Food Labeling: Health Claims; Soy Protein and Coronary Heart Disease

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 101

[Docket No. 98P-0683]

Food Labeling: Health Claims; Soy Protein and Coronary Heart

Disease

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to

authorize the use, on food labels and in food labeling, of health

claims on the association between soy protein and reduced risk of

coronary heart disease (CHD). FDA is proposing this action in response

to a petition filed by Protein Technologies International, Inc. (the

petitioner). The agency has tentatively concluded that, based on the

totality of publicly available scientific evidence, soy protein

included in a diet low in saturated fat and cholesterol may reduce the

risk of CHD.

DATES: Written comments by January 25, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Susan M. Pilch, Center for Food Safety

and Applied Nutrition (HFS-465), Food and Drug Administration, 200 C

St. SW., Washington, DC 20204, 202-205-4500.

SUPPLEMENTARY INFORMATION:

I. Background

On November 8, 1990, the President signed into law the Nutrition

Labeling and Education Act of 1990 (the 1990 amendments) (Pub. L. 101-

535). This new law amended the Federal Food, Drug, and Cosmetic Act

(the act) in a number of important ways. One of the most notable

aspects of the 1990 amendments was that they provided procedures

whereby FDA is to regulate health claims on food labels and in food

labeling.

In the Federal Register of January 6, 1993 (58 FR 2478), FDA issued

a final rule that implemented the health claim provisions of the act

(hereinafter referred to as the 1993 health claims final rule). In that

final rule, FDA adopted Sec. 101.14 (21 CFR 101.14), which sets out the

rules for the authorization and use of health claims. Additionally,

Sec. 101.70 (21 CFR 101.70) establishes a process for petitioning the

agency to authorize health claims about a substance-disease

relationship (Sec. 101.70(a)) and sets out the types of information

that any such petition must include (Sec. 101.70(d)). These regulations

became effective on May 8, 1993.

In response to the 1990 amendments, FDA also conducted an extensive

review of the evidence on the 10 substance-disease relationships listed

in the 1990 amendments. As a result of its review, FDA has authorized

claims for 8 of these 10 relationships, one of which focused on the

relationship between dietary saturated fat and cholesterol and reduced

risk of CHD. CHD is the most common, most frequently reported, and most

serious form of cardiovascular disease (CVD) (58 FR 2739, January 6,

1993). Further, while the agency denied the use on food labeling of

health claims relating dietary fiber to reduced risk of CVD (58 FR

2552), it authorized a health claim relating diets low in saturated fat

and cholesterol and high in fruits, vegetables, and grain products that

contain dietary fiber (particularly soluble fiber) to a reduced risk of

CHD.

In the proposed rule entitled ``Health Claims and Label Statements;

Lipids and Cardiovascular Disease'' (56 FR 60727, November 27, 1991),

FDA set out the criteria for evaluating evidence on diet and CVD

relationships. The agency focused on those aspects of the dietary lipid

and CVD relationship for which the strongest scientific evidence and

agreement existed. FDA noted that, because of the public health

importance of CHD, identification of ``modifiable'' risk factors for

CHD had been the subject of considerable research and public policy

attention. The agency also noted that there is general agreement that

elevated blood cholesterol levels are one of the major ``modifiable''

risk factors in the development of CHD. FDA cited Federal Government

and other reviews that concluded that there is substantial

epidemiologic and clinical evidence that high blood levels of total and

low density lipoprotein (LDL) cholesterol are a cause of

atherosclerosis and represent major contributors to CHD. Further,

factors that decrease total blood cholesterol and LDL-cholesterol will

also decrease the risk of CHD. FDA concluded that it is generally

accepted that blood total and LDL-cholesterol levels are major risk

factors for CHD, and that dietary factors affecting blood cholesterol

levels affect the risk of CHD. High intakes of dietary saturated fat

and, to a lesser degree, of dietary cholesterol are consistently

associated with elevated blood cholesterol levels. FDA concluded that

the publicly available data supported an association between diets low

in saturated fat and cholesterol and reduced risk of CHD (58 FR 2739 at

2751).

Based on its review using the stated criteria, and on its

consideration of comments received in response to the proposed rule

entitled ``Health Claims; Dietary Fiber and Cardiovascular Disease''

(56 FR 60582), FDA concluded that the publicly available scientific

information supported an association between diets low in saturated fat

and cholesterol and high in fruits, vegetables, and grain products

(i.e., foods that are low in saturated fat and cholesterol and that are

good sources of dietary fiber) and reduced risk of heart disease (58 FR

2552 at 2572). In the 1993 dietary fiber and CVD final rule, in

response to a comment regarding the apparent hypocholesterolemic

properties of specific food fibers, FDA again articulated its criteria

for evaluating diet and CHD relationships (58 FR 2552 at 2567). FDA

agreed that

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the effectiveness of naturally occurring fibers in foods in reducing

the risk of CHD may be documented for specific food products. Further,

the agency indicated that if manufacturers could document, through

appropriate studies, that dietary consumption of the soluble fiber in a

particular food has a beneficial effect on blood lipids predictive of

CHD risk, they should petition for a health claim for that particular

product. In response to two petitions that documented such evidence,

FDA has authorized health claims for soluble fiber from certain foods

and reduced risk of CHD in Sec. 101.81 (21 CFR 101.81) (62 FR 3584 at

3600, January 23, 1997, and amended at 62 FR 15343 at 15344, March 31,

1997, and 62 FR 8119, February 18, 1998).

The present rulemaking is in response to a manufacturer's health

claim petition on the relationship between soy protein and the risk of

CHD.

II. Petition for Soy Protein and Reduced Risk of CHD

A. Background

On May 4, 1998, Protein Technologies International, Inc., submitted

a health claim petition to FDA requesting that the agency authorize a

health claim on the relationship between consumption of soy protein and

the risk of CHD (Refs. 1 and 2). On August 12, 1998, the agency sent

the petitioner a letter stating that it had completed its initial

review of the petition, and that the petition would be filed in

accordance with section 403(r)(4) of the act (21 U.S.C. 343(r)(4))

(Ref. 3). In this proposed rule, the agency presents the rationale for

a health claim on this food-disease relationship as provided for under

the standard in section 403(r)(3)(B)(i) of the act and Sec. 101.14(c)

of FDA's regulations.

B. Review of Preliminary Requirements for a Health Claim

1. The Substance Is Associated With a Disease for Which the U.S.

Population Is at Risk

Several previous rules establish that CHD is a disease for which

the U.S. population is at risk, specifically claims for dietary

saturated fat and cholesterol and risk of CHD (Sec. 101.75 (21 CFR

101.75)); fruits, vegetables, and grain products and risk of CHD

(Sec. 101.77 (21 CFR 101.77)); and soluble fiber from certain foods and

risk of CHD (Sec. 101.81). FDA stated in these rules that CHD remains a

major public health problem and the number one cause of death in the

United States. Despite the decline in deaths from CHD over the past 30

years, this disease is still exacting a tremendous toll in morbidity

and mortality (Refs. 4 through 6). There are more than 500,000 deaths

each year for which CHD is an underlying cause, and another 250,000

deaths for which CHD is a contributing cause. About 20 percent of

adults (male and female; black and white) ages 20 to 74 years have

blood total cholesterol (or serum cholesterol) levels in the ``high

risk'' category (total cholesterol greater than (>) 240 milligrams (mg)

per (/) deciliter (dL) and LDL-cholesterol greater than 160 mg/dL)

(Ref. 7). Another 31 percent have ``borderline high'' cholesterol

levels (total cholesterol between 200 and 239 mg/dL and LDL-cholesterol

between 130 and 159 mg/dL) in combination with two or more risk

factors.

