women (n=55 casein 

and n=51 soy protein) by Dalais et al. 

(2003), there was no significant 

difference in blood TC between the 

casein control group and soy protein 

isolate group. However, blood LDL 

cholesterol was significantly (P <0.05) 

lower in the soy protein isolate group 

compared to the casein control group. 

Washburn et al. (1999) was a 

randomized, double-blind, placebocontrolled, crossover trial of moderate 

quality in which 42 perimenopausal 

American women consumed daily: (1) 

20 g/day complex carbohydrate 

supplement mixed with a beverage 

(control); (2) 20 g/day isolated soy 

protein (34 mg/day naturally occurring 

phytoestrogens) supplement mixed with 

a beverage as a single dose; and (3) 20 

g/day soy protein supplement (34 mg/ 

day naturally occurring phytoestrogens) 

mixed with beverages split into two 


ethrower on DSK3G9T082PROD with PROPOSALS
50332 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

equal doses in addition to their usual 

diets for 6 weeks each (Ref. 172). Blood 

TC and LDL cholesterol were 

significantly (P <0.05) lower in the soy 

protein groups compared to the control 

group. 

Gooderham et al. (1996) was a 28-day 

randomized, controlled, parallel trial of 

moderate quality in which 20 Canadian 

men consumed daily a supplement 

containing 60 g/day of soy protein 

isolate (n=10) or a supplement 

containing 60 g/day of casein (control) 

(n=10) in addition to their usual diet 

(Ref. 173). There was no significant 

difference in blood TC and LDL 

cholesterol between the soy protein 

isolate group and casein group. 

b. Studies in subjects with desirable or 

borderline cholesterol levels that were 

feeding studies or substitution studies 

with isolated soy protein. 

Mangano et al. (2013) was a 1-year, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 97 postmenopausal 

American women consumed: (1) 18 g/ 

day isolated soy protein plus 105 mg/ 

day isoflavone tablets (n=25); (2) 18 g/ 

day isolated soy protein plus placebo 

tablets (n=24); (3) 18 g/day control 

protein (casein, whey, and egg protein) 

plus 105 mg/day isoflavone tablets 

(n=26); or (4) control protein and 

placebo tablets (n=22) in a beverage or 

food. Subjects were counseled to reduce 

animal protein foods by approximately 

3 oz/day, which is an amount 

equivalent to the protein powder 

provided in the study (Ref. 174). There 

was no significant difference in blood 

TC or LDL cholesterol between any of 

the soy protein groups and the control 

groups. 

Steinberg et al. (2003) was a 

randomized, double-blind, controlled, 

crossover trial of moderate quality in 

which 28 postmenopausal American 

women consumed: (1) 25 g/day of 

isolated soy protein (107 mg/day 

naturally occurring isoflavones); (2) 25 

g/day of isolated soy protein depleted of 

isoflavones (2 mg/day isoflavones); and 

(3) 25 g/day total milk protein (control) 

for a duration of 6 weeks each (Ref. 

175). Subjects mixed the protein 

powders with a beverage and were 

instructed to incorporate the protein 

into their diet without increasing 

protein or energy intake. There was no 

significant difference in blood TC and 

LDL cholesterol between soy protein 

groups and milk protein control group. 

Bakhit et al. (1994) was a randomized, 

controlled, crossover trial of moderate 

quality in which 21 American men 

consumed muffins containing: (1) 25 g/ 

day isolated soy protein plus 20 g/day 

of dietary fiber from cellulose; (2) 25 g/ 

day isolated soy protein plus 20 g/day 

of soybean cotyledon fiber; (3) 25 g/day 

casein plus 20 g/day soybean cotyledon 

fiber (control); and (4) 25 g/day casein 

plus 20 g/day of dietary fiber from 

cellulose (control) for a duration of 4 

weeks each (Ref. 176). Subjects were 

counseled to incorporate the muffins 

into a low-fat, low-cholesterol diet. 

There were no significant differences 

between isolated soy protein groups and 

control groups for blood TC and LDL 

cholesterol. 

van Raaji et al. (1981) was a 4-week, 

controlled, parallel trial of moderate 

quality in which 69 Dutch men and 

women were fed an average Western 

diet with different types of dietary 

protein incorporated into specifically 

developed products. The dietary protein 

groups were: (1) 54 g/day of isolated soy 

protein (n=24); (2) 17 g/day soy 

(approximately a 2:1 mixture of 

casein:soy) (n=20); or (3) 55 g/day 

casein (control) (n=25) (Ref. 177). 

Participants were matched for initial 

serum cholesterol, energy intake, and 

sex. There was no significant difference 

in blood TC between the isolated soy 

protein groups and casein control group. 

However, blood LDL was significantly 

lower (P <0.05) in the isolated soy 

protein group compared to the casein 

control group. 

c. Studies in subjects with desirable or 

borderline cholesterol levels that added 

soy foods to the diet. 

Takatsuka et al. (2000) was a 60-day, 

randomized, controlled, parallel trial of 

moderate quality in which 52 

premenopausal Japanese women 

consumed approximately 16 g/day of 

soy protein from soy milk (n=27) in 

addition to their usual diet or followed 

their usual diet as a control diet (n=25) 

(Ref. 178). The control diet was a usual 

diet and therefore not a true placebo. 

The change in blood TC was 

significantly lower (P = 0.022) in the soy 

milk group compared to the control 

group. However, there was no 

significant difference in the change in 

blood LDL cholesterol between the two 

groups. 

Mitchell and Collins (1999) was a 4- 

week, randomized, controlled, parallel 

trial of moderate quality in which 10 

British men consumed: (1) One liter of 

soy milk (n=4); (2) one liter of rice milk 

(control) (n=3); or (3) one liter of semi 

skimmed cow’s milk (control) (n=3) in 

addition to their usual diets. There was 

no significant difference in blood TC 

between groups (Ref. 179). 

Murkies et al., (1995) was a 12-week 

randomized, double-blind, controlled 

parallel trial of moderate quality in 

which 47 postmenopausal Australian 

women consumed 45 g/day of wheat 

flour with an estimated 4.6 g/day wheat 

protein (control) (n=24) or 45 g/day soy 

flour with an estimated 15 g/day of soy 

protein (n=23) in addition to their usual 

diet (Ref. 180). There was no significant 

difference in blood TC between the two 

groups. 

d. Studies in subjects with desirable 

or borderline cholesterol levels that were 

feeding studies or substitution studies 

with soy foods. 

Matthan et al. (2007) was a 

randomized, controlled, crossover trial 

of moderate quality in which 28 

American subjects were fed four diets: 

(1) Animal protein (control), (2) soybean 

diet (∼37.5 g/day soy protein), (3) soy 

flour (∼37.5 g/day soy protein), and (4) 

and soy milk (∼37.5 g/day soy protein) 

for a duration of 6 weeks each (Ref. 

181). Blood LDL cholesterol was 

significantly lower (P <0.05) in the 

soymilk diet period compared to the 

animal protein diet period (control). 

However, there was no significant 

difference in blood TC between the 

soymilk diet period and the animal 

protein diet period. Furthermore, there 

was no significant difference in blood 

TC or LDL cholesterol between the 

animal protein diet period (control) and 

the soybean diet period or the soy flour 

diet period. 

Jenkins et al. (1989) was a controlled, 

crossover trial of moderate quality in 

which 11 obese Canadian women who 

consumed a low calorie diet (1,000 kcal) 

had 2 meals replaced by soy-based 

liquid formula made from soy flour and 

soy protein isolate, and a milk-based 

liquid formula for a duration of 4 weeks 

each. The soy formula provided 

approximately 17 g/day soy protein, and 

the cow’s milk formula provided 18 g/ 

day milk protein (control) (Ref. 182). 

There was no significant difference in 

blood TC and LDL cholesterol between 

the soy formula and the cow’s milk 

formula groups. 

Bosello et al. (1988) was a 75-day, 

controlled, parallel trial of moderate 

quality in which 24 obese Italian 

subjects were fed a very low calorie diet 

(375 kcal/day) for 15 days (Ref. 183). 

The very low calorie diets were then 

integrated with a commercial textured 

preparation that provided 

approximately 27 g/day of casein 

(control) or approximately 28 g/day soy 

protein that was consumed daily for 60 

days. The 60-day hypocaloric diet 

provided a total of 800 kcal/day (375 

kcal/day from the very low calorie diet 

and 425 kcal/day from commercial 

textured preparation). Blood TC and 

LDL cholesterol was significantly lower 

(P <0.01) after consuming the soy 

protein diet compared to the casein diet. 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50333 

e. Studies that include subjects with 

normal, borderline, and high cholesterol 

that were fed or substituted isolated soy 

protein in the diet. 

Greany et al. (2004) was a 

randomized, controlled, crossover trial 

of moderate quality in which 33 

postmenopausal American women 

consumed: (1) 26 g/day of soy protein 

isolate; (2) 26 g/day soy protein isolate 

plus probiotic capsules; (3) 26 g/day 

milk protein; and (4) 26 g/day milk 

protein plus probiotic capsules for a 

duration of 6 weeks each (Ref. 184). 

Subjects were counseled to substitute 

the protein powders in two divided 

doses for other protein containing foods 

in their diet. For the analysis, the soy 

protein and milk protein diets (control), 

with or without probiotics, were 

combined. Blood TC and LDL 

cholesterol was significantly lower (P 

<0.05) after consuming the soy protein 

isolate compared to the milk protein 

control period. 

Wong et al. (1998) was a randomized, 

controlled, crossover trial of high 

quality in which 13 American subjects 

with normal or borderline high 

cholesterol and 13 American subjects 

with high cholesterol consumed a 

National Cholesterol Education Program 

(NCEP) Step 1 soy protein diet that 

provided approximately 50 g/day 

isolated soy protein or an NCEP Step 1 

animal protein diet that provided 

approximately 50 g/day animal protein 

(control) for a duration of 5 weeks each 

(Ref. 185). Blood LDL cholesterol was 

significantly lower (P <0.05) after the 

soy protein period compared to the 

animal protein period for both the 

normal and borderline high subjects and 

high cholesterol subjects. However, 

there was no significant difference in 

blood TC between the soy protein diet 

and the control diet for both the normal 

and borderline high subjects and high 

cholesterol subjects. 

Goldberg et al. (1982) was a 

randomized, controlled, crossover trial 

of moderate quality in which 12 

American subjects with high cholesterol 

and 4 American subjects with normal or 

borderline high cholesterol consumed 

daily: (1) An animal protein diet 

(control); and (2) an isolated soy protein 

diet for a duration of 6 weeks each. The 

soy protein diet contained an estimated 

99 g/day of isolated soy protein (Ref. 

186). Blood TC and LDL cholesterol in 

the 12 subjects with high cholesterol 

was significantly lower (P <0.025) after 

the soy protein diet compared to the 

animal protein diet. However, there was 

no significant difference in blood TC 

and LDL between the two diets in the 

four subjects with normal or borderline 

high cholesterol. 

f. Studies in subjects with high 

cholesterol levels that added isolated 

soy protein to the diet. 

Hoie et al. (2007) was an 8-week, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 88 German subjects 

consumed: (1) 25 g/day of isolated soy 

protein in its native, non-denatured 

form (n=28); (2) 25 g/day of isolated soy 

protein (n=32); or (3) 25 g/day of milk 

protein (derived from caseinate and 

skimmed milk powder) (n=28) (control) 

in addition to their usual diets (Ref. 

187). Blood TC and LDL cholesterol was 

significantly lower (P <0.001 and P = 

0.002, respectively) after consuming the 

non-denatured isolated soy protein 

compared to milk protein group. Blood 

TC cholesterol was also significantly 

lower (P = 0.008) after consuming 

isolated soy protein compared to milk 

protein group. However, there was no 

significant difference for blood LDL 

cholesterol after consuming isolated soy 

protein compared to milk protein group. 

Hoie et al. (2006) was a 4-week, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 80 German subjects 

consumed daily: (1) Ultra-heat-treated 

chocolate-flavored milk containing 24.4 

g/day isolated soy protein and 30.4 g/ 

day milk protein (n=20); (2) 43.3 g/day 

milk protein (control) (n=20); (3) ultraheat-treated chocolate flavored milk 

containing 12.2 g/day isolated soy 

protein and 15.2 g/day milk protein 

(n=20); or (4) 21.7 g/day milk protein 

(control) (n=20) (Ref. 188). There was no 

significant difference in blood TC or 

LDL cholesterol between the group that 

consumed the ultra-heat-treated 

chocolate-flavored milk containing 24.4 

g/day isolated soy protein and 30.4 g/ 

day milk protein group and the control 

milk protein group. There was also no 

significant difference in blood TC and 

LDL cholesterol between the group that 

consumed ultra-heat-treated chocolateflavored milk containing 12.2 g/day soy 

protein and 15.2 g/day milk protein per 

day (n=20) or the control milk protein 

group. 

Hoie et al. (2005a) was an 8-week, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 77 German subjects 

consumed 25 g/day soy protein (n=39) 

or 25 g/day milk protein (derived from 

caseinate and skimmed milk powder) 

(control) (n=38) in addition to their 

usual diets (Ref. 189). Blood LDL 

cholesterol was significantly lower (P 

<0.05) in the soy protein group when 

compared to the casein group. There 

was no difference in blood TC between 

the soy protein group and casein group. 

Hoie et al. (2005b) was an 8-week, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 117 German subjects 

consumed: (1) 25 g/day soy protein 

(n=39); (2) 15 g/day soy protein plus 10 

g/day milk protein (derived from 

caseinate and skimmed milk powder) 

(n=39); or (3) 25 g/day milk protein 

(derived from caseinate and skimmed 

milk powder) (control) (n=39) in 

addition to their usual diets (Ref. 190). 

Blood LDL cholesterol was significantly 

lower (P = 0.002) after consumption of 

25 g/day soy protein compared to the 25 

g/day casein group. TC was also 

significantly lower (P = 0.002) after 

consumption of 25 g/day soy protein 

compared to the 25 g/day casein group. 

In the 15 g/day soy protein plus 10 g/ 

day casein group blood LDL cholesterol 

was significantly lower (P = 0.011) 

compared to 25 g/day casein control 

group. TC was also significantly lower 

(P = 0.001) after consumption of 15 g/ 

day soy protein plus 10 g/day casein 

compared to 25 g/day casein control 

group. 

Teede et al. (2005) was a 3-month, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 40 postmenopausal 

Australian women consumed 40 g/day 

isolated soy protein (n=19) or a casein 

placebo in addition to their usual diet 

(n=21) (Ref. 191). There was no 

significant difference in blood TC or 

LDL cholesterol between the soy protein 

and casein group. 

Harrison et al. (2004) was a 5-week, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 112 British men and 

women consumed foods (bread, cracker 

biscuits, and snack bars) that provided 

25 g/day isolated soy protein (n=59) or 

the same foods without soy protein as 

a control (n=53) in addition to their 

usual diet (Ref. 192). There was no 

significant difference in blood TC and 

LDL cholesterol between the soy protein 

and control groups. 

Blum et al. (2003) was a randomized, 

double-blind, placebo-controlled, 

crossover trial of moderate quality in 

which 24 postmenopausal Israeli 

women consumed 25 g/day milk protein 

(control) and 25 g/day isolated soy 

protein in addition to their usual diets 

for a duration of 6 weeks each (Ref. 

193). Blood TC and LDL cholesterol was 

significantly lower (P <0.05) after 

consuming soy protein isolate compared 

to milk protein period. 

Cuevas et al. (2003) was a 

randomized, double-blind, controlled, 

crossover trial of moderate quality in 

which 18 postmenopausal Chilean 

women consumed diets providing 40 g/ 


ethrower on DSK3G9T082PROD with PROPOSALS
50334 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

day caseinate (control) and 40 g/day 

isolated soy protein in addition to an 

NCEP Step 1 diet for a duration of 4 

weeks each (Ref. 194). There was no 

significant difference in blood TC and 

LDL cholesterol between the caseinate 

control diet and soy protein diet. 

Gardner et al. (2001) was a 12-week, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 94 postmenopausal 

American women consumed: (1) 42 g/ 

day total milk protein (control) (n=30); 

(2) 42 g/day isolated soy protein with 

isoflavones depleted (3 mg/day) (n=33); 

or (3) 42 g/day isolated soy protein (80 

mg/day naturally occurring isoflavones) 

(n=31) in addition to their usual diet 

(Ref. 195). There was no significant 

difference in blood TC or LDL 

cholesterol between the isolated soy 

protein groups and the total milk 

protein control group. 

Hori et al. (2001) was a 3-month, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 21 Taiwanese men 

consumed: (1) Casein hydrolysate (n=7); 

(2) 3 g/day of a crude type of soy protein 

hydrolysate (n=7); or (3) 6 g/day of a 

crude type of soy protein hydrolysate 

(n=7) in addition to their usual diet. 

Blood TC was significantly lower (P 

<0.05) after consuming 3 g/day of a 

crude type of soy protein hydrolysate 

group for 3 months compared to the 

casein hydrolysate control (Ref. 196). 

