[Federal Register Volume 63, Number 217 (Tuesday, November 10, 1998)]
[Proposed Rules]
[Pages 62977-63015]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-30008]
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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
[[Page 62978]]
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
[[Page 62980]]
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,
[[Page 62981]]
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 <300 mg/dl)="" the="" agency="" began="" its="" consideration="" of="" the="" data="" with="" the="" 14="" well="" controlled="" and="" representative="" studies="" identified="" previously="" (refs.="" 27,="" 28,="" 30="" (1="" trial),="" 31,="" 36,="" 37="" (1="" trial),="" 40="" (2="" trials),="" 44,="" 49,="" 51,="" 54,="" 58,="" and="" 59).="" several="" of="" these="" studies="" examined="" the="" interaction="" of="" protein="" and="" other="" components="" of="" soy="" protein="" sources="" hypothesized="" to="" have="" an="" impact="" on="" lipid-lowering="" effects="" (i.e.,="" isoflavones,="" dietary="" fiber,="" and="" soy="" lipids)="" (refs.="" 31,="" 28,="" 27,="" 51,="" and="" 44).="" findings="" with="" respect="" to="" soy="" protein="" are="" described="" in="" this="" section,="" while="" findings="" regarding="" the="" specific="" influence="" of="" soy="" isoflavones="" (refs.="" 31="" and="" 28)="" are="" discussed="" in="" more="" detail="" in="" section="" iii.c.5="" of="" this="" document.="" in="" hypercholesterolemic="" subjects,="" crouse="" et="" al.="" (ref.="" 31,="" documented="" in="" ref.="" 1="" with="" corrections="" noted="" in="" ref.="" 2)="" found="" that="" 25="" grams="" (g)="" of="" soy="" protein="" from="" isp="" containing="" 2.5="" mg="" total="" aglycone="" isoflavones/g="" protein="" lowered="" total=""><0.05) and="" ldl-cholesterol="" levels=""><0.05) by="" 4="" and="" 6="" percent,="" respectively,="" while="" hdl-cholesterol="" was="" not="" altered.="" furthermore,="" in="" subjects="" with="" ldl-cholesterol="" levels="" in="" the="" top="" half="" of="" the="" study="" population,="" serum="" total="" and="" ldl-cholesterol="" were="" reduced="" by="" 9="" percent=""><0.03) and="" 12="" percent=""><0.03), respectively,="" by="" the="" isp="" with="" 2.5="" mg="" total="" aglycone="" isoflavones/g="" protein,="" and="" by="" 8="" percent=""><0.03) and="" 9="" percent=""><0.03), respectively,="" by="" the="" isp="" with="" 1.6="" mg="" total="" aglycone="" isoflavones/g="" protein.="" hdl-cholesterol="" concentrations="" were="" unchanged.="" these="" results="" indicate="" that="" soy="" protein,="" in="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol,="" can="" exert="" hypocholesterolemic="" effects="" but="" suggest="" these="" effects="" may="" be="" modulated="" by="" the="" presence="" of="" isoflavones.="" in="" hypercholesterolemic,="" postmenopausal="" women,="" baum="" et="" al.="" (ref.="" 28)="" also="" investigated="" the="" impact="" of="" soy="" protein="" as="" isp="" containing="" different="" levels="" of="" isoflavones.="" adjusted="" mean="" differences="" in="" the="" change="" from="" baseline="" for="" total="" serum="" cholesterol="" level="" did="" not="" differ="" in="" the="" two="" soy="" groups="" and="" the="" control="" group.="" however,="" there="" was="" a="" statistically="" significant="" reduction="" of="" 8="" to="" 9="" percent="" in="" non-hdl="" (ldl="" plus="" very="" low="" density="" lipoprotein="" (vldl))="" cholesterol="" in="" both="" of="" the="" isp="" treatment="" groups=""><0.05) compared="" to="" the="" control="" group.="" hdl-="" cholesterol="" was="" also="" significantly="" increased=""><0.05) in="" both="" soy="" groups="" compared="" to="" the="" control.="" the="" level="" of="" isoflavones="" did="" not="" affect="" any="" of="" the="" blood="" lipid="" levels="" measured.