CHD has a significant effect on health-care costs. In 1985, total

direct costs related to CHD were estimated at $13 billion, and indirect

costs from loss of productivity due to illness, disability, and

premature deaths from this disease were an estimated $36 billion (Ref.

4). Based on these facts, FDA tentatively concludes that, as required

in Sec. 101.14(b)(1), CHD is a disease for which the U.S. population is

at risk.

2. The Substance Is a Food

The substance that is the subject of this rulemaking is soy protein

(Ref. 1). Soy protein is an edible component of the soybean, Glycine

max. Soybeans are a significant source of low-cost, high-quality

protein in the human diet.

Soy protein is used as an ingredient in other foods. It is produced

from raw whole soybeans by a multistep process that removes the lipid

and indigestible components to concentrate the protein and increase its

availability. Depending upon the particular steps used during

processing, soy protein ingredients may take the form of isolated soy

protein (ISP), soy protein concentrate (SPC), or soy flour (SF). Each

of these ingredients may be further processed into texturized soy

protein or texturized vegetable protein (TVP), used in the manufacture

of meat and poultry analogs, by thermoplastic extrusion or steam

texturization to impart structure and shape. In addition to protein,

these soy protein ingredients contain other naturally occurring soy

constituents, such as isoflavones, fiber, and saponins. The specific

processing steps employed determine the extent of retention of such

naturally occurring constituents in the final product.

Soy protein is also consumed in the diet as a component of

traditional fermented and nonfermented soy foods such as tofu, tempeh,

and miso, in addition to whole soybeans, soynuts, soy milk, soy yogurt,

and soy cheese. These products contain variable amounts of soy protein

and other naturally occurring soy constituents depending on the

specific technologies used in their production.

Soy protein ingredients (ISP, SPC, and SF) and soy protein-

containing foods may partially replace or be used in addition to animal

or other vegetable protein sources in the human diet. Therefore, FDA

has tentatively concluded that the substance satisfies the preliminary

requirement of Sec. 101.14(b)(3)(i).

3. The Substance Is Safe and Lawful

The petitioner stated that soy protein ingredients were in common

use in food before January 1, 1958, and that they are generally

recognized as safe (GRAS) by self-determination (Ref. 1). Because the

fractionation procedures used to convert vegetable flours to vegetable

protein isolates and concentrates were commonplace prior to 1958, the

petitioner asserted that ISP and SPC can be defined as soy flour

``subject only to conventional processing as practiced prior to January

1, 1958.'' The petitioner alluded to statements that it attributed to

FDA about the GRAS status of soy protein products. (In point of fact,

however, in one document (35 FR 18530, December 5, 1970), FDA was

restating a petitioner's grounds for its petition, and in the other

document (43 FR 30472, July 14, 1978), FDA was stating a condition on

the vegetable protein products to which the proposed regulation

applied, and was not itself determining the safety or suitability of

any product (43 FR 30472 at 30474 to 30475 (comment 10).) The

petitioner also referred to unidentified statements by the U.S.

Department of Agriculture, the Association of American Feed Control

Officials, and the Codex Alimentarius that it asserted support for the

GRAS status of soy protein products (Ref. 1).

The petition also addressed some concerns that have been raised

about the potential risk of consuming soy products: Allergenicity,

exposure to trypsin inhibitors, reduced bioavailability of minerals,

and hormonal disturbances.

As is true for any protein entering the gastrointestinal tract, soy

protein has the potential to elicit an allergic reaction. Food

allergies most commonly develop in infants and young children. Although

the use of heat or hot aqueous ethanol in the processing of soybeans

destroys the immunochemical reactivity of most of the protein, a small

number of infants fed soy formula experience allergic reactions to soy

(Ref. 9). Such sensitization appears to be a manifestation of an

immature digestive tract and is rarely seen in children more

[[Page 62979]]

than 4 years old or adults. Many children outgrow food allergies (Ref.

10) and soy and seafood allergies are among those likely to be

outgrown, in contrast to allergies to milk, egg white, or peanuts.

Concerns have been raised in the past about exposure to trypsin

inhibitors contained in soybeans because these compounds had been found

to stimulate pancreatic hyperplasia and hypertrophy in animals (Ref.

11). These concerns have been allayed because heat treatment removes

most of the activity of these proteases (Ref. 12). In addition, recent

studies have questioned the applicability of the animal models, which

differ from humans in the type of diet, sensitivity of the pancreas to

trypsin inhibitors, and the anatomic sites of pancreatic cell

proliferation (Refs. 12 through 15) and have found low rates of cancer

in populations with dietary patterns that include soy foods (Ref. 16).

Soybeans contain phytic acid and dietary fiber, which have well

documented effects on reducing the bioavailability of divalent

minerals, and these components are retained in the protein fraction in

variable amounts depending upon processing. In general, the

bioavailability of minerals is lower from plant sources than animal

sources, but soy has not been found to reduce the availability of

minerals from other dietary sources consumed concurrently (Ref. 17).

Data on the possible deleterious effects of soy, and particularly its

phytate content, on mineral balance have been obtained mainly from

studies of animal models; findings in humans are less consistent and

suggest that although absorption may be impaired, overall mineral

balance is not adversely affected (Refs. 13, 18, 19, 20).

Finally, the possibility of hormonal disturbances from the weakly

estrogenic-antiestrogenic effects of soy isoflavones has been raised.

For example, infertility was found in sheep that had consumed clover

containing isoflavones (Ref. 21); however, studies of soy isoflavones

in primates showed no effects on male or female reproductive tissue or

ability (Refs. 22 through 24). Soy isoflavones have been hypothesized

as a protective factor against breast cancer in populations that

consume large amounts of soy protein (Ref. 25), and in one controlled

human trial, a 45-mg/day dose of isoflavones lead to favorable changes

in menstrual cycle length and hormone levels similar to those seen in

women treated with tamoxifen (Ref. 26).

Based on the totality of the evidence and, in particular, its

common use in food, the agency is not prepared, at this time, to take

issue with the petitioner's view that the use of soy protein is safe

and lawful as required in Sec. 101.14(b)(3)(ii). Thus, FDA tentatively

concludes that the petitioner has provided evidence that satisfies the

requirement in Sec. 101.14(b)(3)(ii) that use of soy protein at the

levels necessary to justify a claim is safe and lawful.