Blood TC was also significantly lower 

after consuming 6 g/day crude type of 

soy protein hydrolysate group after 2 

and 3 months compared to the casein 

hydrolysate control. Blood LDL 

cholesterol was significantly lower (P 

<0.05) after consuming 3 g/day of a 

crude type of soy protein hydrolysate 

group after 2 and 3 months compared to 

the casein hydrolysate control. Blood 

LDL cholesterol was also significantly 

lower (P <0.05) after consuming 6 g/day 

a crude type of soy protein hydrolysate 

group after 1, 2, and 3 months compared 

to the casein hydrolysate group. 

g. Studies in subjects with high 

cholesterol levels that were feeding or 

substitution studies with isolated soy 

protein. 

Chen et al. (2006) was a 12-week, 

randomized, double-blind, placebocontrolled, parallel trial of high quality 

in which 26 Taiwanese subjects on 

dialysis consumed daily their usual 

dialysis diet that incorporated 30 g/day 

milk protein (control) (n=13) or an 

isolated soy protein diet containing 30 

g/day soy protein (n=13) (Ref. 197). 

Blood TC was significantly lower (P 

<0.05) in the isolated soy protein diet 

compared to the milk protein control. 

There was no significant difference in 

blood LDL cholesterol between the milk 

protein control and isolated soy protein 

diet. 

Ma et al. (2005) was a 5-week, 

randomized, double-blind, controlled, 

parallel trial of moderate quality in 

which 159 American subjects consumed 

daily 28 g/day milk protein supplement 

(n=78) (control) or a 32 g/day isolated 

soy protein supplement (n=81) in a 

beverage. Subjects were counseled to 

modify their protein and carbohydrate 

intake to account for the protein 

supplement intake. There was no 

significant difference in blood TC and 

LDL cholesterol between the two diets 

(Ref. 198). 

West et al. (2005) and Hilpert et al. 

(2005) both discuss a randomized, 

double-blind, controlled, crossover trial 

of high quality in which 32 American 

subjects were fed an NCEP Step 1 diet 

that incorporated 25 g/day milk protein 

or 25 g/day soy protein isolate for a 

duration of 6 weeks each (Ref. 199–200). 

On each diet, 15 g of the protein 

supplement was consumed in a muffin 

while the remaining protein supplement 

was provided to the subjects to integrate 

into the meals provided. There was no 

significant difference in blood TC and 

LDL cholesterol between the milk 

protein and soy protein isolate diets. 

Jenkins et al. (2002 a and b) was a 

randomized, single-blind, controlled, 

crossover trial of moderate quality in 

which 41 Canadian men and women 

were fed an NCEP Step 2 diet in which 

the main protein containing foods were 

replaced with test foods made with: (1) 

Approximately 60 g/day dairy and egg 

protein; (2) 50 g/day of soy protein 

isolate (10 mg/day naturally occurring 

isoflavones); and (3) 50 g/day soy 

protein isolate (73 mg/day naturally 

occurring isoflavones) for a duration of 

1 month each (Ref. 201–202). The 

percent change in blood TC and LDL 

cholesterol was significantly lower (P 

<0.01) after consuming the soy protein 

diets compared to the dairy and egg 

protein diet (control). 

Lichtenstein et al. (2002) was a 

randomized, double-blind, controlled, 

crossover, feeding trial of moderate 

quality in which 42 American men and 

women consumed diets of: (1) Isolated 

soy protein depleted of isoflavones (25 

g soy protein/1,000 kcal); (2) isolated 

soy protein enriched with isoflavones 

(25 g soy protein plus 50 mg 

isoflavones/1,000 kcal); (3) animal 

protein with no added isoflavones (25 g 

animal protein/1,000 kcal); and (4) 

animal protein with added isoflavones 

(25 g animal protein and 50 mg 

isoflavones/1,000 kcal) for a duration of 

6 weeks each (Ref. 203). The mean soy 

intake for women was 55 g/day and 71 

g/day for men. The treatment effects for 

blood TC and LDL cholesterol were 

significantly lower (P = 0.017 and P = 

0.042, respectively) after consuming the 

soy protein diets compared to the 

animal protein diets. For 20 subjects 

with LCL–C >160 mg/dL, the treatment 

effects for blood TC and LDL–C were 

significantly lower (P <0.001 and P = 

0.003) after consuming the soy protein 

diets compared to the animal protein 

diets. These data were also reported in 

Wang et al., (2004) and Desroches et al., 

(2004) (Ref. 204–205). 

Van Horn et al. (2001) was a 6-week, 

randomized, controlled, parallel trial of 

high quality in which 126 

postmenopausal American women 

consumed an NCEP Step 1 diet in which 

they isocalorically substituted: (1) Oats 

and 29 g/day milk protein (n=31) 

(control); (2) wheat and 29 g/day 

isolated soy protein (n=31); (3) oats and 

29 g/day isolated soy protein (n=31); or 

(4) wheat and 29 g/day milk protein 

(n=32) (control) for other carbohydrates 

and dairy type foods (Ref. 206). There 

was no significant difference in blood 

TC or LDL cholesterol between the two 

control and the two soy protein diets. 

h. Studies in subjects with high 

cholesterol that added soy foods to the 

diet. 

Gardner et al. (2007) was a 4-week, 

randomized, single-blind, controlled, 

crossover trial of high quality in which 

28 American men and women 

consumed daily: (1) 1 percent cow’s 

milk (control); (2) whole bean soy milk; 

and (3) soy protein isolate milk, in 

addition to an American Heart 

Association diet (Ref. 207). The whole 

bean soy milk and the soy protein 

isolate milk provided 25 g/day of soy 

protein, and the 1 percent cow’s milk 

provided 25 g/day of milk protein. 

Blood LDL cholesterol was a 

significantly lower (P = 0.02) after 

consuming whole bean soy milk when 

compared to 1 percent cow’s milk. 

Blood LDL cholesterol was also 

significantly lower (P = 0.02) after 

consuming the soy protein diet 

compared to the 1 percent cow’s milk 

diet. 

i. Study in subjects with high 

cholesterol that were fed soy foods. 

Jenkins et al. (2000) was a 

randomized, controlled, crossover trial 

of moderate quality in which 25 

Canadian men and women consumed 

daily an NCEP Step 2 diet that 

incorporated: (1) A commercial 

breakfast cereal containing 8 g/day 

wheat protein (control); and (2) a 

breakfast cereal made with 70 percent 

soy flour that provided 36 g/day soy 

protein for a duration of 3 weeks each 

(Ref. 208). There was no significant 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50335 

difference between the wheat protein 

cereal (control) period and soy flour 

cereal diet period for blood TC and LDL 

cholesterol. 

2. Intervention Studies That Examined 

Soy Protein Intake and Systolic Blood 

Pressure (SBP) or Diastolic Blood 

Pressure (DBP) 

Twenty-eight studies, described in 30 

publications, either substituted soy 

protein in the diet or were feeding 

studies. These studies did not control 

for or provide information on sodium 

and potassium intake in the diet (Ref. 

44, 55, 66, 74, 77, 84, 91, 96–97, 99, 114, 

116, 123, 125–126, 131–132, 139–140, 

144, 149–151, 153–154, 181, 201–202, 

208–209). Because sodium and 

potassium intake also influence blood 

pressure, the independent effects of soy 

protein intake and blood pressure could 

not be determined. Therefore, we could 

not draw scientific conclusions about 

the relationship between soy protein 

consumption and risk of CHD from 

these studies. 

Four studies did not include an 

appropriate control protein for a 

comparison of the relative effects of soy 

protein (Ref. 40, 42, 210–211). Without 

an appropriate control group, it cannot 

be determined if the changes in SBP or 

DBP were due to soy protein intake or 

uncontrolled, extraneous factors. 

Therefore, we could not draw scientific 

conclusions about the relationship 

between soy protein consumption and 

risk of CHD from these studies. 

Chiechi et al. (2002) was a 6-month, 

randomized, parallel trial in which 67 

subjects with pre-hypertension (SBP 120 

to 139 mmHg or DBP 80 to 89 mmHg) 

consumed their usual diet (n=43) or 

their usual diet plus a soy food serving 

each day (e.g. soy milk, miso soup, tofu, 

tempeh, or soy beans) (n=34) (Ref. 142). 

Subjects in the soy group also 

exchanged two meals twice a week with 

two meals from a study menu that was 

based on traditional Mediterranean 

recipes and soy or soy products. 

Approximately 50 percent of subjects in 

the soy group dropped out of the study 

compared to 20 percent in the control 

group. Therefore, the dropout rate in the 

treatment group makes the results of 

this study difficult to interpret. A high 

dropout rate can introduce bias because 

it changed the number of subjects in the 

treatment group and may also have 

changed the group’s composition 

compared to the control group. In 

addition to a high dropout rate, the 

study had other quality issues (e.g., 

information on study blinding was not 

reported, adequate descriptions were 

not provided for the composition of the 

background diets or the amount of soy 

protein in the diets), the study measured 

biomarkers (SBP or DBP) instead of 

clinical outcomes (e.g., incidence of 

CHD). Therefore, this study is so 

deficient in methodological quality that 

it is considered to be of low-quality 

design (Ref. 1) and, as a result, we could 

not draw scientific conclusions 

regarding the relationship between soy 

protein intake and reduced risk of CHD. 

a. Studies in subjects with normal or 

pre-hypertension (SBP <139 mmHg or 

DBP <89 mmHg). 

Anderson et al. (2007) was a 16-week, 

randomized, single-blind, controlled, 

parallel trial of moderate quality in 

which 35 obese American women with 

pre-hypertension (SBP 120 to 139 

mmHg or DBP 80 to 89 mmHg) were fed 

daily 3 meal replacement shakes 

containing approximately 22 g/day of 

casein (control) (n=18) or 21 g/day 

isolated soy protein (n=17) each (Ref. 

89). There was no significant difference 

in SBP or DBP between the casein and 

soy protein diet. 

Azadbakht et al. (2007) was a 

randomized, controlled, crossover trial 

of moderate quality in which 42 

postmenopausal Iranian women with 

pre-hypertension (SBP 120 to 139 

mmHg or DBP 80 to 89 mmHg) 

consumed daily: (1) A Dietary 

Approaches to Stop Hypertension 

(DASH) control diet; (2) a 30 g/day soy 

protein diet; and (3) a 30 g/day soy nut 

diet for a duration of 8 weeks each (Ref. 

65). The soy protein and soy nut diets 

were the same as the DASH diet with 

soy protein and soy nuts being 

substituted for red meat for the control 

diet. There was no significant difference 

in SBP or DBP between the DASH 

control diet and the soy protein and soy 

nut diets. 

Evans et al. (2007) was a randomized, 

double-blind, placebo-controlled, 

crossover trial of moderate quality in 

which 22 pre-hypertensive (SBP 120 to 

139 mmHg or DBP 80 to 89 mmHg), 

postmenopausal American women 

consumed: (1) 25 g/day isolated soy 

protein plus 20 g/day soy lecithin; (2) 25 

g/day isolated soy protein plus placebo 

lecithin; (3) placebo protein (50:50 

calcium/sodium caseinate) and 20 g/day 

soy lecithin; and (4) double placebo 

(protein placebo and soy lecithin) in 

addition to their usual diet for a 

duration of 4 weeks each (Ref. 162). 

There was no significant difference in 

SBP or DBP between the soy protein 

plus placebo lecithin group and the 

double placebo group (control) or 

between the soy protein plus soy 

lecithin group and the placebo protein 

plus soy lecithin period (control). 

Harrison et al. (2004) was a 5-week, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 112 British men and 

women with pre-hypertension (SBP 120 

to 139 mmHg or DBP 80 to 89 mmHg) 

consumed foods (bread, cracker biscuits, 

and snack bars) that provided 25 g/day 

isolated soy protein (n=59) or the same 

foods without soy protein as a control 

(n=53) in addition to their usual diet 

(Ref. 192). There was no significant 

difference in SBP and DBP between the 

soy protein and control groups. 

Cuevas et al. (2003) was a 

randomized, double-blind, controlled, 

crossover trial of moderate quality in 

which 18 pre-hypertensive (SBP 120 to 

139 mmHg or DBP 80 to 89 mmHg) 

postmenopausal Chilean women 

consumed diets providing 40 g/day 

caseinate (control) or 40 g/day isolated 

soy protein in addition to an NCEP Step 

1 diet for a duration of 4 weeks each 

(Ref. 194). There was no significant 

difference in SBP or DBP between the 

soy protein diet and caseinate control 

diet. 

Teede et al. (2001) was a 3-month 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 179 pre-hypertensive 

(SBP 120 to 139 mmHg or DBP 80 to 89 

mmHg) Australian men and 

postmenopausal women consumed a 

casein placebo (n=93) or 40 g/day soy 

protein isolate mixed with a beverage 

twice a day (n=86) in addition to their 

usual diet (Ref. 170). SBP was 

significantly lower (P <0.05) in the soy 

protein isolate group compared to 

casein control group. However, there 

was no significant difference in DBP 

between the casein control group and 

soy protein isolate group. 

Washburn et al. (1999) was a 

randomized, double-blind, placebocontrolled, crossover trial of moderate 

quality in which 42 pre-hypertensive 

(SBP 120 to 139 mmHg or DBP 80 to 89 

mmHg), perimenopausal American 

women consumed: (1) A complex 

carbohydrate supplement (20 g/day) 

mixed with a beverage (control); (2) 20 

g/day isolated soy protein supplement 

mixed with a beverage as a single dose; 

and (3) 20 g/day soy protein supplement 

mixed with beverages split into two 

equal doses in addition to their usual 

diet for a duration of 6 weeks each (Ref. 

172). There was no difference in SBP or 

DBP between the soy protein 

supplement mixed with a beverage as a 

single dose period and the complex 

carbohydrate control period. However, 

SBP and DBP were significantly lower 

(P <0.05) after consuming the 20 g/day 

soy protein supplement mixed with 

beverages split into two equal doses 

compared to the complex carbohydrate 

supplement. 


ethrower on DSK3G9T082PROD with PROPOSALS
50336 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

b. Studies in normotensive or prehypertensive (SBP <39 mmHg or DBP 

<89 mmHg) and hypertensive subjects 

(SBP ≥140 mmHg or DBP ≥90 mmHg). 

He et al. (2005) was a 12-week, 

randomized, double-blind, parallel trial 

of moderate quality in which 276 

Chinese men and women with prehypertension (SBP 120 to 139 mmHg or 

DBP 80 to 89 mmHg) or hypertension 

(SBP ≥140 mmHg or DBP ≥90 mmHg) 

consumed cookies containing 40 g/day 

complex carbohydrates from wheat 

(n=139) (control) or cookies with 40 g/ 

day isolated soy protein (n=137) (Ref. 

212). Subjects were instructed to reduce 

other food intake to keep total energy 

intake constant. Most subjects 

consumed the cookies in place of their 

usual breakfast or usual lunch. SBP and 

DBP were significantly (P <0.001) lower 

for those who consumed the soy protein 

cookies compared to the wheat cookies 

(control). 

Sagara et al. (2004) was a 5-week 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 50 Scottish men with 

pre-hypertension (SBP 120 to 139 

mmHg or DBP 80 to 89 mmHg) or 

hypertension (SBP ≥140 mmHg or DBP 

≥90 mmHg) consumed 20 g/day of 

isolated soy protein powder in biscuits, 

cereal bars, and bread rolls (n=25) or 

biscuits, cereal bars, and bread rolls 

without added soy protein in addition 

to their usual diets (n=25) (Ref. 166). 

There was no significant difference in 

SBP or DBP between the soy protein and 

control group. 

c. Studies in hypertensive subjects 

(SBP ≥140 mmHg or DBP ≥90 mmHg). 

Webb et al. (2008) was a 5-day, 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 25 hypertensive (SBP 

≥140 mmHg or DBP ≥90 mmHg) British 

men and women with CHD consumed 

25.7 g/day soy protein isolate (n=13) or 

25.7 g/day milk protein isolate (n=12) in 

addition to their usual diets (Ref. 60). 

There was no significant difference in 

SBP or DBP between the soy protein 

isolate group and the control milk 

protein isolate group. 

Jayagopal et al. (2002) was a 

randomized, double-blind, placebocontrolled, crossover trial of moderate 

quality in which 32 hypertensive (SBP 

≥140 mmHg or DBP ≥90 mmHg) 

postmenopausal British women with 

type 2 diabetes consumed 30 g/day of 

isolated soy protein or 30 g/day of 

cellulose (control) in addition to their 

usual diet for a duration of 12 weeks 

each (Ref. 169). There was no significant 

difference in SBP and DBP between the 

control diet and the soy protein diet. 

Rivas et al. (2002) was a 3-month 

randomized, double-blind, placebocontrolled, parallel trial of moderate 

quality in which 40 hypertensive (SBP 

≥140 mmHg or DBP ≥90 mmHg) Spanish 

men and women consumed daily 1 liter 

of soy milk (18 g/day soy protein) or 1 

liter of cow’s milk (15.5 g/day protein) 

in addition to their usual diet (Ref. 213). 

SBP and DBP was significantly lower (P 

<0.0001) in the soy milk group 

compared to the cow’s milk group. 