="" this="" study="" also="" indicates="" the="" ability="" of="" soy="" protein="" provided="" in="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol="" to="" reduce="" ldl-cholesterol.="" two="" studies="" that="" examined="" the="" effect="" of="" soy="" protein="" in="" hypercholesterolemic="" adults="" consuming="" low="" fat="" diets="" also="" evaluated="" whether="" soy="" cotyledon="" fiber="" had="" additional="" lipid-lowering="" effects.="" bakhit="" et="" al.="" (ref.="" 27)="" used="" 25="" g="" protein="" and="" 20="" g="" dietary="" fiber="" as="" treatment="" levels="" while="" potter="" et="" al.="" (ref.="" 51)="" used="" 50="" g="" protein="" and="" 20="" g="" dietary="" fiber.="" soy="" protein="" was="" provided="" as="" isp="" (refs.="" 27="" and="" 51)="" and="" sf="" (ref.="" 51)="" incorporated="" into="" baked="" products.="" bakhit="" et="" al.="" (ref.="" 27)="" studied="" subjects="" who="" had="" initially="" been="" screened="" for="" eligibility="" based="" on="" plasma="" total="" cholesterol="" concentrations="" greater="" than="" 220="" mg/dl="" before="" starting="" the="" study.="" during="" the="" baseline="" dietary="" period,="" plasma="" total="" cholesterol="" decreased="" to="" levels="" below="" 220="" mg/dl="" in="" 10="" of="" the="" subjects;="" these="" subjects="" did="" not="" have="" any="" further="" decrease="" in="" total="" or="" ldl-cholesterol="" with="" any="" of="" the="" experimental="" diets.="" the="" subjects="" whose="" cholesterol="" remained="" greater="" than="" the="" 220="" mg/dl="" intent-to-treat="" level="" did="" show="" a="" statistically="" significant="" decrease="" from="" post-baseline="" dietary="" levels="" for="" total="" cholesterol,="" but="" not="" for="" ldl-cholesterol,="" after="" consuming="" isp.="" in="" the="" subset="" analysis,="" bakhit="" et="" al.="" (ref.="" 27)="" found="" a="" statistically="" significant="" decrease="" in="" total="" cholesterol="" of="" 7="" percent=""><0.05) from="" post-stabilization="" levels="" with="" ingestion="" of="" isp.="" addition="" of="" soy="" cotyledon="" fiber="" to="" the="" isp="" diet="" resulted="" in="" a="" statistically="" significant="" decrease=""><0.05) of="" 8="" percent="" in="" total="" cholesterol.="" ingestion="" of="" the="" casein="" plus="" cellulose="" control="" diet="" produced="" a="" nonsignificant="" decrease="" (p="">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
(p<0.05) decrease="" in="" plasma="" total="" cholesterol="" from="" baseline="" of="" 8="" percent="" with="" ingestion="" of="" diets="" containing="" isp="" whether="" soy="" cotyledon="" fiber="" or="" cellulose="" was="" also="" consumed.="" the="" 8-percent="" decrease="" observed="" in="" ldl-cholesterol="" from="" baseline="" was="" statistically="" significant="" only="" when="" the="" isp="" diet="" also="" contained="" soy="" cotyledon="" fiber=""><0.05). total="" and="" ldl-cholesterol="" were="" also="" significantly=""><0.01) lower="" with="" the="" isp="" diets="" compared="" to="" the="" nonfat="" dry="" milk-cellulose="" control="" diet.="" no="" statistically="" significant="" changes="" in="" hdl-cholesterol="" were="" observed="" with="" any="" of="" the="" soy="" protein="" diets.="" changes="" from="" baseline="" were="" not="" statistically="" significant="" for="" any="" of="" the="" blood="" lipids="" when="" the="" diet="" providing="" soy="" protein="" as="" sf="" was="" consumed.="" however,="" the="" difference="" in="" total="" cholesterol="" observed="" after="" ingestion="" of="" sf="" was="" 19="" mg/dl="" lower="" than="" that="" on="" the="" control="" diet="" of="" nonfat="" dry="" milk="" and="" cellulose=""><0.01). these="" findings="" suggest="" that="" the="" principal="" dietary="" component="" responsible="" for="" the="" lipid-lowering="" observed="" in="" this="" study="" is="" the="" soy="" protein="" fraction,="" and="" that="" soy="" fiber="" may="" have="" an="" incremental="" effect.="" kurowska="" et="" al.="" (ref.