III. Review of Scientific Evidence

A. Basis for Evaluating the Relationship Between Soy Protein and CHD

The review examined the relationship between soy protein and CHD by

focusing on the effects of dietary intake of this substance on blood

lipid levels and on the risk of developing CHD. In the 1991 lipids-CVD

and dietary fiber-CVD health claim proposals, the agency set forth the

basis for the relationship between dietary substances and CVD (56 FR

60727 at 60728 and 56 FR 60582 at 60583). In those documents, the

agency stated that there are many risk factors that contribute to the

development of CVD, and specifically CHD, one of the most serious forms

of CVD and among the leading causes of death and disability. The agency

also stated that there is general agreement that elevated blood

cholesterol levels are one of the major ``modifiable'' risk factors in

the development of CVD and, more specifically, CHD.

The Federal Government and others who have reviewed the matter have

concluded that there is substantial epidemiologic evidence that high

blood levels of total cholesterol and LDL-cholesterol are a cause of

atherosclerosis (inadequate circulation of blood to the heart due to

narrowing of the arteries) and represent major contributors to CHD (56

FR 60727 at 60728, 56 FR 60582 at 60583, Refs. 4 through 6). Factors

that decrease total cholesterol and LDL-cholesterol will also tend to

decrease the risk of CHD. High intakes of saturated fat and, to a

lesser degree, of dietary cholesterol are associated with elevated

blood total and LDL-cholesterol levels (56 FR 60727 at 60728). Thus, it

is generally accepted that blood total cholesterol and LDL-cholesterol

levels can influence the risk of developing CHD, and, therefore, that

dietary factors affecting these blood cholesterol levels affect the

risk of CHD (Refs. 4 through 6).

When considering the effect that the diet or components of the diet

have on blood (or serum) lipids, it is also useful to consider the

effect that these factors may have on blood levels of high density

lipoprotein (HDL)-cholesterol. HDL-cholesterol appears to have a

protective effect because it is involved in the regulation of

cholesterol transport out of cells and to the liver, from which it is

ultimately excreted (Refs. 4 and 8).

For these reasons, the agency based its evaluation of the

relationship between consumption of soy protein and CHD primarily on

changes in blood total and LDL-cholesterol resulting from dietary

intervention with soy protein-containing products. A secondary

consideration was that beneficial changes in total and LDL-cholesterol

should not be accompanied by potentially adverse changes in HDL-

cholesterol. This focus is consistent with that used by the agency in

response to the 1990 amendments in deciding on the dietary saturated

fat and cholesterol and CHD health claim, Sec. 101.75 (56 FR 60727 and

58 FR 2739); the fruits, vegetables, and grain products and CHD claim,

Sec. 101.77 (56 FR 60582 and 58 FR 2552); and the soluble fiber from

certain foods and CHD claim, Sec. 101.81 (61 FR 296, 62 FR 3584, 62 FR

28234, and 63 FR 8119).

B. Review of Scientific Evidence

1. Evidence Considered in Reaching the Decision

The petitioner submitted scientific studies (Refs. 27 through 66)

evaluating the relationship between soy protein in the diet and serum

lipid levels in humans (Refs. 1 and 2). The studies submitted were

conducted between 1976 and 1998. The petition included tables that

summarized the outcome of the studies and a summary of the evidence. In

the approach taken previously in the diet and CVD proposed rules, the

agency began its review of scientific evidence in support of a health

claim by considering those studies that were published since 1988, the

date of publication of the ``Surgeon General's Report on Nutrition and

Health,'' which is the most recent and comprehensive Federal review of

the scientific evidence on dietary factors and CVD. In a brief

discussion of the role of protein in coronary heart disease, the

Surgeon General's report noted that studies of the substitution of soy

protein and other vegetable proteins for animal protein in the diets of

hyperlipidemic patients have shown a marked reduction in serum

cholesterol levels but only a small change in persons with normal

cholesterol levels (Ref. 4). Because of the brevity of this

consideration of soy protein, the agency reviewed all of the studies on

soy protein submitted by the petitioner, including those published

prior to 1988.

The petition also presented some findings from studies that

employed animal models and from in vitro

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experiments. Human studies are weighted most heavily in the evaluation

of evidence on a diet and disease relationship; animal model and in

vitro studies can be considered as supporting evidence but cannot, in

the absence of human studies, serve as the basis for establishing that

a diet and disease relationship exists. Such studies may be useful in

providing information on the mechanism of action of soy protein's

effects on blood cholesterol levels.

2. Criteria for Selection of Human Studies

The criteria that the agency used to select the most pertinent

studies were consistent with those that the agency used to evaluate the

relationship between other substances and CHD. These criteria were that

the studies: (1) Present data and adequate descriptions of the study

design and methods; (2) be available in English; (3) include estimates

of, or enough information to estimate, soy protein intakes; (4) include

direct measurement of blood total cholesterol and other blood lipids

related to CHD; and (5) be conducted in persons who represent the

general U.S. population. In the case of (5), these persons can be

considered to be adults with blood total cholesterol levels less than

300 mg/dL. Studies of special population groups, such as adults with

very high serum cholesterol (mean greater than 300 mg/dL) and children

with hypercholesterolemia, were considered relative to the nature of

the support they provided for evidence of effect seen in studies of

subjects more representative of the general U.S. population.

In a previous rulemaking (62 FR 28234 at 28238 and 63 FR 8103 at

8107), the agency concluded that hypercholesterolemic study populations

are relevant to the general population because, based on data from the

National Health and Nutrition Examination Surveys (NHANES) III, the

prevalence of individuals with elevated blood cholesterol (i.e., 200

mg/dL or greater) is high, i.e., approximately 51 percent of adults

(Ref. 7). The proportion of adults having moderately elevated blood

cholesterol levels (i.e., between 200 and 239 mg/dL) was estimated to

be approximately 31 percent, and the proportion of adults with high

blood cholesterol levels (240 mg/dL or greater) was estimated to be

approximately 20 percent (Ref. 7). It is also estimated that 52 million

Americans 20 years of age and older would be candidates for dietary

intervention to lower blood cholesterol (Ref. 7). As the leading cause

of death in this country, CHD is a disease for which the general U.S.

population is at risk. The risk of dying from CHD is related to serum

cholesterol levels in a continuous and positive manner, increasing

slowly for levels between 150 mg/dL and 200 mg/dL and more rapidly when

the cholesterol level exceeds 200 mg/dL (Ref. 67). The public health

policy elucidated by the National Cholesterol Education Program (NCEP),

National Heart, Lung, and Blood Institute, is to extend the benefits of

cholesterol lowering to the population as a whole by promoting adoption

of eating patterns that can help lower the blood cholesterol levels of

most Americans (Ref. 67). A dietary intervention that lowers blood

cholesterol levels mainly or only in persons with high levels would,

like an intervention that lowers cholesterol levels across the entire

population range, cause a shift in the population distribution of blood

cholesterol levels resulting in a decrease in the mean value for the

blood cholesterol level in the general population (Ref. 67). The

anticipated effect of such a shift would be to reduce the morbidity

from CHD and to produce a continued or accelerated decline in the CHD

mortality rate in the United States. Accordingly, in this proposal, the

agency has reviewed and considered the evidence of effects of soy

protein on serum lipids in hypercholesterolemic subjects.