D. Assessment of Observational Studies 

FDA identified 11 observational 

studies that evaluated soy protein and 

CHD risk (Ref. 214–224). All of these 

observational studies calculated soy 

protein intake from estimated dietary 

intake. In observational studies that 

calculated nutrient intake from 

conventional foods, measures of soy 

protein intake were based on recorded 

dietary intake methods such as food 

frequency questionnaires, diet recalls, or 

diet records, in which the type and 

amount of foods consumed were 

estimated. A common weakness of 

observational studies is the limited 

ability to ascertain the actual food or 

nutrient intake for the population 

studied as a result of poor memory, 

over- or underestimation of portion 

sizes, and recall bias (Ref. 225). 

Furthermore, the nutrient content of 

foods can vary due to a number of 

factors, including soil composition, food 

processing and cooking procedures, and 

storage conditions (e.g., duration, 

temperature). Thus, we cannot ascertain 

an accurate amount of soy protein 

consumed based merely on subjects’ 

reports of dietary intake of foods. 

In addition, soy foods contain not 

only soy protein, but also other 

nutrients that may be associated with 

the metabolism of soy protein or the 

pathogenesis of CHD. Therefore, 

because soy protein containing foods 

consist of many nutrients and 

substances, it is difficult to study the 

nutrient or food components in isolation 

(Ref. 3). For studies based on recorded 

dietary intake of such foods, it is not 

possible to accurately determine 

whether any observed effects of soy 

protein on coronary heart disease risk 

were due to: (1) Soy protein alone; (2) 

interactions between soy protein and 

other nutrients; (3) other nutrients 

acting alone or together; or (4) decreased 

consumption of other nutrients or 

substances contained in foods displaced 

from the diet by the increased intake of 

soy protein containing foods. In some 

instances, epidemiological studies based 

on the recorded dietary intake of 

conventional foods may indicate a 

benefit for a particular nutrient with 

respect to a disease; however, it is 

subsequently demonstrated in an 

intervention study that the nutrientcontaining dietary supplement does not 

confer a benefit or actually increases 

risk of the disease (Ref. 226). For 

example, previous epidemiological 

studies reported an association between 

fruits and vegetables high in betacarotene and a reduced risk of lung 

cancer (Ref. 227). However, subsequent 

intervention studies, the AlphaTocopherol and Beta Carotene 

Prevention Study (ATBC) and the 

Carotene and Retinol Efficiency Trial 

(CARET), demonstrated that betacarotene supplements increase the risk 

of lung cancer in smokers and asbestosexposed workers, respectively (Ref. 

228–229). These studies illustrate that 

the effect of a nutrient provided as a 

dietary supplement exhibits different 

health effects compared to when it is 

consumed as part of a usual diet among 

many other food components. 

Furthermore, these studies demonstrate 

the potential public health risk of 

relying on results from epidemiological 

studies in which the effect of a nutrient 

is based on recorded dietary intake of 

conventional foods as the sole source for 

concluding that a relationship exists 

between a specific nutrient and disease 

risk (i.e., the effect could actually be 

harmful). 

For the reasons provided in this 

section, scientific conclusions cannot be 

drawn from observational studies on 

foods for soy protein as a food 

ingredient or component of food. 

VI. Strength of the Scientific Evidence 

In evaluating the scientific evidence 

using our evidence-based review system 

(Ref. 1), we considered the strength of 

evidence for a relationship between soy 

protein intake and reduced risk of CHD. 

When evaluating the strength of the 

evidence, we consider study types, 

methodological quality, quantity of 

evidence for and against the claim 

(taking into account the numbers of 

various types of studies and study 

sample sizes), relevance to the U.S. 

population or target subgroup, 

replication of study results supporting 

the claim, and overall consistency of the 

evidence (beneficial effect, no effect) 

(Ref. 1). For the outcome of an 

intervention study to demonstrate an 

effect, the validated surrogate or clinical 

endpoint evaluated in the intervention 

group should be statistically 

significantly different from the same 

validated surrogate or clinical endpoint 

evaluated in the control group (P <0.05). 

After assessing the totality of the 

scientific evidence, we then determine 

whether there is SSA to support an 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50337 

authorized health claim, or credible 

evidence to support a qualified health 

claim. 

Our decision about whether to 

authorize a health claim represents our 

determination as to whether there is 

significant scientific agreement among 

qualified experts that the publicly 

available scientific evidence supports 

the substance/disease relationship that 

is the subject of a proposed health 

claim. The SSA standard is intended to 

be a strong standard that provides a high 

level of confidence in the validity of the 

substance/disease relationship. SSA 

occurs well after the stage of emerging 

science, where data and information 

permit an inference, but does not 

require consensus based on unanimous 

and incontrovertible scientific opinion. 

We explained in our 2009 guidance 

(Ref. 1) that we may evaluate new 

information that becomes available to 

determine whether it necessitates a 

change to an existing SSA claim to 

maximize the public health benefit of 

our health claims review. The 2009 

guidance represents our current 

thinking on the meaning of the SSA 

standard in section 403(r)(3) of the 

FD&C Act and § 101.14(c) and the 

process for evaluating the scientific 

evidence for a health claim pursuant to 

these authorities. 

As noted in section V, we reevaluated, 

consistent with the 2009 guidance (Ref. 

1), the studies included in the 1999 final 

rule as well as new studies that were 

published since the original review. As 

discussed in section V.C and D, the 

totality of the scientific evidence 

includes 58 well-designed, wellexecuted intervention studies. Of these 

58 studies, 46 are intervention studies of 

high or moderate quality that measured 

blood TC or LDL cholesterol, and 12 are 

intervention studies of high or moderate 

quality that measured SBP or DBP. The 

results of these studies were 

inconsistent and not conclusive. 

Of the 46 studies intervention studies 

of high or moderate quality that 

measured blood TC or LDL cholesterol, 

25 studies were conducted on subjects 

with desirable or borderline cholesterol 

levels, defined as a blood TC less than 

240 mg/dL or LDL cholesterol less than 

160 mg/dL; 18 were conducted on 

subjects with high TC levels, defined as 

TC levels less than 240 mg/dL or LDL 

cholesterol greater than or equal to 160 

mg/dL; and 3 studies included subjects 

with desirable or borderline TC levels 

and subjects with high TC levels. Of the 

46 intervention studies that looked at 

the relationship between blood TC and/ 

or LCL cholesterol and soy protein 

intake, only 19 intervention studies 

showed a benefit in significantly 

reducing the risk of CHD, while the 

other 27 intervention studies did not. 

Study findings also were inconsistent 

regardless of whether soy protein was 

added to diet as a supplement or 

whether the studies were substitution or 

feeding studies. The study findings also 

were inconsistent regardless of the 

study size (10 subjects to 179 subjects) 

or the dose of soy protein (3 g to 92 g/ 

day). Of the 12 high or moderate quality 

intervention studies that measured SBP 

or DBP from which a conclusion could 

be drawn, only 4 showed a benefit in 

lowering SBP or DBP with soy protein 

consumption, while the other 8 studies 

did not show a benefit. Again, the study 

findings were inconsistent regardless of 

baseline SBP or DBP, study size (18 

subjects to 276 subjects), or dose (18 g 

to 60 g/day). Consistency of findings 

among similar and different study 

designs is important for evaluating 

causation and the strength of scientific 

evidence (Ref. 1). The totality of the 

evidence does not provide a basis on 

which experts would find SSA because 

of the high degree of inconsistency of 

findings across similar and different 

studies with high or moderate 

methodological quality. This degree of 

inconsistency would not be seen when 

SSA exists because, when there is SSA, 

we would find most of the studies to 

consistently find a beneficial 

relationship between a substance and a 

disease risk. 

Although there is some evidence that 

suggests a relationship between soy 

protein intake and reduced risk of CHD, 

the strength of the totality of the current, 

publicly available scientific evidence, 

discussed in sections V and VI and the 

references cited therein, which includes 

many studies that post-date the 

publication of our 1999 rule, is 

inconsistent and not conclusive. See 

also tables 4–8 in Ref. 230. The 

additional evidence now available to us 

includes a number of new studies that 

do not support the relationship, and a 

number of studies that are inconclusive 

that also do not support a relationship. 

This combined body of evidence 

represents the totality of the scientific 

evidence that is currently available. We 

have now evaluated this entire body of 

evidence, which consists of the studies 

in the 1999 rule as well as new evidence 

published since that time, using the 

evidence based process described in our 

2009 guidance. The totality of the 

evidence, which includes the new, nonsupportive studies, does not support the 

statutory standard for authorizing a 

health claim. We have determined that 

the totality of the scientific evidence 

does not provide significant scientific 

agreement, among experts qualified by 

scientific training and experience to 

evaluate such claims, that the claim is 

supported. Therefore, we have 

tentatively concluded that, currently, 

there is not significant scientific 

agreement among experts, under section 

403(r)(3)(B)(i) of the FD&C Act, that a 

health claim about a relationship 

between soy protein intake and CHD 

risk is supported by the evidence. We 

request comment and any supporting 

data and information concerning this 

tentative conclusion. However, while 

the totality of the publicly available 

scientific evidence does not support a 

finding of SSA, if, when we finalize this 

rule, we conclude there is not SSA, but 

there is some credible evidence for the 

use of a qualified health claim about the 

relationship between soy protein and a 

reduced risk of CHD, we intend to issue 

a statement of enforcement discretion 

for the use of a qualified health claim. 

In the 1999 soy protein final rule 

authorizing the use of a health claim 

regarding soy protein and the risk of 

CHD (64 FR 57700) (now codified at 

§ 101.82) (the 1999 authorized soy 

protein health claim), the petitioner 

determined that use of soy as a dietary 

protein is generally recognized as safe. 

Under the health claim petition process, 

we evaluate whether the proponent of 

the claim demonstrates, to FDA’s 

satisfaction, that the food ingredient is 

‘‘safe and lawful’’ under the applicable 

food safety provisions of the FD&C Act. 

In the 1999 soy protein final rule, we 

concluded that there was not sufficient 

evidence to challenge the petitioner’s 

assertion that soy protein ingredients 

are GRAS. The petitioner met the 

showing required by § 101.14(b)(3)(ii) 

that the substance be ‘‘safe and lawful.’’ 

We have reviewed the scientific 

evidence relative to the safety of soy 

protein as a food ingredient and the 

evidence does not change our previous 

conclusion that the use of soy protein at 

the levels necessary to justify a claim 

has been demonstrated, to our 

satisfaction, to be safe and lawful under 

the applicable food safety provisions of 

the FD&C Act. 

VII. Proposal To Revoke § 101.82 

As discussed above, FDA may 

reevaluate the science related to an 

authorized health claim and may take 

action to revoke the claim (see section 

403(r)(7)(B) of the FD&C Act (21 U.S.C. 

343(r)(7)(B)). Based on our review of the 

totality of the publicly available 

scientific evidence, we have tentatively 

concluded that the SSA standard is not 

met for a relationship between soy 

protein and reduced risk of CHD. 

Therefore, we are proposing to revoke 


ethrower on DSK3G9T082PROD with PROPOSALS
50338 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

the soy protein and reduced risk of CHD 

health claim in § 101.82. 

VIII. Economic Analysis of Impacts 

We have examined the impacts of the 

proposed rule under Executive Order 

12866, Executive Order 13563, 

Executive Order 13771, the Regulatory 

Flexibility Act (5 U.S.C. 601–612), and 

the Unfunded Mandates Reform Act of 

1995 (Pub. L. 104–4). Executive Orders 

12866 and 13563 direct Agencies to 

assess all costs and benefits of available 

regulatory alternatives and, when 

regulation is necessary, to select 

regulatory approaches that maximize 

net benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). 

Executive Order 13771 requires that the 

costs associated with new regulations 

shall ‘‘be offset by the elimination of 

existing costs associated with at least 

two prior regulations.’’ It has been 

determined that this proposed rule is an 

action that does not impose more than 

de minimis costs as described below 

and thus is not a regulatory or 

deregulatory action for purposes of 

Executive Order 13771. This proposed 

rule is a significant regulatory action 

under Executive Order 12866. 

The Regulatory Flexibility Act 

requires Agencies to analyze regulatory 

options that would minimize any 

significant impact of a rule on small 

entities. Because up to 40 small 

businesses could be required to relabel 

one or more products, we find that the 

proposed rule may have a significant 

economic impact on a substantial 

number of small entities. 

Section 202(a) of the Unfunded 

Mandates Reform Act of 1995 requires 

that Agencies prepare a written 

statement, which includes an 

assessment of anticipated costs and 

benefits, before proposing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $148 

million, using the most current (2016) 

Implicit Price Deflator for the Gross 

Domestic Product. This proposed rule 

would not result in any year 

expenditure that meets or exceeds this 

amount. 

The costs of this rule are relabeling 

the estimated 200 to 300 products 

currently making the health claim. We 

estimate total annualized costs of 

$35,000 to $81,000, when the relabeling 

costs are annualized over 20 years at a 

7-percent discount rate. The initial, onetime costs are $370,000 to $860,000. 

The benefit of this rule is better 

information for the consumers who are 

considering purchasing products with 

soy protein. This may generate an 

unknown amount of increased 

consumer surplus. Some consumers 

may react to this new information by 

switching their consumption to 

products that they enjoy more, or 

products that still have an authorized 

health claim. We request public 

comment on how many consumers are 

likely to react to the changes in health 

claims caused by this proposed rule, 

and what the nature of their reaction 

will be. By basing their consumption 

decisions on more recent and accurate 

scientific information, they will get 

more consumer surplus, in the form of 

enjoyment and/or potential health 

benefits, from the bundle of products 

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 

the proposed rule performed in 

accordance with Executive Order 12866, 

Executive Order 13563, the Regulatory 

Flexibility Act, and the Unfunded 

Mandates Reform Act is available at 

https://www.regulations.gov under the 

docket number for this proposed rule 

and at: https://www.fda.gov/AboutFDA/ 

ReportsManualsForms/Reports/ 

EconomicAnalyses/default.htm. 

IX. Proposed Effective Date 

We intend that the effective date for 

a final rule resulting from this 

rulemaking be 30 days after the final 

rule’s date of publication in the Federal 

Register. 

With respect to a compliance date, we 

intend that any adjustments to a 

product’s labeling occur in a manner 

consistent with our uniform compliance 

date (see 81 FR 85156, November 25, 

2016). Thus, if we issue a final rule 

before December 31, 2018, then the 

compliance date would be January 1, 

2020. 

X. Analysis of Environmental Impact 

We have determined under 21 CFR 

25.32(p) that this action, revoking a 

health claim, is categorically excluded 

from an environmental assessment or an 

environmental impact statement. 

XI. Paperwork Reduction Act of 1995 

FDA tentatively concludes that this 

proposed rule contains no collection of 

information. Therefore, clearance by the 

Office of Management and Budget under 

the Paperwork Reduction Act of 1995 is 

not required. 

XII. Federalism 

FDA has analyzed this proposed rule 

in accordance with the principles set 

forth in Executive Order 13132. Section 

4(a) of the Executive order requires 

Agencies to ‘‘construe * * * a Federal 

statute to preempt State law only where 

the statute contains an express 

preemption provision or there is some 

other clear evidence that the Congress 

intended preemption of State law, or 

where the exercise of State law conflicts 

with the exercise of Federal authority 

under the Federal statute.’’ Federal law 

includes an express preemption 

provision that preempts ‘‘any 

requirement respecting any claims of 

the type described in [21 U.S.C. 

343(r)(1)] made in the label or labeling 

of food that is not identical to the 

requirement of [21 U.S.C. 343(r)] 

* * *.’’ 21 U.S.C. 343–1(a)(5). However, 

the statutory provision does not 

preempt any State requirement 

respecting a statement in the labeling of 

food that provides for a warning 

concerning the safety of the food or 

component of the food (Pub. L. 101–535, 

section 6, 104 Stat. 2353 (1990)). If this 

proposed rule is made final, the final 

rule would revoke the health claim 

related to soy protein and coronary 

heart disease in the label or labeling of 

food under 21 U.S.C. 343(r). 

XIII. References 

The following references are on 

display in the Dockets Management 

Staff (see ADDRESSES) and are available 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50339 

for viewing by interested persons 

between 9 a.m. and 4 p.m., Monday 

through Friday; they are also available 

electronically at https://

www.regulations.gov. FDA has verified 

the Web site addresses, as of the date 

this document publishes in the Federal 

Register, but Web sites are subject to 

change over time. 

1. U.S. Food and Drug Administration. 

‘‘Guidance for Industry: Evidence-Based 

Review System for the Scientific 

Evaluation of Health Claims‘‘, January 

2009. Retrieved from: http://

www.fda.gov/food/guidanceregulation/ 

guidancedocumentsregulatory

information/labelingnutrition/ 

ucm073332.htm. 

2. Balk E.C.M., Chew P, Ip S, Raman G, 

Kupelnick B, Tatsioni A, Sun Y, Wolk B, 

DeVine D, Lau J. ‘‘Effects of Soy on 

Health Outcomes. Summary, Evidence 

Report/Technology Assessment No. 126. 

(Prepared by the Tufts-New England 

Medical Center Evidence-Based Practice 

Center under Contract No. 290–02– 

0022.)‘‘, AHRQ Publication No. 05– 

E024–1 July 2005. 