="" 44)="" tested="" the="" effects="" of="" soy="" protein="" and="" soy="" oil="" in="" hypercholesterolemic="" subjects="" by="" adding="" combinations="" of="" ``milk''="" and="" desserts="" to="" provide="" a="" total="" of="" 31="" g="" protein="" from="" either="" cow's="" milk="" or="" soy="" milk="" and="" 16="" g="" fat="" from="" either="" cow's="" milk,="" soybean="" oil,="" or="" whole="" soybean="" soy="" milk.="" the="" three="" dietary="" treatments="" were="" cow's="" milk="" (2-="" percent="" fat),="" skim="" cow's="" milk="" (0-percent="" fat)="" plus="" soy="" oil="" (16="" g),="" or="" soybean="" milk.="" no="" statistically="" significant="" changes="" from="" baseline="" in="" total="" cholesterol="" were="" observed="" in="" response="" to="" any="" of="" the="" dietary="" treatments.="" the="" 4-percent="" decline="" in="" ldl-cholesterol="" observed="" with="" the="" soybean="" milk="" diet="" was="" not="" statistically="" significant.="" hdl-cholesterol="" was="" increased="" 7="" percent="" from="" baseline="" (p="0.04)" with="" the="" whole="" soybean="" milk="" treatment.="" in="" the="" subjects="" with="" the="" highest="" initial="" ldl-="" cholesterol="" level="" and="" ldl/hdl-cholesterol="" ratio,="" ldl-cholesterol="" was="" reduced="" by="" 11="" percent="" by="" the="" soybean="" milk="" diet.="" [[page="" 62982]]="" five="" earlier="" studies="" included="" in="" table="" 1="" reported="" on="" effects="" of="" soy="" protein="" in="" hypercholesterolemic="" subjects.="" in="" hypercholesterolemic="" subjects,="" goldberg="" et="" al.="" (ref.="" 37)="" examined="" the="" effects="" of="" isp="" (99="" g="" of="" soy="" protein)="" incorporated="" as="" a="" meat="" analog="" or="" formulated="" in="" beverage="" compared="" to="" a="" control="" animal="" protein="" diet="" consisting="" of="" analogous="" meat="" products="" and="" nonfat="" dry="" milk.="" both="" diets="" resulted="" in="" statistically="" significant="" reductions="" in="" serum="" total="" and="" ldl-cholesterol="" levels.="" with="" the="" soy="" protein="" diet,="" total="" cholesterol="" was="" decreased="" by="" 15="" percent=""><0.001) and="" ldl-cholesterol="" was="" decreased="" by="" 17="" percent=""><0.001) from="" baseline="" values.="" total="" cholesterol="" was="" 8="" mg/dl="" lower=""><0.005), and="" ldl-cholesterol="" was="" 10="" mg/="" dl="" lower=""><0.05), at="" the="" end="" of="" the="" dietary="" period="" when="" soy="" protein="" was="" ingested="" as="" compared="" to="" the="" animal="" protein="" diet.="" both="" the="" change="" in="" hdl-cholesterol="" from="" the="" baseline="" and="" the="" difference="" in="" hdl-cholesterol="" between="" the="" soy="" and="" control="" diets="" were="" small="" and="" not="" statistically="" significant.="" mercer="" et="" al.="" (ref.="" 49)="" tested="" the="" effects="" of="" approximately="" 17="" g="" of="" soy="" protein="" from="" isp="" as="" a="" replacement="" for="" 2-percent="" fat="" cow's="" milk="" in="" subjects="" with="" mild="" to="" moderate="" hypercholesterolemia.="" total="" cholesterol="" levels="" were="" not="" significantly="" different="" (p="">0.05) 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; p<0.05) than="" the="" level="" at="" the="" end="" of="" the="" cow's="" milk="" period.="" there="" were="" no="" statistically="" significant="" differences="" in="" ldl-="" cholesterol="" and="" hdl-cholesterol="" between="" isp="" and="" cow's="" milk="" diets="" either="" for="" all="" subjects="" or="" for="" the="" subset="" of="" subjects="" with="" the="" highest="" initial="" total="" cholesterol="" levels.="" holmes="" et="" al.="" (ref.="" 40)="" conducted="" two="" trials="" with="" hypercholesterolemic="" subjects="" testing="" sf="" as="" a="" texturized="" vegetable="" protein="" product="" formulated="" with="" egg="" yolk,="" beef="" tallow,="" and="" cottonseed="" oil="" to="" create="" an="" analog="" for="" lean="" ground="" beef.