In selecting human studies for review, the agency excluded studies

that were published in abstract form because they lacked sufficient

detail on study design and methodologies, and because they could not

provide the primary data.

3. Criteria for Evaluating the Relationship Between Soy Protein and CHD

Well reasoned approaches for evaluating studies supporting diet/

disease relationships are summarized in the comprehensive report ``Diet

and Health'' issued by the National Academy of Sciences (Ref. 68) and

``The Guide to Clinical Preventive Services'' issued by the U.S.

Preventive Services Task Force (Ref. 69). The criteria articulated in

these documents provided a starting point for FDA's review of

individual studies on the relationship between dietary factors and CHD

in previous rulemakings: In the 1991 proposed rule on lipids and CVD

(56 FR 60727), in the 1991 proposed rule on dietary fiber and CVD (56

FR 60582), in the January 1996 proposed rule on whole oats and CHD (61

FR 296), and in the May 22, 1997, proposed rule on soluble fiber from

psyllium and CHD (62 FR 28234).

The criteria that the agency used in evaluating the studies for

this rulemaking include: (1) Reliability and accuracy of the methods

used in nutrient intake analysis, including measurements of soy protein

intake; (2) estimates of intake of saturated fat and cholesterol; (3)

available information on the soy protein test products and control

foods; (4) measurement of study endpoints (i.e., measurement of blood

lipid levels); and (5) general study design characteristics.

The general study design characteristics for which the agency

looked included randomization of subjects, appropriateness of controls,

selection criteria for subjects, attrition rates (including reasons for

attrition), potential for misclassification of individuals with regard

to dietary intakes, presence of recall bias and interviewer bias,

recognition and control of confounding factors (for example, monitoring

body weight and control of weight loss), appropriateness of statistical

tests and comparisons, and statistical power of the studies. The agency

considered whether the intervention studies that it evaluated had been

of long enough duration, greater than or equal to 3 weeks duration, to

ensure reasonable stabilization of blood lipids.

C. Review of Human Studies

FDA conducted a comprehensive review of 41 of 43 human intervention

studies submitted in the petition and reported in 38 references by the

petitioner (Refs. 27 through 64). The two studies FDA excluded from

consideration at the outset (Refs. 32 and 52) were of infants. Of the

studies reviewed, 27 met the aforementioned criteria for selection

(Refs. 27, 28, 29, 30 (1 trial), 31, 33, 34, 35, 36, 37, 40 (2 trials),

42 and 45 (1 trial), 43, 44, 46, 49, 51, 53, 54, 55, 56, 58, 59, 60,

63, and 64). Of these, the agency gave particular weight to 14 trials

(Refs. 27, 28, 30 (1 trial), 31, 36, 37 (1 trial), 40 (2 trials), 44,

49, 51, 54, 58, and 59) that included subjects representative of the

general U.S. population and that were well controlled, reported intakes

of saturated fat and cholesterol, and avoided problems associated with

small sample size, lack of a placebo, and other design problems. These

studies are summarized in Table 1 at the end of this document and

discussed in section III.C.1 of this document. Three additional similar

trials that were included in the review but accorded less weight

because of issues concerning the populations studied and diets fed

(Refs. 29, 43, and 53) are also summarized in Table 1 of this document

and discussed in section III.C.1 of this document. Seven trials in

adults (Refs. 33, 35, 46,

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55, 56, 60, and 64) and three trials in children (Refs. 34, 42 and 45

(1 trial), and 63) with type II or familial hypercholesterolemia are

summarized in Table 2 at the end of this document and discussed in

section III.C.2 of this document. The fourteen remaining intervention

trials (Refs. 30 (1 trial), 37 (1 trail), 38, 39 (2 trials), 41, 47,

48, 50 (2 trials), 57, 61, and 62 (2 trials)) failed to meet the

inclusion criteria because of small sample size, inadequate period of

intervention, inadequate characterization of the soy protein tested,

inadequate information on dietary intake, or lack of data on outcome

variables. The results of one epidemiological study (Ref. 65) and a

meta-analysis (Ref. 66) that included a number of the soy protein

studies submitted in the petition are discussed in sections III.C.3 and

III.C.4, respectively, of this document.

1. Studies of Adult Subjects Representative of the General U.S.

Population (Serum Cholesterol 0.05) in total cholesterol of 3 percent. Differences in LDL- and

HDL-cholesterol from baseline or control after the two soy diets were

not statistically significant. In the subset analysis, the additional

effect of soy fiber on blood cholesterol levels was not significant

when evaluated by analysis of covariance (p=0.04 for protein effects;

p=0.07 for fiber effects). This study supports a conclusion that the

protein and not the fiber component of the soybean is largely

responsible for effects on blood lipids.

Potter et al. (Ref. 51) reported a statistically significant

(p0.05) on the two diets.

However, among the subjects whose baseline total cholesterol was above

the 90th percentile, the soy protein diet resulted in a decrease from

baseline in mean total cholesterol of 4 percent and a level 9 percent

lower (16 mg/dL; p150 percent of ideal body weight) received 375 kilocalorie

(kcal)/day initially, followed by an 800 kcal/day diet. During both

phases, the 375 kcal portion was provided by commercial textured

protein products that delivered either 27 g protein from casein or 27 g

protein from soy protein (type of soy protein not given). During the

second phase, the 375 kcal/day was ``integrated'' with an extra 425

kcal/day from conventional foods. Mean weight losses for the soy and

casein groups were 17 and 16 kg, respectively. Total cholesterol and

LDL-cholesterol in the soy group were both 16 percent lower compared to

baseline (p0.05) different in the two groups consuming soy as ISP and the

control group. However, there was a statistically significant reduction

of 8 to 9 percent in non-HDL (LDL plus VLDL) cholesterol in both of the

ISP treatment groups (p=0.04) compared to the control group.

Bakhit et al. (Ref. 27) found, in a subset of subjects whose

cholesterol remained greater than the 220 mg/dL intent-to-treat level

after run-in with the baseline diet, a statistically significant

decrease in total cholesterol of 7 percent (p300 mg/dL)

Ten studies (Refs. 33, 35, 46, 55, 56, 60, 64, 34, 42 and 45 (1

trial), and 63) of subjects with severe (type II or familial)

hypercholesterolemia (mean total cholesterol level>300 mg/dL) are

summarized in Table 2 of this document and discussed in section III.