3. Sempos C.T., Liu K., Ernst N.D. ‘‘Food and 

Nutrient Exposures: What to Consider 

When Evaluating Epidemiologic 

Evidence’’. American Journal of Clinical 

Nutrition. 1999;69:1330S–1338S. 

4. Institute of Medicine (IOM) of the National 

Academies. ‘‘Dietary Supplements: A 

Framework for Evaluating Safety, 

Chapter 7, Categories of Scientific 

Evidence—in Vitro Data.‘‘, Washington, 

DC; 2005. 

5. Spilker B. Guide to Clinical Studies. New 

York, New York: Raven Press, 1991; pp. 

59–64, 497–501, 793–800. 

6. National Research Council. Reference 

Manual on Scientific Evidence: Third 

Edition. Washington, DC: The National 

Academies Press, 2011; pp. 220. 

7. Wilson E.B. An Introduction to Scientific 

Research. New York: Dover Publications, 

1990; pp. 46–48. 

8. Hill A.B. ‘‘The Environment and Disease: 

Association or Causation?’’. Proceedings 

of the Royal Society of Medicine. 

1965;58:295–300. 

9. Agency for Healthcare Research and 

Quality. ‘‘Systems to Rate the Scientific 

Evidence’’, March 2002. 

10. Institute of Medicine (IOM) of the 

National Academies. ‘‘Dietary Reference 

Intakes for Energy, Carbohydrate, Fiber, 

Fat, Fatty Acids, Cholesterol, Protein, 

and Amino Acids (Macronutrients), 

Chapter 8: Dietary Fats: Total Fat and 

Fatty Acids’’, Washington, DC: National 

Academies Press; 2002. 

11. Institute of Medicine (IOM) of the 

National Academies. ‘‘Dietary Reference 

Intakes for Energy, Carbohydrate, Fiber, 

Fat, Fatty Acids, Cholesterol, Protein, 

and Amino Acids (Macronutrients), 

Chapter 9: Cholesterol’’, Washington, 

DC: National Academies Press; 2002. 

12. Institute of Medicine (IOM) of the 

National Academies. ‘‘Dietary Reference 

Intakes for Energy, Carbohydrate, Fiber, 

Fat, Fatty Acids, Cholesterol, Protein, 

and Amino Acids (Macronutrients), 

Chapter 7: Dietary, Functional, and Total 

Fiber’’, Washington, DC: National 

Academies Press; 2002. 

13. U.S. Department of Agriculture. ‘‘Soy 

Milk’’, USDA National Nutrient Database 

for Standard Reference, release 28, 2016. 

Retrieved from: https://

ndb.nal.usda.gov/ndb/. 

14. U.S. Department of Agriculture. ‘‘Soy 

Flour’’, USDA National Nutrient 

Database for Standard Reference, release 

28, 2016. Retrieved from: https://

ndb.nal.usda.gov/ndb/. 

15. U.S. Department of Agriculture. ‘‘Soy 

Protein Isolate’’, USDA National Nutrient 

Database for Standard Reference, release 

28, 2016. Retrieved from: https://

ndb.nal.usda.gov/ndb/. 

16. Institute of Medicine (IOM) of the 

National Academies. ‘‘Dietary Reference 

Intakes for Water, Potassium, Sodium, 

Chloride, and Sulfate’’, Washington, DC: 

National Academies Press; 2005. 

17. Persky V.W., Turyk M.E., Wang L., Freels 

S., Chatterton R., Jr., Barnes S., Erdman 

J., Jr., Sepkovic D.W., Bradlow H.L., 

Potter S. ‘‘Effect of Soy Protein on 

Endogenous Hormones in 

Postmenopausal Women’’. American 

Journal of Clinical Nutrition. 

2002;75:145–153. 

18. Siefker K., DiSilvestro R.A. ‘‘Safety and 

Antioxidant Effects of a Modest Soy 

Protein Intervention in Hemodialysis 

Patients’’. Journal of Medicinal Food. 

2006;9:368–372. 

19. Tormala R.M., Nikander E., Tiitinen A., 

Vaisanen-Tommiska M., Ylikorkala O., 

Mikkola T.S. ‘‘Serum Cholesterol Efflux 

Potential in Postmenopausal Women 

Treated with Isolated Isoflavones’’. 

Menopause. 2006;13:96–101. 

20. Wiseman H., O’Reilly J.D., Adlercreutz 

H., Mallet A.I., Bowey E.A., Rowland 

I.R., Sanders T.A. ‘‘Isoflavone 

Phytoestrogens Consumed in Soy 

Decrease F(2)-Isoprostane Concentrations 

and Increase Resistance of Low-Density 

Lipoprotein to Oxidation in Humans’’. 

American Journal of Clinical Nutrition. 

2000;72:395–400. 

21. Hill S., Box W., DiSilvestro R.A. 

‘‘Moderate Intensity Resistance Exercise, 

Plus or Minus Soy Intake: Effects on 

Serum Lipid Peroxides in Young Adult 

Males’’. International Journal of Sport 

Nutrition and Exercise Metabolism. 

2004;14:125–132. 

22. Heneman K.M., Chang H.C., Prior R.L., 

Steinberg F.M. ‘‘Soy Protein with and 

without Isoflavones Fails to 

Substantially Increase Postprandial 

Antioxidant Capacity’’. Journal of 

Nutritional Biochemistry. 2007;18:46–53. 

23. Greany K.A., Nettleton J.A., Wangen K.E., 

Thomas W., Kurzer M.S. ‘‘Consumption 

of Isoflavone-Rich Soy Protein Does Not 

Alter Homocysteine or Markers of 

Inflammation in Postmenopausal 

Women’’. European Journal of Clinical 

Nutrition. 2008;62:1419–1425. 

24. Vega-Lopez S., Yeum K.J., Lecker J.L., 

Ausman L.M., Johnson E.J., Devaraj S., 

Jialal I., Lichtenstein A.H. ‘‘Plasma 

Antioxidant Capacity in Response to 

Diets High in Soy or Animal Protein with 

or without Isoflavones’’. American 

Journal of Clinical Nutrition. 

2005;81:43–49. 

25. Hanson L.N., Engelman H.M., Alekel 

D.L., Schalinske K.L., Kohut M.L., Reddy 

M.B. ‘‘Effects of Soy Isoflavones and 

Phytate on Homocysteine, C-Reactive 

Protein, and Iron Status in 

Postmenopausal Women’’. American 

Journal of Clinical Nutrition. 

2006;84:774–780. 

26. Higashi K., Abata S., Iwamoto N., Ogura 

M., Yamashita T., Ishikawa O., Ohslzu 

F., Nakamura H. ‘‘Effects of Soy Protein 

on Levels of Remnant-Like Particles 

Cholesterol and Vitamin E in Healthy 

Men’’. Journal of Nutritional Science and 

Vitaminology. 2001;47:283–288. 

27. Urban D., Irwin W., Kirk M., Markiewicz 

M.A., Myers R., Smith M., Weiss H., 

Grizzle W.E., Barnes S. ‘‘The Effect of 

Isolated Soy Protein on Plasma 

Biomarkers in Elderly Men with Elevated 

Serum Prostate Specific Antigen’’. 

Journal of Urology. 2001;165:294–300. 

28. Cupisti A., D’Alessandro C., Ghiadoni L., 

Morelli E., Panichi V., Barsotti G. ‘‘Effect 

of a Soy Protein Diet on Serum Lipids of 

Renal Transplant Patients’’. Journal of 

Renal Nutrition. 2004;14:31–35. 

29. Gallagher J.C., Satpathy R., Rafferty K., 

Haynatzka V. ‘‘The Effect of Soy Protein 

Isolate on Bone Metabolism’’. 

Menopause. 2004;11:290–298. 

30. Tonstad S., Smerud K., Hoie L. ‘‘A 

Comparison of the Effects of 2 Doses of 

Soy Protein or Casein on Serum Lipids, 

Serum Lipoproteins, and Plasma Total 

Homocysteine in Hypercholesterolemic 

Subjects’’. American Journal of Clinical 

Nutrition. 2002;76:78–84. 

31. Wangen K.E., Duncan A.M., Xu X., 

Kurzer M.S. ‘‘Soy Isoflavones Improve 

Plasma Lipids in Normocholesterolemic 

and Mildly Hypercholesterolemic 

Postmenopausal Women’’. American 

Journal of Clinical Nutrition. 

2001;73:225–231. 

32. Yildirir A., Tokgozoglu S.L., Oduncu T., 

Oto A., Haznedaroglu I., Akinci D., 

Koksal G., Sade E., Kirazli S., Kes S. 

‘‘Soy Protein Diet Significantly Improves 

Endothelial Function and Lipid 

Parameters’’. Clinical Cardiology. 

2001;24:711–716. 

33. Merz-Demlow B.E., Duncan A.M., 

Wangen K.E., Xu X., Carr T.P., Phipps 

W.R., Kurzer M.S. ‘‘Soy Isoflavones 

Improve Plasma Lipids in 

Normocholesterolemic, Premenopausal 

Women’’. American Journal of Clinical 

Nutrition. 2000;71:1462–1469. 

34. Wong W.W., Hachey D.L., Clarke L.L., 

Zhang S. ‘‘Cholesterol Synthesis and 

Absorption by 2h2o and 18o-Cholesterol 

and Hypocholesterolemic Effect of Soy 

Protein’’. Journal of Nutrition. 

1995;125:612S–618S. 

35. Sathyapalan T., Manuchehri A.M., 

Thatcher N.J., Rigby A.S., Chapman T., 

Kilpatrick E.S., Atkin S.L. ‘‘The Effect of 

Soy Phytoestrogen Supplementation on 

Thyroid Status and Cardiovascular Risk 

Markers in Patients with Subclinical 

Hypothyroidism: A Randomized, 


ethrower on DSK3G9T082PROD with PROPOSALS
50340 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

Double-Blind, Crossover Study’’. Journal 

of Clinical Endocrinology and 

Metabolism. 2011;96:1442–1449. 

36. Mackey R., Ekangaki A., Eden J.A. ‘‘The 

Effects of Soy Protein in Women and 

Men with Elevated Plasma Lipids’’. 

Biofactors. 2000;12:251–257. 

37. Engelman H.M., Alekel D.L., Hanson 

L.N., Kanthasamy A.G., Reddy M.B. 

‘‘Blood Lipid and Oxidative Stress 

Responses to Soy Protein with 

Isoflavones and Phytic Acid in 

Postmenopausal Women’’. American 

Journal of Clinical Nutrition. 

2005;81:590–596. 

38. Scheiber M.D., Liu J.H., Subbiah M.T., 

Rebar R.W., Setchell K.D. ‘‘Dietary 

Inclusion of Whole Soy Foods Results in 

Significant Reductions in Clinical Risk 

Factors for Osteoporosis and 

Cardiovascular Disease in Normal 

Postmenopausal Women’’. Menopause. 

2001;8:384–392. 

39. Ristic Medic D., Ristic V., Arsic A., Postic 

M., Ristic G., Blazencic Mladenovic V., 

Tepsic J. ‘‘Effects of Soybean D-Lecivita 

Product on Serum Lipids and Fatty Acid 

Composition in Type 2 Diabetic Patients 

with Hyperlipidemia’’. Nutrition, 

Metabolism and Cardiovascular 

Diseases. 2006;16:395–404. 

40. Jenkins D.J., Kendall C.W., Nguyen T.H., 

Marchie A., Faulkner D.A., Ireland C., 

Josse A.R., Vidgen E., Trautwein E.A., 

Lapsley K.G., Holmes C., Josse R.G., 

Leiter L.A., Connelly P.W., Singer W. 

‘‘Effect of Plant Sterols in Combination 

with Other Cholesterol-Lowering 

Foods’’. Metabolism. 2008;57:130–139. 

41. Sirtori C.R., Gatti E., Mantero O., Conti 

F., Agradi E., Tremoli E., Sirtori M., 

Fraterrigo L., Tavazzi L., Kritchevsky D. 

‘‘Clinical Experience with the Soybean 

Protein Diet in the Treatment of 

Hypercholesterolemia’’. American 

Journal of Clinical Nutrition. 

1979;32:1645–1658. 

42. Hermansen K., Sondergaard M., Hoie L., 

Carstensen M., Brock B. ‘‘Beneficial 

Effects of a Soy-Based Dietary 

Supplement on Lipid Levels and 

Cardiovascular Risk Markers in Type 2 

Diabetic Subjects’’. Diabetes Care. 

2001;24:228–233. 

43. Onning G., Akesson B., Oste R., 

Lundquist I. ‘‘Effects of Consumption of 

Oat Milk, Soya Milk, or Cow’s Milk on 

Plasma Lipids and Antioxidative 

Capacity in Healthy Subjects’’. Annals of 

Nutrition and Metabolism. 1998;42:211– 

220. 

44. Cupisti A., Ghiadoni L., D’Alessandro C., 

Kardasz I., Morelli E., Panichi V., Locati 

D., Morandi S., Saba A., Barsotti G., 

Taddei S., Arnoldi A., Salvetti A. ‘‘Soy 

Protein Diet Improves Endothelial 

Dysfunction in Renal Transplant 

Patients’’. Nephrology Dialysis 

Transplantation. 2007;22:229–234. 

45. Gardner-Thorpe D., O’Hagen C., Young I., 

Lewis S.J. ‘‘Dietary Supplements of Soya 

Flour Lower Serum Testosterone 

Concentrations and Improve Markers of 

Oxidative Stress in Men’’. European 

Journal of Clinical Nutrition. 

2003;57:100–106. 

46. Lovati M.R., Manzoni C., Canavesi A., 

Sirtori M., Vaccarino V., Marchi M., 

Gaddi G., Sirtori C.R. ‘‘Soybean Protein 

Diet Increases Low Density Lipoprotein 

Receptor Activity in Mononuclear Cells 

from Hypercholesterolemic Patients’’. 

Journal of Clinical Investigation. 

1987;80:1498–1502. 

47. Holmes W., Rubel G., Hood S. 

‘‘Comparison of the Effect of Dietary 

Meat Verus Dietary Soybean Protein on 

Plasma Lipids of Hyperlipidemic 

Individuals’’. Atherosclerosis. 

1980;36:379–387. 

48. Sirtori C.R., Agradi E., Conti F., Mantero 

O., Gatti E. ‘‘Soybean-Protein Diet in the 

Treatment of Type-Ii 

Hyperlipoproteinaemia’’. Lancet. 

1977;1:275–277. 

49. Shorey R.L., Bazan B., Lo G.S., Steinke 

F.H. ‘‘Determinants of 

Hypocholesterolemic Response to Soy 

and Animal Protein-Based Diets’’. 

American Journal of Clinical Nutrition. 

1981;34:1769–1778. 

50. Borodin E.A., Menshikova I.G., 

Dorovskikh V.A., Feoktistova N.A., 

Shtarberg M.A., Yamamoto T., 

Takamatsu K., Mori H., Yamamoto S. 

‘‘Effects of Two-Month Consumption of 

30 G a Day of Soy Protein Isolate or 

Skimmed Curd Protein on Blood Lipid 

Concentration in Russian Adults with 

Hyperlipidemia’’. Journal of Nutritional 

Science and Vitaminology. 2009;55:492– 

497. 

51. Potter J.M., Nestel P.J. ‘‘Greater Bile Acid 

Excretion with Soy Bean Than with Cow 

Milk in Infants’’. American Journal of 

Clinical Nutrition. 1976;29:546–551. 

52. Takahashi K., Kamada Y., HiraokaYamamoto J., Mori M., Nagata R., 

Hashimoto K., Aizawa T., Matsuda K., 

Kometani T., Ikeda K., Yamori Y. ‘‘Effect 

of a Soybean Product on Serum Lipid 

Levels in Female University Students’’. 

Clinical and Experimental Pharmacology 

and Physiology. 2004;31 Suppl 2:S42–43. 

53. Campbell C.G., Brown B.D., Dufner D., 

Thorland W.G. ‘‘Effects of Soy or Milk 

Protein During a High-Fat Feeding 

Challenge on Oxidative Stress, 

Inflammation, and Lipids in Healthy 

Men’’. Lipids. 2006;41:257–265. 

54. Meredith L., Liebman M., Graves K. 

‘‘Alterations in Plasma Lipid Levels 

Resulting from Tofu and Cheese 

Consumption in Adult Women’’. Journal 

of the American College of Nutrition. 

1989;8:573–579. 

55. Fujii M., Fukui T., Miyoshi T. ‘‘Effect of 

Freeze-Dried Soybean Curd (Tofu) on 

Various Bodily Functions’’. Journal of 

Medical Investigation. 1999;46:67–74. 

56. Fumagalli R., Soleri L., Farina R., Musanti 

R., Mantero O., Noseda G., Gatti E., 

Sirtori C.R. ‘‘Fecal Cholesterol Excretion 

Studies in Type Ii Hypercholesterolemic 

Patients Treated with the Soybean 

Protein Diet’’. Atherosclerosis. 

1982;43:341–353. 