="" an="" average="" of="" 27="" g="" of="" soy="" protein="" was="" consumed="" in="" the="" partially="" substituted="" diet="" in="" the="" first="" trial="" and="" 62="" g="" was="" consumed="" in="" the="" completely="" substituted="" diet="" in="" the="" second="" trial.="" in="" trial="" 1,="" statistically="" significant="" changes="" in="" total="" cholesterol=""><0.02) and="" ldl-cholesterol=""><0.05) occurred="" during="" the="" initial="" stabilization="" period="" when="" the="" control="" diet="" was="" consumed;="" no="" further="" changes="" occurred="" after="" the="" second="" period="" during="" which="" the="" partially="" substituted="" soy="" diet="" was="" consumed.="" in="" trial="" 2,="" both="" diets="" significantly="" lowered="" mean="" total="" cholesterol="" during="" the="" first="" dietary="" sequence=""><0.05), the="" animal="" protein="" diet="" by="" 18="" percent="" and="" the="" soy="" diet="" by="" 19="" percent.="" crossing="" over="" the="" diets="" had="" no="" further="" effect.="" ldl-="" cholesterol="" levels="" were="" not="" reduced="" by="" either="" diet.="" hdl-cholesterol="" levels="" were="" not="" significantly="" affected="" by="" diet="" in="" either="" trial.="" the="" two="" trials="" were="" unique="" in="" the="" source="" of="" soy="" protein="" and="" in="" including="" subjects="" with="" type="" iv="" hyperlipidemia.="" shorey="" et="" al.="" (ref.="" 54)="" examined="" the="" effects="" of="" 57="" g="" of="" soy="" protein="" (mean="" intake)="" consumed="" as="" isp="" incorporated="" both="" into="" meat="" analogs="" and="" a="" soy-based="" beverage="" in="" hypercholesterolemic="" young="" men.="" a="" statistically="" significant="" (p="0.027)" decrease="" from="" baseline="" total="" cholesterol="" of="" 7="" percent="" was="" noted="" in="" the="" group="" consuming="" the="" soy="" protein="" diet;="" however,="" these="" values="" were="" 6="" mg/dl="" higher="" than="" change="" from="" baseline="" values="" obtained="" from="" the="" control="" group.="" hdl-cholesterol="" also="" significantly="" (p="0.001)" decreased="" from="" baseline="" values="" by="" 15="" percent.="" ldl-cholesterol="" was="" not="" measured="" in="" this="" study.="" although="" the="" two="" diets="" were="" well="" matched="" for="" saturated="" fat="" and="" cholesterol,="" interpretation="" of="" these="" findings="" is="" complicated="" by="" the="" fact="" that="" body="" weight="" was="" significantly=""><0.004) decreased="" in="" both="" groups="" of="" subjects.="" subjects="" who="" showed="" a="" significant="" hypocholesterolemic="" response="" on="" either="" diet="" were="" those="" who="" substantially="" reduced="" their="" customary="" protein="" and="" fat="" intakes="" on="" the="" experimental="" diets.="" in="" contrast="" to="" other="" studies,="" subjects="" in="" this="" study="" with="" lower="" baseline="" values="" experienced="" more="" pronounced="" reductions="" in="" total="" cholesterol="" level.="" four="" additional="" well-controlled="" studies="" included="" in="" table="" 1="" of="" this="" document="" examined="" the="" effects="" of="" soy="" protein="" in="" normocholesterolemic="" subjects.="" the="" study="" of="" carroll="" et="" al.="" (ref.="" 30)="" compared="" isp="" (44="" g="" soy="" protein="" estimated)="" incorporated="" into="" foods="" and="" a="" soy-based="" beverage="" to="" a="" mixed="" protein/animal-based="" diet="" in="" healthy="" young="" women.="" plasma="" total="" cholesterol="" was="" significantly=""><0.05) lower,="" by="" 10="" mg/dl,="" when="" the="" soy="" protein="" diet="" was="" consumed="" as="" compared="" with="" the="" mixed="" protein="" diet.="" neither="" ldl-cholesterol="" nor="" hdl-cholesterol="" was="" measured.="" giovannetti="" et="" al.="" (ref.="" 36)="" examined="" the="" effects="" of="" isp="" (66="" to="" 80="" g="" of="" soy="" protein="" depending="" on="" energy="" intake)="" incorporated="" as="" meat="" and="" dairy="" analogs="" in="" healthy="" young="" adult="" women="" in="" both="" high-="" and="" low-fat="" diets.