C.2 of this document. Seven report results in adults (Refs. 33, 35, 46,

55, 56, 60, and 64) and three in children (Refs. 34, 42 and 45 (1

trial), and 63).

a. Studies in adults. Sirtori et al. (Ref. 55) reported a decrease

of 21 percent in both total (p 4.95

g/day for men and 6.88

[[Page 62987]]

4.06 g/day for women. The authors noted that their FFQ may

underestimate soy product intake; they also estimated that 4 to 9 g

additional soy protein may be consumed daily from soy protein added to

meats and fish pastes that was not accounted for in the FFQ. Thus,

analyses were presented in terms of relative soy protein intake. Using

energy-adjusted means for quartiles of soy protein intake, a

statistically significant negative trend was observed for lower serum

total cholesterol concentrations with higher levels of soy protein

intake (p140 mg/dL) were given a

casein drink containing 25 g protein to consume in place of other

protein in the NCEP Step 1 diet. Subjects compliant with this regimen

were then randomized into one of five treatment groups and baseline

blood lipid values were obtained. The treatment groups received 25 g

protein from ISP prepared from soy with different levels of isoflavones

(either 1.0, 1.6, or 2.5 mg total aglycone isoflavones/g protein), or

25 g protein from alcohol-washed ISP that contained essentially no

isoflavones (0.2 mg total aglycone isoflavones/g protein) or 25 g

protein from casein (no isoflavones) in beverages for 9 weeks. Dietary

intake was assessed at baseline and at the end of the study. Diet was

reported to be stable and comparable between groups throughout the

study, with 9 percent of energy derived from saturated fat. Body weight

was also stable, with no differences between groups at baseline or at

the end of the trial. Results indicated the ISP containing the highest

level of isoflavones significantly lowered total (p20 percent) reductions in both total and LDL-

cholesterol in subjects with type II hypercholesterolemia.

Based on these data that support a dose-response and that show

clinically significant reductions in total and LDL-

[[Page 62992]]

cholesterol with soy protein ingestion in the range of 17 to 31 g/day,

and recognizing that the hypocholesterolemic effects of soy protein are

highly dependent on initial blood lipid levels, the agency has

tentatively accepted that 25 g/day represents a reasonable effective

amount of soy protein. In addition, an amount of 25 g/day of soy

protein represents half of the Reference Daily Intake (RDI) of 50 g for

protein and is a reasonable level of consumption in the context of the

total daily diet. Thus, FDA tentatively concludes that the amount of

soy protein associated with reduction in total and LDL-cholesterol

levels and, thus, with reduced risk of CHD is 25 g or more of soy

protein per day. The agency is asking for comments on this tentative

determination.

C. Nature of the Substance

Proposed Sec. 101.82(c)(2)(ii)(A) indicates that soy protein from

the legume seed Glycine max is the substance that is the subject of

this claim.

Proposed Sec. 101.82(c)(2)(ii) (B) sets out FDA's tentative

decision that soy protein when evaluated for compliance purposes by the

agency will be measured using the Association of Official Analytical

Chemists International (AOAC) official method of analysis No. 988.10.

The petitioner proposed that measurement of total soy isoflavones

be used as a marker for the content of soy protein in foods and as an

indicator of the effectiveness of soy protein products in reducing

blood cholesterol. As discussed in section C.III.5 of this document,

FDA disagrees with the petitioner's conclusions regarding the

significance of soy isoflavones with respect to the observed

hypocholesterolemic effects of soy protein. Accordingly, FDA finds the

proposed methodology to assess isoflavones irrelevant. The AOAC method

that FDA is proposing instead is an enzyme-linked immunosorbant assay

that detects soy protein in raw and heat-processed meat products. With

this assay, samples are compared to standard commercial soy protein and

appropriate blanks. The method is described as semi-quantitative, but

it can be quantitative when the nature of the soy protein in the

samples is known and the assay is calibrated accordingly. The sample

extraction procedure, which involves preparation of an acetone powder,

has been shown to be appropriate for a complex food matrix (meat). FDA

believes, therefore, that this assay should also be suitable for other

food matrices. FDA is requesting comments on the suitability of this

method for assuring that foods bearing the health claim contain

qualifying levels of soy protein.

D. Nature of the Food

Proposed Sec. 101.82(c)(2)(iii)(A) requires that the food bearing

the health claim contain at least 6.25 g of soy protein per reference

amount customarily consumed (RACC) of the food product.

Using 25 g of soy protein as the qualifying amount for a CHD claim,

the petitioner suggested that a single serving of a soy protein-

containing product (i.e., 1 RACC) should provide 1/4 of this amount

(based on 4 servings a day). Thus, a soy protein-containing product

would have to contain at least 6.25 g soy protein (1/4 x 25 g) per

RACC. The petitioner stated that this approach is reasonable because it

would permit a wide variety of low fat, soy protein containing products

to bear the health claim. The petitioner provided a list of products on

the market that currently meet the proposed requirements and a list of

products that could be modified to meet them (Ref. 1, Appendix V).

The agency has generally made the assumption that a daily food

consumption pattern includes three meals and a snack (see 58 FR 2302 at

2379, January 6, 1993). Because of the wide variety of types of foods

that could contain qualifying levels of soy protein (baked goods, tofu,

soy beverages and shakes, meat analogs), the agency has tentatively

concluded that the assumption of 4 servings/d of soy protein containing

foods is reasonable. Therefore, the agency tentatively finds that use

of the qualifying criterion set forth in the petition for this proposed

rule is appropriate and is proposing this level in this document. The

qualifying level of protein, 6.25 g/RACC, exceeds the amount required

for a food to qualify as a ``good source'' of protein, i.e., 10 percent

of the RDI of 50 g or 5 g/RACC).

In Sec. 101.82(c)(2)(iii)(B), the agency is proposing, consistent

with other authorized heart disease health claims, that foods bearing

the health claim meet requirements for ``low saturated fat,'' ``low

cholesterol,'' and ``low fat.'' In the preamble to the final rule on

fruits, vegetables, and grain products and heart disease (Sec. 101.77,

58 FR 2552 at 2572), the agency stated that populations with diets rich

in these low saturated fat and low cholesterol foods experience many

health advantages, including lower rates of heart disease. In the

preamble to the proposed rule on dietary lipids and heart disease (56

FR 60727 at 60739), the agency stated that while total fat is not

directly linked to increased risk of CHD, it may have significant

indirect effects. Foods that are low in total fat facilitate reductions

in intakes of saturated fat and cholesterol to recommended levels.

Therefore, the agency tentatively concludes that proposed

Sec. 101.82(c)(2)(iii)(B) sets forth an appropriate requirement for

food to be eligible to bear the soy protein and CHD claim.

E. Optional Information

FDA is proposing in Sec. 101.82(d)(1) that the claim may state that

the development of heart disease depends on many factors and,

consistent with authorized CHD health claims, may list the risk factors

for heart disease that are listed in Secs. 101.75(d)(1), 101.77(d)(1),

and 101.81(d)(1). The agency is also proposing, in response to the

petition, that the claim may provide additional information about the

benefits of exercise and body weight management. This additional

information can provide a context that is useful for an understanding

of the relationship between soy protein and heart disease, but

manufacturers should be cautioned that it should not be presented in a

way that is misleading to the consumer.

In proposed Sec. 101.82(d)(2), consistent with Secs. 101.75(d)(2),

101.77(d)(2), and 101.81(d)(2), FDA is providing that the claim may

state that the relationship between a diet high in soy protein and

reduced risk of heart disease is through the intermediate link of

``blood cholesterol'' or ``blood total cholesterol'' and ``LDL-

cholesterol.'' The relationship between soy protein and reduced blood

total cholesterol and LDL-cholesterol is supported by the scientific

evidence presented in this proposal.