57. Vessby B., Karlstrom B., Lithell H., 

Gustafsson I.B., Werner I. ‘‘The Effects 

on Lipid and Carbohydrate Metabolism 

of Replacing Some Animal Protein by 

Soy-Protein in a Lipid-Lowering Diet for 

Hypercholesterolaemic Patients’’. 

Human Nutrition Applied Nutrition. 

1982;36:179–189. 

58. Sanders T.A., Dean T.S., Grainger D., 

Miller G.J., Wiseman H. ‘‘Moderate 

Intakes of Intact Soy Protein Rich in 

Isoflavones Compared with EthanolExtracted Soy Protein Increase Hdl but 

Do Not Influence Transforming Growth 

Factor Beta(1) Concentrations and 

Hemostatic Risk Factors for Coronary 

Heart Disease in Healthy Subjects’’. 

American Journal of Clinical Nutrition. 

2002;76:373–377. 

59. Blumenschein S., Torres E., Kushmaul E., 

Crawford J., Fixler D. ‘‘Effect of Oat 

Bran/Soy Protein in 

Hypercholesterolemic Children’’. Annals 

of the New York Academy of Science. 

1991;623:413–415. 

60. Webb C.M., Hayward C.S., Mason M.J., 

Ilsley C.D., Collins P. ‘‘Coronary 

Vasomotor and Blood Flow Responses to 

Isoflavone-Intact Soya Protein in 

Subjects with Coronary Heart Disease or 

Risk Factors for Coronary Heart Disease’’. 

Clinical Science. 2008;115:353–359. 

61. Bonanome A., Grundy S.M. ‘‘Effect of 

Dietary Stearic Acid on Plasma 

Cholesterol and Lipoprotein Levels’’. 

New England Journal of Medicine. 

1988;318:1244–1248. 

62. Tabibi H., Imani H., Hedayati M., Atabak 

S., Rahmani L. ‘‘Effects of Soy 

Consumption on Serum Lipids and 

Apoproteins in Peritoneal Dialysis 

Patients: A Randomized Controlled 

Trial’’. Peritoneal Dialysis International. 

2010;30:611–618. 

63. St-Onge M.P., Claps N., Wolper C., 

Heymsfield S.B. ‘‘Supplementation with 

Soy-Protein-Rich Foods Does Not 

Enhance Weight Loss’’. Journal of the 

Americian Dietetic Association. 

2007;107:500–505. 

64. van Raaij J.M., Katan M.B., West C.E., 

Hautvast J.G. ‘‘Influence of Diets 

Containing Casein, Soy Isolate, and Soy 

Concentrate on Serum Cholesterol and 

Lipoproteins in Middle-Aged 

Volunteers’’. American Journal of 

Clinical Nutrition. 1982;35:925–934. 

65. Azadbakht L., Kimiagar M., Mehrabi Y., 

Esmaillzadeh A., Padyab M., Hu F.B., 

Willett W.C. ‘‘Soy Inclusion in the Diet 

Improves Features of the Metabolic 

Syndrome: A Randomized Crossover 

Study in Postmenopausal Women’’. 

American Journal of Clinical Nutrition. 

2007;85:735–741. 

66. Jenkins D.J., Kendall C.W., Mehling C.C., 

Parker T., Rao A.V., Agarwal S., 

Novokmet R., Jones P.J., Raeini M., Story 

J.A., Furumoto E., Vidgen E., Griffin L.C., 

Cunnane S.C., Ryan M.A., Connelly P.W. 

‘‘Combined Effect of Vegetable Protein 

(Soy) and Soluble Fiber Added to a 

Standard Cholesterol-Lowering Diet’’. 

Metabolism. 1999;48:809–816. 

67. Pipe E.A., Gobert C.P., Capes S.E., 

Darlington G.A., Lampe J.W., Duncan 

A.M. ‘‘Soy Protein Reduces Serum Ldl 

Cholesterol and the Ldl Cholesterol:Hdl 

Cholesterol and Apolipoprotein 

B:Apolipoprotein a-I Ratios in Adults 

with Type 2 Diabetes’’. Journal of 

Nutrition. 2009;139:1700–1706. 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50341 

68. Haub M.D., Wells A.M., Campbell W.W. 

‘‘Beef and Soy-Based Food Supplements 

Differentially Affect Serum LipoproteinLipid Profiles Because of Changes in 

Carbohydrate Intake and Novel Nutrient 

Intake Ratios in Older Men Who 

Resistive-Train’’. Metabolism. 

2005;54:769–774. 

69. Stephenson T.J., Setchell K.D., Kendall 

C.W., Jenkins D.J., Anderson J.W., Fanti 

P. ‘‘Effect of Soy Protein-Rich Diet on 

Renal Function in Young Adults with 

Insulin-Dependent Diabetes Mellitus’’. 

Clinical Nephrology. 2005;64:1–11. 

70. Azadbakht L., Atabak S., Esmaillzadeh A. 

‘‘Soy Protein Intake, Cardiorenal Indices, 

and C-Reactive Protein in Type 2 

Diabetes with Nephropathy: A 

Longitudinal Randomized Clinical 

Trial’’. Diabetes Care. 2008;31:648–654. 

71. Thorp A.A., Howe P.R., Mori T.A., Coates 

A.M., Buckley J.D., Hodgson J., Mansour 

J., Meyer B.J. ‘‘Soy Food Consumption 

Does Not Lower Ldl Cholesterol in Either 

Equol or Nonequol Producers’’. 

American Journal of Clinical Nutrition. 

2008;88:298–304. 

72. Allen J.K., Becker D.M., Kwiterovich P.O., 

Lindenstruth K.A., Curtis C. ‘‘Effect of 

Soy Protein-Containing Isoflavones on 

Lipoproteins in Postmenopausal 

Women’’. Menopause. 2007;14:106–114. 

73. Bricarello L.P., Kasinski N., Bertolami 

M.C., Faludi A., Pinto L.A., Relvas W.G., 

Izar M.C., Ihara S.S., Tufik S., Fonseca 

F.A. ‘‘Comparison between the Effects of 

Soy Milk and Non-Fat Cow Milk on 

Lipid Profile and Lipid Peroxidation in 

Patients with Primary 

Hypercholesterolemia’’. Nutrition. 

2004;20:200–204. 

74. Meyer B.J., Larkin T.A., Owen A.J., 

Astheimer L.B., Tapsell L.C., Howe P.R. 

‘‘Limited Lipid-Lowering Effects of 

Regular Consumption of Whole Soybean 

Foods’’. Annals of Nutrition and 

Metabolism. 2004;48:67–78. 

75. Ridges L., Sunderland R., Moerman K., 

Meyer B., Astheimer L., Howe P. 

‘‘Cholesterol Lowering Benefits of Soy 

and Linseed Enriched Foods’’. Asia 

Pacific Journal of Clinical Nutrition. 

2001;10:204–211. 

76. Widhalm K., Brazda G., Schneider B., 

Kohl S. ‘‘Effect of Soy Protein Diet 

Versus Standard Low Fat, Low 

Cholesterol Diet on Lipid and 

Lipoprotein Levels in Children with 

Familial or Polygenic 

Hypercholesterolemia’’. Journal of 

Pediatrics. 1993;123:30–34. 

77. Kurowska E.M., Jordan J., Spence J.D., 

Wetmore S., Piche L.A., Radzikowski M., 

Dandona P., Carroll K.K. ‘‘Effects of 

Substituting Dietary Soybean Protein and 

Oil for Milk Protein and Fat in Subjects 

with Hypercholesterolemia’’. Clinical 

Investigative Medicine. 1997;20:162–170. 

78. Ashton E.L., Dalais F.S., Ball M.J. ‘‘Effect 

of Meat Replacement by Tofu on Chd 

Risk Factors Including Copper Induced 

Ldl Oxidation’’. Journal of the American 

College of Nutrition. 2000;19:761–767. 

79. Ashton E., Ball M. ‘‘Effects of Soy as Tofu 

Vs Meat on Lipoprotein Concentrations’’. 

European Journal of Clinical Nutrition. 

2000;54:14–19. 

80. Gaddi A., Ciarrocchi A., Matteucci A., 

Rimondi S., Ravaglia G., Descovich G.C., 

Sirtori C.R. ‘‘Dietary Treatment for 

Familial Hypercholesterolemia— 

Differential Effects of Dietary Soy Protein 

According to the Apolipoprotein E 

Phenotypes’’. American Journal of 

Clinical Nutrition. 1991;53:1191–1196. 

81. Gaddi A., Descovich G.C., Noseda G., 

Fragiacomo C., Nicolini A., Montanari 

G., Vanetti G., Sirtori M., Gatti E., Sirtori 

C.R. ‘‘Hypercholesterolaemia Treated by 

Soybean Protein Diet’’. Archives of 

Diseases in Childhood. 1987;62:274–278. 

82. Duane W.C. ‘‘Effects of Soybean Protein 

and Very Low Dietary Cholesterol on 

Serum Lipids, Biliary Lipids, and Fecal 

Sterols in Humans’’. Metabolism. 

1999;48:489–494. 

83. Grundy S.M., Abrams J.J. ‘‘Comparison of 

Actions of Soy Protein and Casein on 

Metabolism of Plasma Lipoproteins and 

Cholesterol in Humans’’. American 

Journal of Clinical Nutrition. 

1983;38:245–252. 

84. Hermansen K., Hansen B., Jacobsen R., 

Clausen P., Dalgaard M., Dinesen B., 

Holst J.J., Pedersen E., Astrup A. ‘‘Effects 

of Soy Supplementation on Blood Lipids 

and Arterial Function in 

Hypercholesterolaemic Subjects’’. 

European Journal of Clinical Nutrition. 

2005;59:843–850. 

85. Baum J.A., Teng H., Erdman J.W., Jr., 

Weigel R.M., Klein B.P., Persky V.W., 

Freels S., Surya P., Bakhit R.M., Ramos 

E., Shay N.F., Potter S.M. ‘‘Long-Term 

Intake of Soy Protein Improves Blood 

Lipid Profiles and Increases 

Mononuclear Cell Low-DensityLipoprotein Receptor Messenger Rna in 

Hypercholesterolemic, Postmenopausal 

Women’’. American Journal of Clinical 

Nutrition. 1998;68:545–551. 

86. Potter S.M., Baum J.A., Teng H., Stillman 

R.J., Shay N.F., Erdman J.W., Jr. ‘‘Soy 

Protein and Isoflavones: Their Effects on 

Blood Lipids and Bone Density in 

Postmenopausal Women’’. American 

Journal of Clinical Nutrition. 

1998;68:1375S–1379S. 

87. Wang M.F., Yamamoto S., Chung H.M., 

Chung S.Y., Miyatani S., Mori M., Okita 

T., Sugano M. 

‘‘Antihypercholesterolemic Effect of 

Undigested Fraction of Soybean Protein 

in Young Female Volunteers’’. Journal of 

Nutritional Science and Vitaminology. 

1995;41:187–195. 

88. Potter S.M., Bakhit R.M., Essex-Sorlie 

D.L., Weingartner K.E., Chapman K.M., 

Nelson R.A., Prabhudesai M., Savage 

W.D., Nelson A.I., Winter L.W., . 

‘‘Depression of Plasma Cholesterol in 

Men by Consumption of Baked Products 

Containing Soy Protein’’. American 

Journal of Clinical Nutrition. 

1993;58:501–506. 

89. Anderson J.W., Fuller J., Patterson K., 

Blair R., Tabor A. ‘‘Soy Compared to 

Casein Meal Replacement Shakes with 

Energy-Restricted Diets for Obese 

Women: Randomized Controlled Trial’’. 

Metabolism. 2007;56:280–288. 

90. Campbell S.C., Khalil D.A., Payton M.E., 

Arjmandi B.H. ‘‘One-Year Soy Protein 

Supplementation Does Not Improve 

Lipid Profile in Postmenopausal 

Women’’. Menopause. 2010;17:587–593. 

91. Anderson J.W., Hoie L.H. ‘‘Weight Loss 

and Lipid Changes with Low-Energy 

Diets: Comparator Study of Milk-Based 

Versus Soy-Based Liquid Meal 

Replacement Interventions’’. Journal of 

the American College of Nutrition. 

2005;24:210–216. 

92. Wu A.H., Stanczyk F.Z., Martinez C., 

Tseng C.C., Hendrich S., Murphy P., 

Chaikittisilpa S., Stram D.O., Pike M.C. 

‘‘A Controlled 2-Mo Dietary Fat 

Reduction and Soy Food 

Supplementation Study in 

Postmenopausal Women’’. American 

Journal of Clinical Nutrition. 

2005;81:1133–1141. 

93. Steele M.G. ‘‘The Effect on Serum 

Cholesterol Levels of Substituting Milk 

with a Soya Beverage’’. Australian 

Journal of Nutrition and Dietetics. 

1992;49:24–28. 

94. Deibert P., Konig D., Schmidt-Trucksaess 

A., Zaenker K.S., Frey I., Landmann U., 

Berg A. ‘‘Weight Loss without Losing 

Muscle Mass in Pre-Obese and Obese 

Subjects Induced by a High-Soy-Protein 

Diet’’. International Journal of Obesity. 

2004;28:1349–1352. 

95. Puska P., Korpelainen V., Hoie L.H., 

Skovlund E., Lahti T., Smerud K.T. ‘‘Soy 

in Hypercholesterolaemia: A DoubleBlind, Placebo-Controlled Trial’’. 

European Journal of Clinical Nutrition. 

2002;56:352–357. 

96. Puska P., Korpelainen V., Hoie L.H., 

Skovlund E., Smerud K.T. ‘‘Isolated Soya 

Protein with Standardised Levels of 

Isoflavones, Cotyledon Soya Fibres and 

Soya Phospholipids Improves Plasma 

Lipids in Hypercholesterolaemia: A 

Double-Blind, Placebo-Controlled Trial 

of a Yoghurt Formulation’’. British 

Journal of Nutrition. 2004;91:393–401. 

97. Allison D.B., Gadbury G., Schwartz L.G., 

Murugesan R., Kraker J.L., Heshka S., 

Fontaine K.R., Heymsfield S.B. ‘‘A Novel 

Soy-Based Meal Replacement Formula 

for Weight Loss among Obese 

Individuals: A Randomized Controlled 

Clinical Trial’’. European Journal of 

Clinical Nutrition. 2003;57:514–522. 

98. Kreijkamp-Kaspers S., Kok L., Grobbee 

D.E., de Haan E.H., Aleman A., Lampe 

J.W., van der Schouw Y.T. ‘‘Effect of Soy 

Protein Containing Isoflavones on 

Cognitive Function, Bone Mineral 

Density, and Plasma Lipids in 

Postmenopausal Women: A Randomized 

Controlled Trial’’. Journal of the 

American Medical Association. 

2004;292:65–74. 

99. Kreijkamp-Kaspers S., Kok L., Bots M.L., 

Grobbee D.E., Lampe J.W., van der 

Schouw Y.T. ‘‘Randomized Controlled 

Trial of the Effects of Soy Protein 

Containing Isoflavones on Vascular 

Function in Postmenopausal Women’’. 

American Journal of Clinical Nutrition. 

2005;81:189–195. 

100. Dent S.B., Peterson C.T., Brace L.D., 

Swain J.H., Reddy M.B., Hanson K.B., 

Robinson J.G., Alekel D.L. ‘‘Soy Protein 

Intake by Perimenopausal Women Does 


ethrower on DSK3G9T082PROD with PROPOSALS
50342 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

Not Affect Circulating Lipids and 

Lipoproteins or Coagulation and 

Fibrinolytic Factors’’. Journal of 

Nutrition. 2001;131:2280–2287. 

101. Swain J.H., Alekel D.L., Dent S.B., 

Peterson C.T., Reddy M.B. ‘‘Iron Indexes 

and Total Antioxidant Status in 

Response to Soy Protein Intake in 

Perimenopausal Women’’. American 

Journal of Clinical Nutrition. 

2002;76:165–171. 

102. Sirtori C.R., Bosisio R., Pazzucconi F., 

Bondioli A., Gatti E., Lovati M.R., 

Murphy P. ‘‘Soy Milk with a High 

Glycitein Content Does Not Reduce LowDensity Lipoprotein Cholesterolemia in 

Type Ii Hypercholesterolemic Patients’’. 

Annals of Nutrition and Metabolism. 

2002;46:88–92. 

103. Sirtori C.R., Zucchi-Dentone C., Sirtori 

M., Gatti E., Descovich G.C., Gaddi A., 

Cattin L., Da Col P.G., Senin U., 

Mannarino E., . ‘‘Cholesterol-Lowering 

and Hdl-Raising Properties of 

Lecithinated Soy Proteins in Type Ii 

Hyperlipidemic Patients’’. Annals of 

Nutrition and Metabolism. 1985;29:348– 

357. 

104. Sirtori C.R., Pazzucconi F., Colombo L., 

Battistin P., Bondioli A., Descheemaeker 

K. ‘‘Double-Blind Study of the Addition 

of High-Protein Soya Milk V. Cows’ Milk 

to the Diet of Patients with Severe 

Hypercholesterolaemia and Resistance to 

or Intolerance of Statins’’. British Journal 

of Nutrition. 1999;82:91–96. 