="" on="" the="" high-fat="" diet,="" serum="" total="" cholesterol="" was="" 4="" mg/dl="" lower,="" ldl-cholesterol="" was="" 6="" mg/dl="" lower,="" and="" hdl-cholesterol="" was="" 3="" mg/dl="" lower="" after="" ingestion="" of="" the="" soy="" protein="" than="" after="" ingestion="" of="" the="" mixed="" protein="" control.="" none="" of="" the="" changes="" in="" blood="" lipids="" reached="" statistical="" significance.="" on="" the="" low-fat="" diet,="" serum="" total="" cholesterol="" was="" 1="" mg/dl="" higher,="" ldl-cholesterol="" was="" 5="" mg/dl="" lower,="" and="" hdl-="" cholesterol="" was="" 2="" mg/dl="" higher="" after="" soy="" protein="" than="" after="" the="" mixed="" protein="" control;="" these="" differences="" were="" not="" statistically="" significant.="" the="" magnitude="" of="" reduction="" in="" serum="" total="" cholesterol="" with="" soy="" protein="" was="" similar="" on="" the="" high-fat="" and="" low-fat="" diets,="" 10="" percent="" and="" 9="" percent,="" respectively.="" substitution="" of="" soy="" protein="" caused="" reductions="" in="" ldl-cholesterol="" levels="" during="" the="" high-fat="" diet="" in="" 11="" of="" 12="" subjects="" and="" during="" the="" low-fat="" diet="" in="" 9="" of="" 12="" subjects.="" van="" raaij="" et="" al.="" (ref.="" 58)="" tested="" the="" effects="" of="" isp="" in="" young="" normocholesterolemic="" men="" and="" women="" consuming="" three="" diets="" that="" differed="" in="" protein="" composition="" with="" 65="" percent="" of="" the="" total="" protein="" replaced="" by="" either="" soy="" protein="" (54="" g),="" or="" casein,="" or="" an="" approximately="" 2:1="" mixture="" of="" casein="" (36="" g):soy="" (17="" g).="" in="" the="" group="" consuming="" the="" soy="" protein="" diet,="" total="" serum="" cholesterol="" and="" ldl-cholesterol="" were="" decreased="" (-2="" percent="" and="" -8="" percent,="" respectively)="" and="" hdl-cholesterol="" increased="" (+10="" percent)="" compared="" to="" values="" at="" the="" end="" of="" the="" lead-in="" period.="" the="" changes="" in="" both="" ldl-cholesterol="" and="" hdl-cholesterol="" were="" statistically="" significant=""><0.05). in="" addition,="" decreases="" in="" ldl-cholesterol="" were="" significantly=""><0.05) greater="" with="" the="" soy="" protein="" diet="" compared="" to="" changes="" with="" the="" casein="" diet.="" although="" weight="" loss="" did="" occur="" among="" subjects="" consuming="" both="" the="" soy="" protein="" diet="" (n="9)" and="" the="" casein="" diet="" (n="6)," when="" data="" from="" the="" subset="" without="" a="" weight="" loss="" of="" more="" than="" 2="" kilograms="" (kg)="" were="" analyzed="" separately,="" the="" same="" effects="" of="" soy="" protein="" ingestion="" on="" blood="" lipid-lowering="" were="" observed.="" the="" lipid="" changes="" in="" the="" group="" that="" remained="" on="" the="" 2:1="" casein:soy="" diet="" were="" not="" statistically="" significantly="" different="" from="" the="" casein="" group,="" nor="" were="" changes="" from="" the="" end="" of="" the="" stabilization="" period="" significant="" in="" this="" group.="" in="" a="" trial="" with="" both="" normocholesterolemic="" and="" hypercholesterolemic="" subjects,="" van="" raaij="" et="" al.="" (ref.="" 59)="" tested="" both="" isp="" and="" spc="" (each="" providing="" an="" average="" of="" 55="" g="" of="" soy="" protein)="" compared="" to="" a="" casein="" control.="" serum="" total="" cholesterol="" was="" decreased="" from="" baseline="" by="" 4="" percent="" and="" ldl-cholesterol="" was="" decreased="" by="" 3="" percent="" on="" the="" isp="" diet.="" these="" changes="" were="" significantly="" different="" from="" those="" on="" the="" spc="" diet=""><0.05) but="" not="" significantly="" different="" from="" those="" on="" the="" casein="" diet.