In Sec. 101.82(d)(3), the agency is proposing that, consistent with

Secs. 101.75(d)(3), 101.77(d)(3), and 101.81(d)(3), the claim may

include information from Sec. 101.82(a) and (b). These paragraphs

summarize information regarding the relationship between diets high in

soy protein and the risk of CHD and about the significance of that

relationship. This information helps to convey the seriousness of CHD

and the role that a diet high in soy protein can play to help reduce

the risk of CHD.

The agency is proposing that the claim may include any of the

optional information authorized to be included in Secs. 101.75(d)(5),

(d)(6), and (d)(7), 101.77(d)(5), (d)(6), and (d)(7), and 101.81(d)(5),

(d)(6), and (d)(7). The health claim may state that diets high in soy

protein and low in saturated fat and cholesterol are part of a dietary

pattern

[[Page 62993]]

that is consistent with dietary guidelines for Americans. The claim may

state that individuals with elevated serum lipids should consult their

physicians for medical advice and treatment and may include information

on the prevalence of CHD in the United States. The intent of this

information is to provide consumers with information that will help

them understand the seriousness of CHD in the United States and to help

them understand that diets high in soy protein are consistent with

dietary guidelines.

F. Model Health Claims

In proposed Sec. 101.82(e), FDA is providing model health claims to

illustrate the requirements of new Sec. 101.82. FDA emphasizes that

these model health claims are illustrative only. These model claims

illustrate the required, and some of the optional, elements of the

proposed rule. If the agency authorizes a claim about the relationship

between soy protein and CHD, manufacturers will be free to design their

own claim so long as it is consistent with Sec. 101.82(c).

In Secs. 101.82(e)(1) and (e)(2), the model claim illustrates all

of the required elements of the proposed health claim. The claim states

``25 grams of soy protein a day, as part of a diet low in saturated fat

and cholesterol, may reduce the risk of heart disease. A serving of

[name of food] supplies ---------- grams of soy protein.'' or ``Diets

low in saturated fat and cholesterol that include 25 grams of soy

protein may reduce the risk of heart disease. One serving of [name of

food] provides ---------- grams of soy protein.''

VI. Environmental Impact

The agency has determined under 21 CFR 25.30(k) that this action is

of a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

VII. Analysis of Impacts

A. Cost-Benefit Analysis

FDA has examined the impacts of the proposed rule under Executive

Order 12866. Executive Order 12866 directs Federal 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). According to Executive Order 12866, a regulatory action is

``economically significant'' if it meets any one of a number of

specified conditions, including having an annual effect on the economy

of $100 million or adversely affecting in a material way a sector of

the economy, competition, or jobs. A regulation is considered

``significant'' under Executive Order 12866 if it raises novel legal or

policy issues. FDA finds that this proposed rule is neither an

economically significant nor a significant regulatory action as defined

by Executive Order 12866.

In addition, in accordance with the Small Business Regulatory

Enforcement Fairness Act (5 U.S.C. 801(a)(1)(A)(ii)), the Administrator

of the Office of Information and Regulatory Affairs of the Office and

Management and Budget (the Administrator) has determined that this

proposed rule is not a major rule for the purpose of congressional

review. A major rule for this purpose is defined in 5 U.S.C. 804(2) as

one that the Administrator has determined has resulted or is likely to

result in: (1) An annual effect on the economy of $100,000,000 or more;

or (2) a major increase in costs for prices for consumers, individual

industries, Federal, State, or local government agencies, or geographic

regions; or (3) significant adverse effects on competition, employment,

investment, productivity, innovation, or on the ability of U.S.-based

enterprises to compete with foreign-based enterprises in domestic or

export markets.

This proposed rule will give firms the option of making certain

label claims involving soy protein. No costs will be generated by this

proposed rule because it will not require any labels to be changed or

any product to be reformulated. Firms will only relabel or reformulate

products if the benefits to those firms outweigh the costs. Social

benefits may be generated by this proposed rule because the value some

consumers place on the information provided in these claims may be

greater than the cost to industry of making these claims. In general,

consumers may value this type of information because it will enable

them to eat a healthier diet. Consumers may value this type of

information presented on product labels, in particular, because it

would obviate the need to consult other sources of information and

because it may reassure consumers who are aware of the role of FDA in

regulating health claims on product labels that the information is

truthful, not misleading, and scientifically valid.

Consumer valuation of this information will reflect the value that

consumers place on reducing the likelihood of CHD and the perceived

usefulness of this information for reducing the likelihood of CHD.

However, consumers may either underestimate or overestimate the

usefulness of this information in reducing the likelihood of CHD.

Therefore, another metric for valuing the social benefits of this

proposed rule is the health care costs avoided by the reduction in CHD-

related disease and disability made possible by this proposed rule. If

consumers were aware of these health care costs and had an accurate

notion of the likelihood that such costs could be avoided by using the

information provided in the claims allowed by this proposed rule, then

consumer valuation of this information would be at least as great as

the value of any health care costs avoided. The value of the

information might be greater because some consumers might value the

information but might not choose to modify their behavior so as to

reduce the likelihood of CHD.

In general terms, the relevant regulatory options available to FDA

are as follows: (1) Allow this claim to be made under a broader set of

conditions than those specified in this proposed rule (e.g., with fewer

required elements in the claim, or with a lower level of soy protein in

a serving of food), and (2) allow this claim to be made under a more

restricted set of conditions than those specified in this rule (e.g.,

more required elements or higher levels of soy protein). Neither of

these alternatives would generate net costs because, like the proposed

action, firms would only relabel or reformulate products if the

benefits to those firms outweigh the costs. These options would

generate higher benefits than the proposed action if allowing this

claim to be made under either a broader set of conditions or more

restricted set of conditions than the proposed conditions would provide

consumers with more valuable information (that would nonetheless be

truthful, not misleading, and scientifically valid) or would make

possible a greater reduction in health care costs than would the

proposed action. FDA tentatively believes that no alternative

conditions exist that would render the net benefits of this proposed

rule greater than the proposed conditions. In particular, FDA believes

that the information proposed to be required in a health claim about

the relationship between soy protein and CHD is the minimum necessary

for the claim to be truthful, not misleading, and

[[Page 62994]]

scientifically valid, thereby maximizing the likelihood that qualifying

foods will be labeled with the claim and that consumers will be able to

use the information. Similarly, FDA believes that the amount of soy

protein proposed to be required for a food bearing this claim will

allow both the claim to appear on a significant number of foods and

consumers who use the claim, in the aggregate, to benefit from the use

of soy protein in their diet. However, FDA requests comments and

supporting information on any modifications of the conditions under

which this claim is allowed that would increase the net benefits of

this proposed rule.

B. Small Entity Analysis

FDA has examined the impacts of this proposed rule under the

Regulatory Flexibility Act (5 U.S.C. 601-612). The Regulatory

Flexibility Act requires Federal agencies to consider alternatives that

would minimize the economic impact of their regulations on small

businesses and other small entities. No costs will be generated by this

proposed rule because it will not require any labels to be changed, or

any product to be reformulated. Therefore, small businesses will only

relabel or reformulate products if the benefits (e.g., increased sales

of their products) to those small businesses outweigh the costs.