105. Descovich G.C., Ceredi C., Gaddi A., 

Benassi M.S., Mannino G., Colombo L., 

Cattin L., Fontana G., Senin U., 

Mannarino E., Caruzzo C., Bertelli E., 

Fragiacomo C., Noseda G., Sirtori M., 

Sirtori C.R. ‘‘Multicentre Study of 

Soybean Protein Diet for Outpatient 

Hyper-Cholesterolaemic Patients’’. 

Lancet. 1980;2:709–712. 

106. Carroll K.K., Giovannetti P.M., Huff 

M.W., Moase O., Roberts DC, Wolfe B.M. 

‘‘Hypocholesterolemic Effect of 

Substituting Soybean Protein for Animal 

Protein in the Diet of Healthy Young 

Women’’. American Journal of Clinical 

Nutrition. 1978;31:1312–1321. 

107. Giovannetti P.M., Carroll K.K., Wolfe 

B.M. ‘‘Constancy of Fasting Serum 

Cholesterol of Healthy Young Women 

Upon Substitution of Soy Protein Isolate 

for Meat and Dairy Protein in Medium 

and Low Fat Diets’’. Nutrition Research. 

1986;6:609–618. 

108. Sacks F.M., Breslow J.L., Wood P.G., 

Kass E.H. ‘‘Lack of an Effect of Dairy 

Protein (Casein) and Soy Protein on 

Plasma Cholesterol of Strict Vegetarians. 

An Experiment and a Critical Review’’. 

Journal of Lipid Research. 1983;24:1012– 

1020. 

109. Meinertz H., Nilausen K., Hilden J. 

‘‘Alcohol-Extracted, but Not Intact, 

Dietary Soy Protein Lowers 

Lipoprotein(a) Markedly’’. 

Arteriosclerosis, Thrombosis, and 

Vascular Biology. 2002;22:312–316. 

110. Nilausen K., Meinertz H. ‘‘Variable 

Lipemic Response to Dietary Soy Protein 

in Healthy, Normolipemic Men’’. 

American Journal of Clinical Nutrition. 

1998;68:1380S–1384S. 

111. Nilausen K., Meinertz H. 

‘‘Lipoprotein(a) and Dietary Proteins: 

Casein Lowers Lipoprotein(a) 

Concentrations as Compared with Soy 

Protein’’. American Journal of Clinical 

Nutrition. 1999;69:419–425. 

112. Meinertz H., Faergeman O., Nilausen K., 

Chapman M.J., Goldstein S., Laplaud 

P.M. ‘‘Effects of Soy Protein and Casein 

in Low Cholesterol Diets on Plasma 

Lipoproteins in Normolipidemic 

Subjects’’. Atherosclerosis. 1988;72:63– 

70. 

113. Meinertz H., Nilausen K., Faergeman O. 

‘‘Soy Protein and Casein in CholesterolEnriched Diets: Effects on Plasma 

Lipoproteins in Normolipidemic 

Subjects’’. American Journal of Clinical 

Nutrition. 1989;50:786–793. 

114. Welty F.K., Lee K.S., Lew N.S., Zhou J.R. 

‘‘Effect of Soy Nuts on Blood Pressure 

and Lipid Levels in Hypertensive, 

Prehypertensive, and Normotensive 

Postmenopausal Women’’. Archives of 

Internal Medicine. 2007;167:1060–1067. 

115. Teixeira S.R., Potter S.M., Weigel R., 

Hannum S., Erdman J.W., Jr., Hasler C.M. 

‘‘Effects of Feeding 4 Levels of Soy 

Protein for 3 and 6 Wk on Blood Lipids 

and Apolipoproteins in Moderately 

Hypercholesterolemic Men’’. American 

Journal of Clinical Nutrition. 

2000;71:1077–1084. 

116. Crouse J.R., III, Morgan T., Terry J.G., 

Ellis J., Vitolins M., Burke G.L. ‘‘A 

Randomized Trial Comparing the Effect 

of Casein with That of Soy Protein 

Containing Varying Amounts of 

Isoflavones on Plasma Concentrations of 

Lipids and Lipoproteins’’. Arch Intern 

Med. 1999;159:2070–2076. 

117. Weghuber D., Widhalm K. ‘‘Effect of 3- 

Month Treatment of Children and 

Adolescents with Familial and Polygenic 

Hypercholesterolaemia with a SoyaSubstituted Diet’’. British Journal of 

Nutrition. 2008;99:281–286. 

118. Laurin D., Jacques H., Moorjani S., 

Steinke F.H., Gagne C., Brun D., Lupien 

P.J. ‘‘Effects of a Soy-Protein Beverage on 

Plasma Lipoproteins in Children with 

Familial Hypercholesterolemia’’. 

American Journal of Clinical Nutrition. 

1991;54:98–103. 

119. Jacques H., Laurin D., Moorjani S., 

Steinke F.H., Gagne C., Brun D., Lupien 

P.J. ‘‘Influence of Diets Containing Cow’s 

Milk or Soy Protein Beverage on Plasma 

Lipids in Children with Familial 

Hypercholesterolemia’’. Journal of the 

American College of Nutrition. 1992;11 

Suppl:69S–73S. 

120. Verrillo A., de T.A., Carandente G.P., La 

R.S. ‘‘Soybean Protein Diets in the 

Management of Type Ii 

Hyperlipoproteinaemia’’. 

Atherosclerosis. 1985;54:321–331. 

121. Huff M.W., Giovannetti P.M., Wolfe 

B.M. ‘‘Turnover of Very Low-Density 

Lipoprotein-Apoprotein B Is Increased 

by Substitution of Soybean Protein for 

Meat and Dairy Protein in the Diets of 

Hypercholesterolemic Men’’. American 

Journal of Clinical Nutrition. 

1984;39:888–897. 

122. Wolfe B.M., PM G., CH C., Roberts DC, 

Carroll K.K. ‘‘Hypolipidemic Effect of 

Substituting Soybean Protein Isolate for 

All Meat and Dairy Protein in the Diets 

of Hypercholesterolemic Men’’. Nutrition 

Reports International. 1981;24:1187– 

1198. 

123. Wheeler M.L., Fineberg SE., Fineberg 

N.S., Gibson R.G., Hackward L.L. 

‘‘Animal Versus Plant Protein Meals in 

Individuals with Type 2 Diabetes and 

Microalbuminuria: Effects on Renal, 

Glycemic, and Lipid Parameters’’. 

Diabetes Care. 2002;25:1277–1282. 

124. Mercer N., Carroll K.K., PM G., FH S., 

Wolfe B.M. ‘‘Effects of Human Plasma 

Lipids of Substituting Soybean Protein 

Isolate for Milk Protein in the Diet’’. 

Nutrition Reports International. 

1987;35:279–287. 

125. D’Amico G., Gentile M.G. ‘‘Effect of 

Dietary Manipulation on the Lipid 

Abnormalities and Urinary Protein Loss 

in Nephrotic Patients’’. Mineral and 

Electrolyte Metabolism. 1992;18:203– 

206. 

126. D’Amico G., Gentile M.G., Manna G., 

Fellin G., Ciceri R., Cofano F., Petrini C., 

Lavarda F., Perolini S., Porrini M. ‘‘Effect 

of Vegetarian Soy Diet on 

Hyperlipidaemia in Nephrotic 

Syndrome’’. Lancet. 1992;339:1131– 

1134. 

127. Anderson J.W., Blake J.E., Turner J., 

Smith B.M. ‘‘Effects of Soy Protein on 

Renal Function and Proteinuria in 

Patients with Type 2 Diabetes’’. 

American Journal of Clinical Nutrition. 

1998;68:1347S–1353S. 

128. Soroka N., Silverberg D.S., Greemland 

M., Birk Y., Blum M., Peer G., Iaina A. 

‘‘Comparison of a Vegetable-Based (Soya) 

and an Animal-Based Low-Protein Diet 

in Predialysis Chronic Renal Failure 

Patients’’. Nephron. 1998;79:173–180. 

129. Shige H., Ishikawa T., Higashi K., 

Yamashita T., Tomiyasu K., Yoshida H., 

Hosoai H., Ito T., Nakajima K., Ayaori 

M., Yonemura A., Suzukawa M., 

Nakamura H. ‘‘Effects of Soy Protein 

Isolate (Spi) and Casein on the 

Postprandial Lipemia in Normolipidemic 

Men’’. Journal of Nutritional Science and 

Vitaminology. 1998;44:113–127. 

130. Padhi E.M., Blewett H.J., Duncan A.M., 

Guzman R.P., Hawke A., Seetharaman 

K., Tsao R., Wolever T.M., Ramdath D.D. 

‘‘Whole Soy Flour Incorporated into a 

Muffin and Consumed at 2 Doses of Soy 

Protein Does Not Lower Ldl Cholesterol 

in a Randomized, Double-Blind 

Controlled Trial of Hypercholesterolemic 

Adults’’. Journal of Nutrition. 

2015;145:2665–2674. 

131. Jenkins D.J., Kendall C.W., Faulkner D., 

Vidgen E., Trautwein E.A., Parker T.L., 

Marchie A., Koumbridis G., Lapsley 

K.G., Josse R.G., Leiter L.A., Connelly 

P.W. ‘‘A Dietary Portfolio Approach to 

Cholesterol Reduction: Combined Effects 

of Plant Sterols, Vegetable Proteins, and 

Viscous Fibers in 

Hypercholesterolemia’’. Metabolism. 

2002;51:1596–1604. 

132. Jenkins D.J., Kendall C.W., Vidgen E., 

Mehling C.C., Parker T., Seyler H., 

Faulkner D., Garsetti M., Griffin L.C., 

Agarwal S., Rao A.V., Cunnane S.C., 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50343 

Ryan M.A., Connelly P.W., Leiter L.A., 

Vuksan V., Josse R. ‘‘The Effect on Serum 

Lipids and Oxidized Low-Density 

Lipoprotein of Supplementing SelfSelected Low-Fat Diets with SolubleFiber, Soy, and Vegetable Protein 

Foods’’. Metabolism. 2000;49:67–72. 

133. Jenkins D.J., Kendall C.W., Garsetti M., 

Rosenberg-Zand R.S., Jackson C.J., 

Agarwal S., Rao A.V., Diamandis E.P., 

Parker T., Faulkner D., Vuksan V., 

Vidgen E. ‘‘Effect of Soy Protein Foods 

on Low-Density Lipoprotein Oxidation 

and Ex Vivo Sex Hormone Receptor 

Activity—a Controlled Crossover Trial’’. 

Metabolism. 2000;49:537–543. 

134. Ham J.O., Chapman K.M., Essex-Sorlie 

D., Bakhit R.M., Prabhudesai M., Winter 

L.W., Erdman J.W., Jr., Potter S.M. 

‘‘Endocrinological Response to Soy 

Protein and Fiber in Mildly 

Hypercholesterolemic Men’’. Nutrition 

Research. 1993;13:873–884. 

135. Roughead Z.K., Hunt J.R., Johnson L.K., 

Badger T.M., Lykken G.I. ‘‘Controlled 

Substitution of Soy Protein for Meat 

Protein: Effects on Calcium Retention, 

Bone, and Cardiovascular Health Indices 

in Postmenopausal Women’’. Journal of 

Clinical Endocrinology and Metabolism. 

2005;90:181–189. 

136. Yamashita T., Sasahara T., Pomeroy SE., 

Collier G., Nestel P.J. ‘‘Arterial 

Compliance, Blood Pressure, Plasma 

Leptin, and Plasma Lipids in Women 

Are Improved with Weight Reduction 

Equally with a Meat-Based Diet and a 

Plant-Based Diet’’. Metabolism. 

1998;47:1308–1314. 

137. Chen S.T., Ferng S.H., Yang C.S., Peng 

S.J., Lee H.R., Chen J.R. ‘‘Variable Effects 

of Soy Protein on Plasma Lipids in 

Hyperlipidemic and Normolipidemic 

Hemodialysis Patients’’. American 

Journal of Kidney Diseases. 

2005;46:1099–1106. 

138. Azadbakht L., Shakerhosseini R., Atabak 

S., Jamshidian M., Mehrabi Y., EsmaillZadeh A. ‘‘Beneficiary Effect of Dietary 

Soy Protein on Lowering Plasma Levels 

of Lipid and Improving Kidney Function 

in Type Ii Diabetes with Nephropathy’’. 

European Journal of Clinical Nutrition. 

2003;57:1292–1294. 

139. D’Amico G., Remuzzi G., Maschio G., 

Gentile M.G., Gotti E., Oldrizzi L., 

Manna G., Mecca G., Rugiu C., Fellin G. 

‘‘Effect of Dietary Proteins and Lipids in 

Patients with Membranous Nephropathy 

and Nephrotic Syndrome’’. Clinical 

Nephrology. 1991;35:237–242. 

140. Liao F.H., Shieh M.J., Yang S.C., Lin 

S.H., Chien Y.W. ‘‘Effectiveness of a SoyBased Compared with a Traditional LowCalorie Diet on Weight Loss and Lipid 

Levels in Overweight Adults’’. Nutrition. 

2007;23:551–556. 

141. Li Z., Hong K., Saltsman P., DeShields 

S., Bellman M., Thames G., Liu Y., Wang 

H.J., Elashoff R., Heber D. ‘‘Long-Term 

Efficacy of Soy-Based Meal 

Replacements Vs an Individualized Diet 

Plan in Obese Type Ii Dm Patients: 

Relative Effects on Weight Loss, 

Metabolic Parameters, and C-Reactive 

Protein’’. European Journal of Clinical 

Nutrition. 2005;59:411–418. 

142. Chiechi L.M., Secreto G., Vimercati A., 

Greco P., Venturelli E., Pansini F., 

Fanelli M., Loizzi P., Selvaggi L. ‘‘The 

Effects of a Soy Rich Diet on Serum 

Lipids: The Menfis Randomized Trial’’. 

Maturitas. 2002;41:97–104. 

143. Chiechi L.M., Secreto G., D’Amore M., 

Fanelli M., Venturelli E., Cantatore F., 

Valerio T., Laselva G., Loizzi P. ‘‘Efficacy 

of a Soy Rich Diet in Preventing 

Postmenopausal Osteoporosis: The 

Menfis Randomized Trial’’. Maturitas. 

2002;42:295–300. 

144. Gentile M.G., Fellin G., Cofano F., Delle 

F.A., Manna G., Ciceri R., Petrini C., 

Lavarda F., Pozzi F., D’Amico G. 

‘‘Treatment of Proteinuric Patients with 

a Vegetarian Soy Diet and Fish Oil’’. 

Clinical Nephrology. 1993;40:315–320. 

145. Vigna G.B., Pansini F., Bonaccorsi G., 

Albertazzi P., Donega P., Zanotti L., De 

A.D., Mollica G., Fellin R. ‘‘Plasma 

Lipoproteins in Soy-Treated 

Postmenopausal Women: A DoubleBlind, Placebo-Controlled Trial’’. 

Nutrition, Metabolism and 

Cardiovascular Diseases. 2000;10:315– 

322. 

146. Zittermann A., Geppert J., Baier S., Zehn 

N., Gouni-Berthold I., Berthold H.K., 

Reinsberg J., Stehle P. ‘‘Short-Term 

Effects of High Soy Supplementation on 

Sex Hormones, Bone Markers, and Lipid 

Parameters in Young Female Adults’’. 

European Journal of Nutrition. 

2004;43:100–108. 

147. Cicero A.F., Fiorito A., Panourgia M.P., 

Sangiorgi Z., Gaddi A. ‘‘Effects of a New 

Soy/Beta-Sitosterol Supplement on 

Plasma Lipids in Moderately 

Hypercholesterolemic Subjects’’. Journal 

of the Americian Dietetic Association. 

2002;102:1807–1811. 

148. Cicero A.F., Minardi M., Mirembe S., 

Pedro E., Gaddi A. ‘‘Effects of a New Low 

Dose Soy Protein/Beta-Sitosterol 

Association on Plasma Lipid Levels and 

Oxidation’’. European Journal of 

Nutrition. 2004;43:319–322. 

149. Lukaczer D., Liska D.J., Lerman R.H., 

Darland G., Schiltz B., Tripp M., Bland 

J.S. ‘‘Effect of a Low Glycemic Index Diet 

with Soy Protein and Phytosterols on 

Cvd Risk Factors in Postmenopausal 

Women’’. Nutrition. 2006;22:104–113. 

150. Jenkins D.J., Kendall C.W., Marchie A., 

Faulkner D., Vidgen E., Lapsley K.G., 

Trautwein E.A., Parker T.L., Josse R.G., 

Leiter L.A., Connelly P.W. ‘‘The Effect of 

Combining Plant Sterols, Soy Protein, 

Viscous Fibers, and Almonds in Treating 

Hypercholesterolemia’’. Metabolism. 

2003;52:1478–1483. 

151. Jenkins D.J., Kendall C.W., Marchie A., 

Faulkner D.A., Wong J.M., de Souza R., 

Emam A., Parker T.L., Vidgen E., Lapsley 

K.G., Trautwein E.A., Josse R.G., Leiter 

L.A., Connelly P.W. ‘‘Effects of a Dietary 

Portfolio of Cholesterol-Lowering Foods 

Vs Lovastatin on Serum Lipids and CReactive Protein’’. Journal of the 

American Medical Association. 