="" hdl-cholesterol="" showed="" a="" slight="" but="" statistically="" significant="" [[page="" 62983]]="" increase="" of="" 2="" percent="" from="" baseline="" on="" the="" isp="" diet,="" a="" change="" that="" was="" also="" significantly="" different="" from="" that="" on="" the="" casein="" diet.="" when="" spc="" was="" used="" as="" the="" protein="" source,="" total="" cholesterol="" was="" not="" altered,="" ldl-="" cholesterol="" was="" increased="" by="" 6="" percent,="" and="" hdl-cholesterol="" decreased="" by="" 3="" percent="" compared="" to="" baseline.="" none="" of="" these="" changes="" in="" blood="" lipids="" from="" baseline="" or="" differences="" between="" the="" casein="" and="" spc="" diets="" was="" statistically="" significant.="" interpretation="" of="" this="" study="" is="" complicated="" by="" differential="" weight="" loss="" on="" the="" experimental="" diets="" (weight="" loss="" was="" greatest="" in="" the="" casein="" group)="" and="" differential="" fiber="" intake.="" three="" additional="" studies="" (refs.="" 29,="" 43,="" and="" 53),="" in="" which="" interpretation="" is="" complicated="" by="" design="" issues="" such="" as="" choice="" of="" subjects,="" concerns="" about="" weight="" loss,="" or="" uncertainties="" about="" other="" components="" in="" diets,="" are="" also="" summarized="" in="" table="" 1="" of="" this="" document="" and="" discussed="" as="" follows.="" bosello="" et="" al.="" (ref.="" 29)="" and="" jenkins="" et="" al.="" (ref.="" 43)="" both="" studied="" the="" hypocholesterolemic="" effects="" of="" soy="" protein="" versus="" casein="" in="" the="" context="" of="" hypocaloric="" diets="" fed="" to="" obese="" persons="" to="" achieve="" significant="" weight="" reduction.="" in="" bosello="" et="" al.="" (ref.="" 29),="" obese="" subjects="" (="">150 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 (p<0.01). compared="" to="" the="" casein="" group,="" total="" cholesterol="" was="" 20="" mg/dl="" lower=""><0.01 )="" and="" ldl-cholesterol="" was="" 16="" mg/dl="" lower=""><0.01). hdl-cholesterol="" was="" decreased="" in="" both="" groups="" at="" the="" end="" of="" the="" study;="" however,="" only="" in="" the="" casein="" group="" was="" the="" difference="" statistically="" significant=""><0.01). additionally,="" the="" decrease="" in="" hdl-="" cholesterol="" in="" the="" casein="" group="" was="" significantly=""><0.01) greater="" than="" that="" observed="" in="" the="" soy="" protein="" group.="" jenkins="" et="" al.="" (ref.="" 43)="" examined="" the="" effects="" of="" soy="" protein="" ingestion="" on="" serum="" cholesterol="" in="" obese="" women="" who="" were="" also="" consuming="" a="" hypocaloric="" diet="" for="" weight="" reduction.="" the="" three="" treatments="" were:="" a="" control,="" hypocaloric="" diet="" of="" 1,000="" total="" kcal="" consumed="" as="" conventional="" foods;="" the="" same="" diet="" with="" two="" meals="" per="" day="" replaced="" by="" a="" soy="" protein="" (18.4="" g="" provided="" as="" isp)="" liquid="" formula="" preparation;="" or="" the="" same="" diet="" with="" two="" meals="" per="" day="" replaced="" by="" a="" milk="" protein="" (17.6="" g="" as="" milk="" protein="" isolate="" and="" nonfat="" dry="" milk)="" liquid="" formula.="" an="" average="" 2.5="" kg="" weight="" loss="" per="" month="" occurred="" during="" the="" study=""><0.05) across="" diet="" treatments.="" statistically="" significant="" decreases="" from="" baseline="" in="" total="" cholesterol="" of="" 10="" percent=""><0.05) and="" in="" ldl-cholesterol="" of="" 17="" percent=""><0.05) occurred="" only="" during="" the="" period="" when="" the="" soy="" protein="" formula="" was="" ingested.="" changes="" in="" hdl-cholesterol="" were="" not="" statistically="" significant.="" these="" effects="" of="" soy="" protein="" were="" independent="" of="" the="" order="" the="" soy="" diet="" was="" consumed="" relative="" to="" the="" conventional="" hypocaloric="" diet.