Accordingly, under the Regulatory Flexibility Act) (5 U.S.C. 605(b)),

the Commissioner of Food and Drugs certifies that this proposed rule,

if issued, will not have a significant economic impact on a substantial

number of small entities.

VIII. Paperwork Reduction Act

FDA tentatively concludes that the labeling requirements proposed

in this document are not subject to review by the Office of Management

and Budget because they do not constitute a ``collection of

information'' under the Paperwork Reduction Act of 1995 (44 U.S.C.

3501-3520). Rather, the proposed food labeling health claim on the

association between soy protein and coronary heart disease would be a

``public disclosure of information originally supplied by the Federal

government to the recipient for the purpose of disclosure to the

public'' (5 CFR 1320.3(c)(2)).

IX. Effective Date

FDA is proposing to make these regulations effective upon

publication in the Federal Register of a final rule based upon this

proposal.

X. Comments

Interested persons may, on or before January 25, 1999, submit to

the Dockets Management Branch (address above) written comments

regarding this proposal. Two copies of any comments are to be

submitted, except that individuals may submit one copy. Comments are to

be identified with the docket number found in brackets in the heading

of this document. Received comments may be seen in the office above

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

XI. References

The following references have been placed on display in the Dockets

Management Branch (address above) and may be seen by interested persons

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

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Blood Lipid Profiles and Increases Mononuclear Cell LDL Receptor mRNA

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30. Carroll, K. K., P. M. Giovannetti, M. W. Huff, O. Moase, D. C.

K. Roberts, and B. M. Wolfe, ``Hypocholesterolemic Effect of

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31. Crouse, J. R. III, T. Morgan, J. G. Terry, J. Ellis, M.

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Ravaglia, G. C. Descovich, and C. R. Sirtori, ``Dietary Treatment for

Familial Hypercholesterolemia--Differential Effects of Dietary Soy

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36. Giovannetti, P. M., K. K. Carroll, and B. M. Wolfe, ``Constancy

of Fasting Serum Cholesterol of Healthy Young Women Upon Substitution

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37. Goldberg, A. P., A. Lim, J. B. Kolar, J. J. Grundhauser, F. H.

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38. Gooderham, M. J., H. Adlercreutz, S. T. Ojala, K. Wahala, and

B. J. Holub, ``A Soy Protein Isolate Rich in Genistein and Daidzein and

its Effects on Plasma Isoflavone Concentrations, Platelet Aggregation,

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Normal Men,'' Journal of Nutrition, 126:2000-2006, 1996.

39. Grundy, S. M. and J. J. Abrams, ``Comparison of Actions of Soy

Protein and Casein on Metabolism of Plasma Lipoproteins and Cholesterol

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39:888-897, 1984.

42. Jacques, H., D. Laurin, S. Moorjani, F. H. Steinke, C. Gagne,

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47. Meinertz, H., O. Faergeman, K. Nilausen, M. J. Chapman, S.

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50. Meredith, L., M. Liebman, and K. Graves, ``Alterations in

Plasma Lipid Levels Resulting From Tofu and Cheese Consumption in Adult

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51. Potter, S. M., R. M. Bakhit, D. L. Essex-Sorlie, K. E.

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W. Winter, and J. W. Erdman, Jr., ``Depression of Plasma Cholesterol in

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52. Potter, J. M. and P. J. Nestel, ``Greater Bile Acid Excretion

With Soy Bean Than With Cow Milk In Infants,'' American Journal of

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53. Sacks, F. M., J. L. Breslow, P. G. Wood, and E. H. Kass, ``Lack

of an Effect of Dairy Protein (Casein) and Soy Protein on Plasma

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54. Shorey, R. L., B. Bazan, G. S. Lo, and F. H. Steinke,

``Determinants of Hypercholesterolemic Response to Soy and Animal

Protein-Based Diets,'' American Journal of Clinical Nutrition, 34:1769-

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55. Sirtori, C. R., E. Agradi, F. Conti, O. Mantero, and E. Gatti,

``Soybean-protein Diet in the Treatment of Type-II

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56. Sirtori, C. R., C. Zucchi-Dentone, M. Sirtori, E. Gatti, G. C.

Descovich, A. Gaddi, L. Cattin, P. G. Da Col, U. Senin, E. Mannarino,

G. Avellone, L. Colombo, C. Fragiacomo, G. Noseda, and S. Lenzi,

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57. Steele, M. G., ``The Effect on Serum Cholesterol Levels of

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58. Van Raaij, J. M. A., M. B. Katan, J. G. A. J. Hautvast, and R.

J. J. Hermus, ``Effects of Casein Versus Soy Protein Diets on Serum

Cholesterol and Lipoproteins in Young Healthy Volunteers,'' American

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59. Van Raaij, J. M. A., M. B. Katan, C. E. West, and J. G. A. J.

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60. Verrilo, A., A. de Teresa, P. C. Giarrusso, and S. La Rocca,

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Werner, ``The Effects on Lipid and Carbohydrate Metabolism of Replacing

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Hypercholesterolaemic Patients,'' Human Nutrition: Applied Nutrition,

36A:179-189, 1982.

62. Wang, M. F., S. Yamamoto, H. M. Chung, S. Y. Chung, S.

Miyatani, M. Mori, T. Okita, and M. Sugano, ``Antihypercholesterolemic

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63. Widhalm, K., G. Brazda, B. Schneider, and S. Kohl, ``Effect of

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64. Wolfe, B. M., P. M. Giovannetti, D. C. H. Cheng, D. C. K.

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24:(6)1187-1198, 1981.

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66. Anderson, J.W., B.M. Johnstone, and M.E. Cook-Newell, ``Meta-

analysis of the Effects of Soy Protein Intake on Serum Lipids,'' New

England Journal of Medicine,, 333:276-282, 1995.

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Cholesterol Education Porgram, ``Report of the Expert Panel on

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Report),'' Chapter II. Background and Introduction, NIH Publication No.

93-3046, Bethesda, MD, 1993.

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and Health: Implications for Reducing Chronic Disease Risk,'' National

Academy Press, Washington, DC, pp. 23-40, 1989.

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Proteins in the Clinic,'' letter to the editor, American Journal of

Clinical Nutrition, 65:166-167, 1997.

List of Subjects in 21 CFR Part 101

Food labeling, Incorporation by reference, 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 21 CFR 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.

2. New Sec. 101.82 is added to subpart E to read as follows:

Sec. 101.82 Health claims: Soy protein and risk of coronary heart

disease (CHD).