2003;290:502–510. 

152. Jenkins D.J., Kendall C.W., Faulkner 

D.A., Nguyen T., Kemp T., Marchie A., 

Wong J.M., de Souza R., Emam A., 

Vidgen E., Trautwein E.A., Lapsley K.G., 

Holmes C., Josse R.G., Leiter L.A., 

Connelly P.W., Singer W. ‘‘Assessment 

of the Longer-Term Effects of a Dietary 

Portfolio of Cholesterol-Lowering Foods 

in Hypercholesterolemia’’. American 

Journal of Clinical Nutrition. 

2006;83:582–591. 

153. Jenkins D.J., Kendall C.W., Marchie A., 

Faulkner D.A., Wong J.M., de Souza R., 

Emam A., Parker T.L., Vidgen E., 

Trautwein E.A., Lapsley K.G., Josse R.G., 

Leiter L.A., Singer W., Connelly P.W. 

‘‘Direct Comparison of a Dietary Portfolio 

of Cholesterol-Lowering Foods with a 

Statin in Hypercholesterolemic 

Participants’’. American Journal of 

Clinical Nutrition. 2005;81:380–387. 

154. Jenkins D.J., Kendall C.W., Marchie A., 

Faulkner D.A., Josse A.R., Wong J.M., de 

Souza R., Emam A., Parker T.L., Li T.J., 

Josse R.G., Leiter L.A., Singer W., 

Connelly P.W. ‘‘Direct Comparison of 

Dietary Portfolio Vs Statin on C-Reactive 

Protein’’. European Journal of Clinical 

Nutrition. 2005;59:851–860. 

155. Jones P.J., Raeini-Sarjaz M., Jenkins D.J., 

Kendall C.W., Vidgen E., Trautwein E.A., 

Lapsley K.G., Marchie A., Cunnane S.C., 

Connelly P.W. ‘‘Effects of a Diet High in 

Plant Sterols, Vegetable Proteins, and 

Viscous Fibers (Dietary Portfolio) on 

Circulating Sterol Levels and Red Cell 

Fragility in Hypercholesterolemic 

Subjects’’. Lipids. 2005;40:169–174. 

156. National Heart L., and Blood Institute. 

‘‘Clinical Guidelines on Cholesterol 

Management in Adults (Atp Iii)—‘‘, NIH 

Publication No. 02–5215. 2002. 

157. James P.A., Oparil S., Carter B.L., 

Cushman W.C., Dennison-Himmelfarb 

C., Handler J., Lackland D.T., LeFevre 

M.L., MacKenzie T.D., Ogedegbe O., 

Smith S.C., Jr., Svetkey L.P., Taler S.J., 

Townsend R.R., Wright J.T., Jr., Narva 

A.S., Ortiz E. ‘‘2014 Evidence-Based 

Guideline for the Management of High 

Blood Pressure in Adults: Report from 

the Panel Members Appointed to the 

Eighth Joint National Committee (Jnc 8)’’. 

Journal of the American Medical 

Association. 2014;311:507–520. 

158. National Heart L.a.B.I. ‘‘Seventh Report 

of the Joint National Committee on 

Prevention, Detection, Evaluation and 

Treatment of High Blood Pressure’’, NIH 

Publication No. 03–5233. 2003. 

159. Carmignani L.O., Pedro A.O., da CostaPaiva L.H., Pinto-Neto A.M. ‘‘The Effect 

of Soy Dietary Supplement and Low 

Dose of Hormone Therapy on Main 

Cardiovascular Health Biomarkers: A 

Randomized Controlled Trial’’. Revista 

Brasileira de Ginecologia e Obstetricia. 

2014;36:251–258. 

160. Liu Z.M., Ho S.C., Chen Y.M., Ho Y.P. 

‘‘The Effects of Isoflavones Combined 

with Soy Protein on Lipid Profiles, CReactive Protein and Cardiovascular Risk 

among Postmenopausal Chinese 

Women’’. Nutrition, Metabolism and 

Cardiovascular Diseases. 2012;22:712– 

719. 

161. Santo A.S., Cunningham A.M., Alhassan 

S., Browne R.W., Burton H., Leddy J.J., 

Grandjean P.W., Horvath S.M., Horvath 


ethrower on DSK3G9T082PROD with PROPOSALS
50344 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

P.J. ‘‘Nmr Analysis of Lipoprotein 

Particle Size Does Not Increase 

Sensitivity to the Effect of Soy Protein on 

Cvd Risk When Compared with the 

Traditional Lipid Profile’’. Applied 

Physiology, Nutrition, and Metabolism. 

2008;33:489–500. 

162. Evans M., Njike V.Y., Hoxley M., 

Pearson M., Katz D.L. ‘‘Effect of Soy 

Isoflavone Protein and Soy Lecithin on 

Endothelial Function in Healthy 

Postmenopausal Women’’. Menopause. 

2007;14:141–149. 

163. Maesta N., Nahas E.A., Nahas-Neto J., 

Orsatti F.L., Fernandes C.E., Traiman P., 

Burini R.C. ‘‘Effects of Soy Protein and 

Resistance Exercise on Body 

Composition and Blood Lipids in 

Postmenopausal Women’’. Maturitas. 

2007;56:350–358. 

164. Kohno M., Hirotsuka M., Kito M., 

Matsuzawa Y. ‘‘Decreases in Serum 

Triacylglycerol and Visceral Fat 

Mediated by Dietary Soybean BetaConglycinin’’. Journal of Atherosclerosis 

and Thrombosis. 2006;13:247–255. 

165. McVeigh B.L., Dillingham B.L., Lampe 

J.W., Duncan A.M. ‘‘Effect of Soy Protein 

Varying in Isoflavone Content on Serum 

Lipids in Healthy Young Men’’. 

American Journal of Clinical Nutrition. 

2006;83:244–251. 

166. Sagara M., Kanda T., NJelekera M., 

Teramoto T., Armitage L., Birt N., Birt C., 

Yamori Y. ‘‘Effects of Dietary Intake of 

Soy Protein and Isoflavones on 

Cardiovascular Disease Risk Factors in 

High Risk, Middle-Aged Men in 

Scotland’’. Journal of the American 

College of Nutrition. 2004;23:85–91. 

167. Teixeira S.R., Tappenden K.A., Carson 

L., Jones R., Prabhudesai M., Marshall 

W.P., Erdman J.W., Jr. ‘‘Isolated Soy 

Protein Consumption Reduces Urinary 

Albumin Excretion and Improves the 

Serum Lipid Profile in Men with Type 2 

Diabetes Mellitus and Nephropathy’’. 

Journal of Nutrition. 2004;134:1874– 

1880. 

168. Murray M.J., Meyer W.R., Lessey B.A., 

Oi R.H., DeWire R.E., Fritz M.A. ‘‘Soy 

Protein Isolate with Isoflavones Does Not 

Prevent Estradiol-Induced Endometrial 

Hyperplasia in Postmenopausal Women: 

A Pilot Trial’’. Menopause. 2003;10:456– 

464. 

169. Jayagopal V., Albertazzi P., Kilpatrick 

E.S., Howarth E.M., Jennings P.E., 

Hepburn D.A., Atkin S.L. ‘‘Beneficial 

Effects of Soy Phytoestrogen Intake in 

Postmenopausal Women with Type 2 

Diabetes’’. Diabetes Care. 2002;25:1709– 

1714. 

170. Teede H.J., Dalais F.S., Kotsopoulos D., 

Liang Y.L., Davis S., McGrath B.P. 

‘‘Dietary Soy Has Both Beneficial and 

Potentially Adverse Cardiovascular 

Effects: A Placebo-Controlled Study in 

Men and Postmenopausal Women’’. 

Journal of Clinical Endocrinology and 

Metabolism. 2001;86:3053–3060. 

171. Dalais F.S., Ebeling P.R., Kotsopoulos 

D., McGrath B.P., Teede H.J. ‘‘The Effects 

of Soy Protein Containing Isoflavones on 

Lipids and Indices of Bone Resorption in 

Postmenopausal Women’’. Clinical 

Endocrinology. 2003;58:704–709. 

172. Washburn S., Burke G.L., Morgan T., 

Anthony M. ‘‘Effect of Soy Protein 

Supplementation on Serum 

Lipoproteins, Blood Pressure, and 

Menopausal Symptoms in 

Perimenopausal Women’’. Menopause. 

1999;6:7–13. 

173. Gooderham M.H., Adlercreutz H., Ojala 

S.T., Wahala K., Holub B.J. ‘‘A Soy 

Protein Isolate Rich in Genistein and 

Daidzein and Its Effects on Plasma 

Isoflavone Concentrations, Platelet 

Aggregation, Blood Lipids and Fatty 

Acid Composition of Plasma 

Phospholipid in Normal Men’’. Journal 

of Nutrition. 1996;126:2000–2006. 

174. Mangano K.M., Hutchins-Wiese H.L., 

Kenny A.M., Walsh S.J., Abourizk R.H., 

Bruno R.S., Lipcius R., Fall P., 

Kleppinger A., Kenyon-Pesce L., 

Prestwood K.M., Kerstetter J.E. ‘‘Soy 

Proteins and Isoflavones Reduce 

Interleukin-6 but Not Serum Lipids in 

Older Women: A Randomized Controlled 

Trial’’. Nutrition Research. 

2013;33:1026–1033. 

175. Steinberg F.M., Guthrie N.L., Villablanca 

A.C., Kumar K., Murray M.J. ‘‘Soy 

Protein with Isoflavones Has Favorable 

Effects on Endothelial Function That Are 

Independent of Lipid and Antioxidant 

Effects in Healthy Postmenopausal 

Women’’. American Journal of Clinical 

Nutrition. 2003;78:123–130. 

176. Bakhit R.M., Klein B.P., Essex-Sorlie D., 

Ham J.O., Erdman J.W., Jr., Potter S.M. 

‘‘Intake of 25 G of Soybean Protein with 

or without Soybean Fiber Alters Plasma 

Lipids in Men with Elevated Cholesterol 

Concentrations’’. Journal of Nutrition. 

1994;124:213–222. 

177. van Raaij J.M., Katan M.B., Hautvast J.G., 

Hermus R.J. ‘‘Effects of Casein Versus 

Soy Protein Diets on Serum Cholesterol 

and Lipoproteins in Young Healthy 

Volunteers’’. American Journal of 

Clinical Nutrition. 1981;34:1261–1271. 

178. Takatsuka N., Nagata C., Kurisu Y., 

Inaba S., Kawakami N., Shimizu H. 

‘‘Hypocholesterolemic Effect of Soymilk 

Supplementation with Usual Diet in 

Premenopausal Normolipidemic 

Japanese Women’’. Preventive Medicine. 

2000;31:308–314. 

179. Mitchell J.H., Collins A.R. ‘‘Effects of a 

Soy Milk Supplement on Plasma 

Cholesterol Levels and Oxidative DNA 

Damage in Men—a Pilot Study’’. 

European Journal of Nutrition. 

1999;38:143–148. 

180. Murkies A.L., Lombard C., Strauss B.J., 

Wilcox G., Burger H.G., Morton M.S. 

‘‘Dietary Flour Supplementation 

Decreases Post-Menopausal Hot Flushes: 

Effect of Soy and Wheat’’. Maturitas. 

1995;21:189–195. 

181. Matthan N.R., Jalbert S.M., Ausman 

L.M., Kuvin J.T., Karas R.H., Lichtenstein 

A.H. ‘‘Effect of Soy Protein from 

Differently Processed Products on 

Cardiovascular Disease Risk Factors and 

Vascular Endothelial Function in 

Hypercholesterolemic Subjects’’. 

American Journal of Clinical Nutrition. 

2007;85:960–966. 

182. Jenkins D.J., Wolever T.M., Spiller G., 

Buckley G., Lam Y., Jenkins A.L., Josse 

R.G. ‘‘Hypocholesterolemic Effect of 

Vegetable Protein in a Hypocaloric Diet’’. 

Atherosclerosis. 1989;78:99–107. 

183. Bosello O., Cominacini L., Zocca I., 

Garbin U., Compri R., Davoli A., Brunetti 

L. ‘‘Short- and Long-Term Effects of 

Hypocaloric Diets Containing Proteins of 

Different Sources on Plasma Lipids and 

Apoproteins of Obese Subjects’’. Annals 

of Nutrition and Metabolism. 

1988;32:206–214. 

184. Greany K.A., Nettleton J.A., Wangen 

K.E., Thomas W., Kurzer M.S. ‘‘Probiotic 

Consumption Does Not Enhance the 

Cholesterol-Lowering Effect of Soy in 

Postmenopausal Women’’. Journal of 

Nutrition. 2004;134:3277–3283. 

185. Wong W.W., Smith E.O., Stuff J.E., 

Hachey D.L., Heird W.C., Pownell H.J. 

‘‘Cholesterol-Lowering Effect of Soy 

Protein in Normocholesterolemic and 

Hypercholesterolemic Men’’. American 

Journal of Clinical Nutrition. 

1998;68:1385S–1389S. 

186. Goldberg A.P., Lim A., Kolar J.B., 

Grundhauser J.J., Steinke F.H., Schonfeld 

G. ‘‘Soybean Protein Independently 

Lowers Plasma Cholesterol Levels in 

Primary Hypercholesterolemia’’. 

Atherosclerosis. 1982;43:355–368. 

187. Hoie L.H., Guldstrand M., Sjoholm A., 

Graubaum H.J., Gruenwald J., Zunft H.J., 

Lueder W. ‘‘Cholesterol-Lowering Effects 

of a New Isolated Soy Protein with High 

Levels of Nondenaturated Protein in 

Hypercholesterolemic Patients’’. 

Advances in Therapy. 2007;24:439–447. 

188. Hoie L.H., Sjoholm A., Guldstrand M., 

Zunft H.J., Lueder W., Graubaum H.J., 

Gruenwald J. ‘‘Ultra Heat Treatment 

Destroys Cholesterol-Lowering Effect of 

Soy Protein’’. International Journal of 

Food Sciences and Nutrition. 

2006;57:512–519. 

189. Hoie L.H., Morgenstern E.C., Gruenwald 

J., Graubaum H.J., Busch R., Luder W., 

Zunft H.J. ‘‘A Double-Blind PlaceboControlled Clinical Trial Compares the 

Cholesterol-Lowering Effects of Two 

Different Soy Protein Preparations in 

Hypercholesterolemic Subjects’’. 

European Journal of Nutrition. 

2005;44:65–71. 

190. Hoie L.H., Graubaum H.J., Harde A., 

Gruenwald J., Wernecke K.D. ‘‘LipidLowering Effect of 2 Dosages of a Soy 

Protein Supplement in 

Hypercholesterolemia’’. Advances in 

Therapy. 2005;22:175–186. 

191. Teede H.J., Dalais F.S., Kotsopoulos D., 

McGrath B.P., Malan E., Gan T.E., 

Peverill R.E. ‘‘Dietary Soy Containing 

Phytoestrogens Does Not Activate the 

Hemostatic System in Postmenopausal 

Women’’. Journal of Clinical 

Endocrinology and Metabolism. 

2005;90:1936–1941. 

192. Harrison R.A., Sagara M., Rajpura A., 

Armitage L., Birt N., Birt C.A., Yamori Y. 

‘‘Can Foods with Added Soya-Protein or 

Fish-Oil Reduce Risk Factors for 

Coronary Disease? A Factorial 

Randomised Controlled Trial’’. 

Nutrition, Metabolism and 

Cardiovascular Diseases. 2004;14:344– 

350. 


ethrower on DSK3G9T082PROD with PROPOSALS
Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 50345 

193. Blum A., Lang N., Vigder F., Israeli P., 

Gumanovsky M., Lupovitz S., Elgazi A., 

Peleg A., Ben-Ami M. ‘‘Effects of Soy 

Protein on Endothelium-Dependent 

Vasodilatation and Lipid Profile in 

Postmenopausal Women with Mild 

Hypercholesterolemia’’. Clinical 

Investigative Medicine. 2003;26:20–26. 

194. Cuevas A.M., Irribarra V.L., Castillo 

O.A., Yanez M.D., Germain A.M. 

‘‘Isolated Soy Protein Improves 

Endothelial Function in Postmenopausal 

Hypercholesterolemic Women’’. 

European Journal of Clinical Nutrition. 

2003;57:889–894. 

195. Gardner C.D., Newell K.A., Cherin R., 

Haskell W.L. ‘‘The Effect of Soy Protein 

with or without Isoflavones Relative to 

Milk Protein on Plasma Lipids in 

Hypercholesterolemic Postmenopausal 

Women’’. American Journal of Clinical 

Nutrition. 2001;73:728–735. 

196. Hori G., Wang M.F., Chan Y.C., Komatsu 

T., Wong Y., Chen T.H., Yamamoto K., 

Nagaoka S., Yamamoto S. ‘‘Soy Protein 

Hydrolyzate with Bound Phospholipids 

Reduces Serum Cholesterol Levels in 

Hypercholesterolemic Adult Male 

Volunteers’’. Bioscience, Biotechnology, 

and Biochemistry. 2001;65:72–78. 

197. Chen S.T., Chen J.R., Yang C.S., Peng 

S.J., Ferng S.H. ‘‘Effect of Soya Protein 

on Serum Lipid Profile and Lipoprotein 

Concentrations in Patients Undergoing 

Hypercholesterolaemic Haemodialysis’’. 

British Journal of Nutrition. 

2006;95:366–371. 

198. Ma Y., Chiriboga D., Olendzki B.C., 

Nicolosi R., Merriam P.A., Ockene I.S. 

‘‘Effect of Soy Protein Containing 

Isoflavones on Blood Lipids in 

Moderately Hypercholesterolemic 

Adults: A Randomized Controlled Trial’’. 

Journal of the American College of 

Nutrition. 2005;24:275–285. 

199. West S.G., Hilpert K.F., Juturu V., Bordi 

P.L., Lampe J.W., Mousa S.A., KrisEtherton P.M. ‘‘Effects of Including Soy 

Protein in a Blood Cholesterol-Lowering 

Diet on Markers of Cardiac Risk in Men 

and in Postmenopausal Women with and 

without Hormone Replacement 

Therapy’’. Journal of Womens Health. 

2005;14:253–262. 

200. Hilpert K.F., Kris-Etherton P.M., West 

S.G. ‘‘Lipid Response to a Low-Fat Diet 

with or without Soy Is Modified by CReactive Protein Status in Moderately 

Hypercholesterolemic Adults’’. Journal 

of Nutrition. 2005;135:1075–1079. 

201. Jenkins D.J., Kendall C.W., Jackson C.J., 

Connelly P.W., Parker T., Faulkner D., 

Vidgen E., Cunnane S.C., Leiter L.A., 

Josse R.G. ‘‘Effects of High- and LowIsoflavone Soyfoods on Blood Lipids, 

Oxidized Ldl, Homocysteine, and Blood 

Pressure in Hyperlipidemic Men and 

Women’’. American Journal of Clinical 

Nutrition. 2002;76:365–372. 

202. Jenkins D.J., Kendall C.W., Connelly 

P.W., Jackson C.J., Parker T., Faulkner D., 

Vidgen E. ‘‘Effects of High- and LowIsoflavone (Phytoestrogen) Soy Foods on 

Inflammatory Biomarkers and 

Proinflammatory Cytokines in MiddleAged Men and Women’’. Metabolism. 

2002;51:919–924. 

203. Lichtenstein A.H., Jalbert S.M., 

Adlercreutz H., Goldin B.R., Rasmussen 

H., Schaefer E.J., Ausman L.M. 

‘‘Lipoprotein Response to Diets High in 

Soy or Animal Protein with and without 

Isoflavones in Moderately 

Hypercholesterolemic Subjects’’. 

Arteriosclerosis, Thrombosis, and 

Vascular Biology. 2002;22:1852–1858. 

204. Wang Y., Jones P.J., Ausman L.M., 

Lichtenstein A.H. ‘‘Soy Protein Reduces 

Triglyceride Levels and Triglyceride 

Fatty Acid Fractional Synthesis Rate in 

Hypercholesterolemic Subjects’’. 

Atherosclerosis. 2004;173:269–275. 

205. Desroches S., Mauger J.F., Ausman L.M., 

Lichtenstein A.H., Lamarche B. ‘‘Soy 

Protein Favorably Affects Ldl Size 

Independently of Isoflavones in 

Hypercholesterolemic Men and 

Women’’. Journal of Nutrition. 

2004;134:574–579. 

206. Van H.L., Liu K., Gerber J., Garside D., 

Schiffer L., Gernhofer N., Greenland P. 

‘‘Oats and Soy in Lipid-Lowering Diets 

for Women with Hypercholesterolemia: 

Is There Synergy?’’. Journal of the 

American Dietetic Association. 

2001;101:1319–1325. 

207. Gardner C.D., Messina M., Kiazand A., 

Morris J.L., Franke A.A. ‘‘Effect of Two 

Types of Soy Milk and Dairy Milk on 

Plasma Lipids in Hypercholesterolemic 

Adults: A Randomized Trial’’. Journal of 

the American College of Nutrition. 

2007;26:669–677. 

208. Jenkins D.J., Kendall C.W., Vidgen E., 

Vuksan V., Jackson C.J., Augustin L.S., 

Lee B., Garsetti M., Agarwal S., Rao A.V., 

Cagampang G.B., Fulgoni V., III. ‘‘Effect 

of Soy-Based Breakfast Cereal on Blood 

Lipids and Oxidized Low-Density 

Lipoprotein’’. Metabolism. 

2000;49:1496–1500. 

209. Teede H.J., Giannopoulos D., Dalais F.S., 

Hodgson J., McGrath B.P. ‘‘Randomised, 

Controlled, Cross-over Trial of Soy 

Protein with Isoflavones on Blood 

Pressure and Arterial Function in 

Hypertensive Subjects’’. Journal of the 

American College of Nutrition. 

2006;25:533–540. 

210. Burke V., Hodgson J.M., Beilin L.J., 

Giangiulioi N., Rogers P., Puddey I.B. 

‘‘Dietary Protein and Soluble Fiber 

Reduce Ambulatory Blood Pressure in 

Treated Hypertensives’’. Hypertension. 

2001;38:821–826. 

211. Jenkins D.J., Kendall C.W., Faulkner 

D.A., Kemp T., Marchie A., Nguyen T.H., 

Wong J.M., de Souza R., Emam A., 

Vidgen E., Trautwein E.A., Lapsley K.G., 

Josse R.G., Leiter L.A., Singer W. ‘‘LongTerm Effects of a Plant-Based Dietary 

Portfolio of Cholesterol-Lowering Foods 

on Blood Pressure’’. European Journal of 

Clinical Nutrition. 2008;62:781–788. 

212. He J., Gu D., Wu X., Chen J., Duan X., 

Chen J., Whelton P.K. ‘‘Effect of Soybean 

Protein on Blood Pressure: A 

Randomized, Controlled Trial’’. Annals 

of Internal Medicine. 2005;143:1–9. 

213. Rivas M., Garay R.P., Escanero J.F., Cia 

P., Jr., Cia P., Alda J.O. ‘‘Soy Milk Lowers 

Blood Pressure in Men and Women with 

Mild to Moderate Essential 

Hypertension’’. Journal of Nutrition. 

2002;132:1900–1902. 

214. Chan Y.H., Lau K.K., Yiu K.H., Li S.W., 

Chan H.T., Tam S., Shu X.O., Lau C.P., 

Tse H.F. ‘‘Isoflavone Intake in Persons at 

High Risk of Cardiovascular Events: 

Implications for Vascular Endothelial 

Function and the Carotid Atherosclerotic 

Burden’’. American Journal of Clinical 

Nutrition. 2007;86:938–945. 

215. Ho S.C., Woo J.L., Leung S.S., Sham 

A.L., Lam T.H., Janus E.D. ‘‘Intake of Soy 

Products Is Associated with Better 

Plasma Lipid Profiles in the Hong Kong 

Chinese Population’’. Journal of 

Nutrition. 2000;130:2590–2593. 

216. Ho S.Y., Schooling M., Hui L.L., 

McGhee S.M., Mak K.H., Lam T.H. ‘‘Soy 

Consumption and Mortality in Hong 

Kong: Proxy-Reported Case-Control 

Study of All Older Adult Deaths in 

1998’’. Preventive Medicine. 2006;43:20– 

26. 

217. Kokubo Y., Iso H., Ishihara J., Okada K., 

Inoue M., Tsugane S., Group J.S. 

‘‘Association of Dietary Intake of Soy, 

Beans, and Isoflavones with Risk of 

Cerebral and Myocardial Infarctions in 

Japanese Populations: The Japan Public 

Health Center-Based (Jphc) Study Cohort 

I’’. Circulation. 2007;116:2553–2562. 

218. Nagata C., Shimizu H., Takami R., 

Hayashi M., Takeda N., Yasuda K. ‘‘Soy 

Product Intake Is Inversely Associated 

with Serum Homocysteine Level in 

Premenopausal Japanese Women’’. 

Journal of Nutrition. 2003;133:797–800. 

219. Nagata C., Takatsuka N., Kurisu Y., 

Shimizu H. ‘‘Decreased Serum Total 

Cholesterol Concentration Is Associated 

with High Intake of Soy Products in 

Japanese Men and Women’’. Journal of 

Nutrition. 1998;128:209–213. 

220. Rosell M.S., Appleby P.N., Spencer E.A., 

Key T.J. ‘‘Soy Intake and Blood 

Cholesterol Concentrations: A CrossSectional Study of 1033 Pre- and 

Postmenopausal Women in the Oxford 

Arm of the European Prospective 

Investigation into Cancer and Nutrition’’. 

American Journal of Clinical Nutrition. 

2004;80:1391–1396. 

221. Sasazuki S., Fukuoka Heart Study G. 

‘‘Case-Control Study of Nonfatal 

Myocardial Infarction in Relation to 

Selected Foods in Japanese Men and 

Women’’. Jpn Circ J. 2001;65:200–206. 

222. Yang G., Shu X.O., Jin F., Zhang X., Li 

H.L., Li Q., Gao Y.T., Zheng W. 

‘‘Longitudinal Study of Soy Food Intake 

and Blood Pressure among Middle-Aged 

and Elderly Chinese Women’’. American 

Journal of Clinical Nutrition. 

2005;81:1012–1017. 

223. Zhang B., Chen Y.M., Huang L.L., Zhou 

X.X., Chen C.G., Ye Y.B., Su Y.X. 

‘‘Greater Habitual Soyfood Consumption 

Is Associated with Decreased Carotid 

Intima-Media Thickness and Better 

Plasma Lipids in Chinese Middle-Aged 

Adults’’. Atherosclerosis. 2008;198:403– 

411. 

224. Zhang X., Shu X.O., Gao Y.T., Yang G., 

Li Q., Li H., Jin F., Zheng W. ‘‘Soy Food 

Consumption Is Associated with Lower 

Risk of Coronary Heart Disease in 


ethrower on DSK3G9T082PROD with PROPOSALS
50346 Federal Register / Vol. 82, No. 209 / Tuesday, October 31, 2017 / Proposed Rules 

Chinese Women’’. Journal of Nutrition. 

2003;133:2874–2878. 

225. Flegal K.M. ‘‘Evaluating Epidemiologic 

Evidence of the Effects of Food and 

Nutrient Exposures’’. American Journal 

of Clinical Nutrition. 1999;69:1339S– 

1344S. 

226. Lichtenstein A.H., Russell R.M. 

‘‘Essential Nutrients: Food or 

Supplements? Where Should the 

Emphasis Be?’’. Journal of the American 

Medical Association. 2005;294:351–358. 

227. Peto R., Doll R., Buckley J.D., Sporn 

M.B. ‘‘Can Dietary Beta-Carotene 

Materially Reduce Human Cancer 

Rates?’’. Nature. 1981;290:201–208. 

228. ‘‘The Effect of Vitamin E and Beta 

Carotene on the Incidence of Lung 

Cancer and Other Cancers in Male 

Smokers. The Alpha-Tocopherol, Beta 

Carotene Cancer Prevention Study 

Group’’. New England Journal of 

Medicine. 1994;330:1029–1035. 

229. Omenn G.S., Goodman G.E., Thornquist 

M.D., Balmes J., Cullen M.R., Glass A., 

Keogh J.P., Meyskens F.L., Valanis B., 

Williams J.H., Barnhart S., Hammar S. 

‘‘Effects of a Combination of Beta 

Carotene and Vitamin a on Lung Cancer 

and Cardiovascular Disease’’. New 

England Journal of Medicine. 

1996;334:1150–1155. 

230. Food and Drug Administration, ‘‘Tables 

of Scientific Evidence Regarding the 

Relationship Between Soy Protein and 

CHD’’ 

List of Subjects in 21 CFR Part 101 

Food labeling, Nutrition, Reporting 

and recordkeeping requirements. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act and under 

authority delegated to the Commissioner 

of Food and Drugs, it is proposed that 

21 CFR part 101 be amended as follows: 

PART 101—FOOD LABELING 

■ 1. The authority citation for part 101 

continues to read as follows: 

Authority: 15 U.S.C. 1453, 1454, 1455; 21 

U.S.C. 321, 331, 342, 343, 348, 371; 42 U.S.C. 

243, 264, 271. 

§ 101.82 [Removed] 

■ 2. Remove § 101.82. 

Dated: October 26, 2017. 

Anna K. Abram, 

Deputy Commissioner for Policy, Planning, 

Legislation, and Analysis. 

[FR Doc. 2017–23629 Filed 10–30–17; 8:45 am] 

BILLING CODE 4164–01–P 

POSTAL SERVICE 

39 CFR Part 111 

eInduction Option, Seamless 

Acceptance Program, and Full-Service 

Automation Option, Verification 

Standards 

AGENCY: Postal ServiceTM. 

ACTION: Proposed rule. 

SUMMARY: The Postal Service is 

proposing to amend Mailing Standards 

of the United States Postal Service, 

Domestic Mail Manual (DMM®), 

sections 705.20, eInduction Option, 

705.22, Seamless Acceptance Program, 

and 705.23, Full-Service Automation 

Option, to add the verification 

standards. 

DATES: Submit comments on or before 

November 30, 2017. 

ADDRESSES: Mail or deliver written 

comments to the manager, Product 

Classification, U.S. Postal Service, 475 

L’Enfant Plaza SW., Room 4446, 

Washington, DC 20260–5015. If sending 

comments by email, include the name 

and address of the commenter and send 

to ProductClassification@usps.gov, with 

a subject line of ‘‘Verification 

Standards’’. Faxed comments are not 

accepted. You may inspect and 

photocopy all written comments, by 

appointment only, at USPS®

Headquarters Library, 475 L’Enfant 

Plaza SW., 11th Floor North, 

Washington, DC 20260. These records 

are available for review on Monday 

through Friday, 9 a.m.–4 p.m., by 

calling 202–268–2906. 

FOR FURTHER INFORMATION CONTACT: 

Heather Dyer at (207) 482–7217, or 

Garry Rodriguez at (202) 268–7281. 

SUPPLEMENTARY INFORMATION: The Postal 

Service is proposing to amend DMM 

sections 705.20, eInduction Option, 

705.22, Seamless Acceptance Program, 

and 705.23, Full-Service Automation 

Option, to add the applicable 

verification descriptions, error 

thresholds, and postage assessments, 

standards. These standards have been 

made available to the public via 

Publication 6850, Publication for 

Streamlined Mail Acceptance for Letters 

and Flats, available at https://

postalpro.usps.com, which also 

contains additional information on the 

verification processes. 

List of Subjects in 39 CFR Part 111 

Administrative practice and 

procedure, Postal Service. 

Although we are exempt from the 

notice and comment requirements of the 

Administrative Procedure Act (5 U.S.C. 

553(b), (c)) regarding proposed 

rulemaking by 39 U.S.C. 410(a), we 

invite public comments on the 

following proposed revisions to Mailing 

Standards of the United States Postal 

Service, Domestic Mail Manual (DMM), 

incorporated by reference in the Code of 

Federal Regulations. See 39 CFR 111.1. 

Accordingly, 39 CFR part 111 is 

proposed to be amended as follows: 

PART 111—[AMENDED] 

■ 1. The authority citation for 39 CFR 

part 111 continues to read as follows: 

Authority: 5 U.S.C. 552(a); 13 U.S.C. 301– 

307; 18 U.S.C. 1692–1737; 39 U.S.C. 101, 

401, 403, 404, 414, 416, 3001–3011, 3201– 

3219, 3403–3406, 3621, 3622, 3626, 3632, 

3633, and 5001. 

■ 2. Revise the following sections of 

Mailing Standards of the United States 

Postal Service, Domestic Mail Manual 

(DMM), as follows: 

Mailing Standards of the United States 

Postal Service, Domestic Mail Manual 

(DMM) 

* * * * * 

700 Special Standards 

* * * * * 

705 Advanced Preparation and 

Special Postage Payment Systems 

* * * * * 

705.20.0 eInduction Option 

20.1 Description 

[Revise the fourth sentence of 20.1 to 

read as follows:] 

* * * For additional information on 

the eInduction Option see Publication 

6850, Publication for Streamlined Mail 

Acceptance for Letters and Flats, 

available at https://postalpro.usps.com. 

* * * * * 

[Add new subsection 20.5, 

Verifications, to read as follows:] 

20.5 Verifications 

The six eInduction option verification 

descriptions, error thresholds, and 

postage assessments, are provided in 

20.5.1 through 20.5.6. 

20.5.1 Undocumented (Extra) 

Containers Verification 

An Undocumented Container error 

occurs when a scanned IMcb is not 

found in an eDoc, or is included in an 

eDoc and associated to a postage 

statement in estimated (EST) status. 

Containers will be flagged as 

Undocumented 10 days after the scan 

unload date/time if no eDoc has been 

uploaded or if the postage statement is 

still in EST status. The threshold is 0%. 

All errors will be subject to an 


ethrower on DSK3G9T082PROD with PROPOSALS