(a) Relationship between diets that are low in saturated fat and

cholesterol and that include soy protein and the risk of CHD. (1)

Cardiovascular disease means diseases of the heart and circulatory

system. CHD is one of the most common and serious forms of

cardiovascular disease and refers to diseases of the heart muscle and

supporting blood vessels. High blood total cholesterol and low density

lipoprotein (LDL)-cholesterol levels are associated with increased risk

of developing CHD. High CHD rates occur among people with high total

cholesterol levels of 240 milligrams per deciliter (mg/dL) (6.21

(millimole per liter (mmol/L))) or above and LDL-cholesterol levels of

160 mg/dL (4.13 mmol/L) or above. Borderline high risk total

cholesterol levels range from 200 to 239 mg/dL (5.17 to 6.18 mmol/L)

and 130 to 159 mg/dL (3.36 to 4.11 mmol/L) of LDL-cholesterol. The

scientific evidence establishes that diets high in saturated fat and

cholesterol are associated with increased levels of blood total and

LDL-cholesterol and, thus, with increased risk of CHD.

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(2) Populations with a low incidence of CHD tend to have

relatively low blood total cholesterol and LDL-cholesterol levels.

These populations also tend to have dietary patterns that are not only

low in total fat, especially saturated fat and cholesterol, but are

also relatively high in plant foods that contain dietary fiber and

other components.

(3) Scientific evidence demonstrates that diets low in saturated

fat and cholesterol may reduce the risk of CHD. Other evidence

demonstrates that the addition of soy protein to a diet that is low in

saturated fat and cholesterol may also help to reduce the risk of CHD.

(b) Significance of the relationship between diets that are low in

saturated fat and cholesterol and that include soy protein and the risk

of CHD. (1) CHD is a major public health concern in the United States.

It accounts for more deaths than any other disease or group of

diseases. Early management of risk factors for CHD is a major public

health goal that can assist in reducing risk of CHD. High blood total

and LDL-cholesterol are major modifiable risk factors in the

development of CHD.

(2) Intakes of saturated fat exceed recommended levels in the

diets of many people in the United States. One of the major public

health recommendations relative to CHD risk is to consume less than 10

percent of calories from saturated fat and an average of 30 percent or

less of total calories from all fat. Recommended daily cholesterol

intakes are 300 mg or less per day. Scientific evidence demonstrates

that diets low in saturated fat and cholesterol are associated with

lower blood total and LDL-cholesterol levels. Soy protein, when

included in a low saturated fat and cholesterol diet, also helps to

lower blood total and LDL-cholesterol levels.

(c) Requirements. (1) All requirements set forth in Sec. 101.14

shall be met.

(2) Specific requirements--(i) Nature of the claim. A health claim

associating diets that are low in saturated fat and cholesterol and

that include soy protein with reduced risk of heart disease may be made

on the label or labeling of a food described in paragraph (c)(2)(iii)

of this section, provided that:

(A) The claim states that diets that are low in saturated fat and

cholesterol and that include soy protein ``may'' or ``might'' reduce

the risk of heart disease;

(B) In specifying the disease, the claim uses the following terms:

``heart disease'' or ``coronary heart disease'';

(C) In specifying the substance, the claim uses the term ``soy

protein'';

(D) In specifying the fat component, the claim uses the terms

``saturated fat'' and ``cholesterol'';

(E) The claim does not attribute any degree of risk reduction for

CHD to diets that are low in saturated fat and cholesterol and that

include soy protein;

(F) The claim does not imply that consumption of diets that are low

in saturated fat and cholesterol and that include soy protein is the

only recognized means of achieving a reduced risk of CHD; and

(G) The claim specifies the daily dietary intake of soy protein

that is necessary to reduce the risk of coronary heart disease and the

contribution one serving of the product makes to the specified daily

dietary intake level. The daily dietary intake level of soy protein

that has been associated with reduced risk of coronary heart disease is

25 grams (g) or more per day of soy protein.

(ii) Nature of the substance. (A) Soy protein from the legume seed

Glycine max.

(B) FDA will measure soy protein by method No. 988.10 from the

``Official Methods of Analysis of the Association of Official

Analytical Chemists International,'' 16th Ed. (1995), which is

incorporated by reference in accordance with 5 U.S.C. 522(a) and 1 CFR

part 51. Copies may be obtained from the Association of Official

Analytical Chemists International, 481 North Frederick Ave., suite 500,

Gaithersburg, MD 20877-2504, or may be examined at the Center for Food

Safety and Applied Nutrition's Library, 200 C St. SW., rm. 3321,

Washington, DC, or at the Office of the Federal Register, 800 North

Capitol St. NW., suite 700, Washington, DC;

(iii) Nature of the Food Eligible to Bear the Claim. (A) The food

product shall contain at least 6.25 g of soy protein reference amount

customarily consumed of the food product;

(B) The food shall meet the nutrient content requirements in

Sec. 101.62 for a ``low saturated fat,'' ``low cholesterol,'' and ``low

fat'' food.

(d) Optional information. (1) The claim may state that the

development of heart disease depends on many factors and may identify

one or more of the following risk factors for heart disease about which

there is general scientific agreement: A family history of CHD;

elevated blood total and LDL-cholesterol; excess body weight; high

blood pressure; cigarette smoking; diabetes; and physical inactivity.

The claim may also provide additional information about the benefits of

exercise and management of body weight to help lower the risk of heart

disease;

(2) The claim may state that the relationship between intake of

diets that are low in saturated fat and cholesterol and that include

soy protein and reduced risk of heart disease is through the

intermediate link of ``blood cholesterol'' or ``blood total and LDL-

cholesterol;''

(3) The claim may include information from paragraphs (a) and (b)

of this section, which summarize the relationship between diets that

are low in saturated fat and cholesterol and that include soy protein

and CHD and the significance of the relationship;

(4) The claim may state that a diet low in saturated fat and

cholesterol that includes soy protein is consistent with ``Nutrition

and Your Health: Dietary Guidelines for Americans,'' U.S. Department of

Agriculture (USDA) and Department of Health and Human Services (DHHS),

Government Printing Office (GPO);

(5) The claim may state that individuals with elevated blood total

and LDL-cholesterol should consult their physicians for medical advice

and treatment. If the claim defines high or normal blood total and LDL-

cholesterol levels, then the claim shall state that individuals with

high blood cholesterol should consult their physicians for medical

advice and treatment;

(6) The claim may include information on the number of people in

the United States who have heart disease. The sources of this

information shall be identified, and it shall be current information

from the National Center for Health Statistics, the National Institutes

of Health, or ``Nutrition and Your Health: Dietary Guidelines for

Americans,'' USDA and DHHS, GPO;

(e) Model health claim. The following model health claims may be

used in food labeling to describe the relationship between diets that

are low in saturated fat and cholesterol and that include soy protein

and reduced risk of heart disease:

(1) 25 grams of soy protein a day, as part of a diet low in

saturated fat and cholesterol, may reduce the risk of heart disease. A

serving of [name of food] supplies -------------- grams of soy protein.

(2) Diets low in saturated fat and cholesterol that include 25

grams of soy protein may reduce the risk of heart disease. One serving

of [name of food] provides ---------------- grams of soy protein.

Dated: November 2, 1998.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 98-30008 Filed 11-9-98; 8:45 am]

BILLING CODE 4160-01-F

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[FR Doc. 98-30008 Filed 11-9-98; 8:45 am]

BILLING CODE 4160-01-C