="" the="" levels="" of="" total="" and="" ldl-cholesterol="" achieved="" with="" ingestion="" of="" soy="" protein="" were,="" respectively,="" 10="" mg/dl="" and="" 8="" mg/dl="" lower="" with="" the="" soy="" protein="" diet="" as="" compared="" with="" the="" casein="" diet.="" neither="" the="" conventional="" hypocaloric="" diet="" nor="" the="" casein="" formula="" hypocaloric="" diet="" resulted="" in="" statistically="" significant="" decreases="" in="" total="" or="" ldl-="" cholesterol="" despite="" weight="" loss.="" calculations="" of="" the="" expected="" decline="" in="" serum="" total="" cholesterol="" based="" on="" changes="" in="" weight,="" dietary="" cholesterol,="" and="" saturated="" and="" polyunsaturated="" fat="" accurately="" predicted="" the="" observed="" changes="" in="" both="" the="" hypocaloric="" diet="" and="" milk="" formula="" groups,="" but="" significantly="" underestimated="" the="" decrease="" observed="" in="" the="" soy="" formula="" group.="" sacks="" et="" al.="" (ref.="" 53)="" studied="" the="" effects="" of="" 27="" g="" of="" protein="" consumed="" daily="" as="" isp="" or="" casein="" incorporated="" into="" muffins="" and="" oatmeal="" in="" adults="" who="" were="" strict="" vegetarians.="" not="" unexpectedly,="" given="" the="" very="" low="" baseline="" lipid="" concentrations="" and="" very="" low="" dietary="" fat="" and="" cholesterol="" intake,="" no="" statistically="" significant="" changes="" or="" differences="" in="" total="" cholesterol,="" ldl-cholesterol="" or="" hdl-cholesterol="" were="" observed="" from="" consumption="" of="" either="" soy="" protein="" or="" casein.="" a.="" summary--hypercholesterolemic="" subjects="" consuming="" diets="" low="" in="" saturated="" fat="" and="" cholesterol.="" in="" five="" (refs.="" 31,="" 28,="" 27,="" 51,="" and="" 44)="" of="" seven="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" and="" 40="" (2="" trials))="" well-controlled="" studies="" of="" hypercholesterolemic="" subjects="" consuming="" low="" saturated="" fat="" and="" low="" cholesterol="" diets,="" soy="" protein="" intake="" was="" associated="" with="" significant="" decreases="" in="" total="" and/or="" ldl-cholesterol="" levels.="" crouse="" et="" al.="" (ref.="" 31,="" documented="" in="" ref.="" 1="" with="" corrections="" noted="" in="" ref.="" 2)="" found="" that="" soy="" protein="" from="" isp="" containing="" 2.5="" mg="" total="" aglycone="" isoflavones/g="" protein="" statistically="" significantly="" lowered="" total=""><0.05) and="" ldl-cholesterol="" levels=""><0.05), by="" 4="" and="" 6="" percent,="" respectively,="" while="" hdl-cholesterol="" was="" not="" altered.="" in="" a="" subset="" of="" subjects="" with="" ldl-cholesterol="" levels="" in="" the="" top="" half="" of="" the="" study="" population,="" serum="" total="" and="" ldl-cholesterol="" were="" reduced="" by="" 9="" percent=""><0.03) and="" 12="" percent=""><0.03), respectively,="" by="" the="" isp="" with="" 2.5="" mg="" total="" aglycone="" isoflavones/g="" protein,="" and="" by="" 8="" percent=""><0.03) and="" 9="" percent=""><0.03), respectively,="" by="" the="" isp="" with="" 1.6="" mg="" total="" aglycone="" isoflavones/g="" protein.="" baum="" et="" al.="" (ref.="" 28)="" found="" that="" the="" adjusted="" mean="" difference="" in="" total="" serum="" cholesterol="" level="" was="" not="" significantly="" (p="">0.05) 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 (p<0.05) from="" post-="" stabilization="" levels="" with="" ingestion="" of="" isp;="" addition="" of="" soy="" cotyledon="" fiber="" to="" the="" isp="" diet="" resulted="" in="" a="" significant="" decrease=""><0.05) of="" 8="" percent="" in="" total="" cholesterol.="" levels="" of="" ldl-cholesterol="" were="" not="" statistically="" significantly="" affected="" by="" either="" soy="" diet.="" potter="" et="" al.="" (ref.="" 51)="" reported="" a="" statistically="" significant="" decrease=""><0.05) from="" baseline="" in="" total="" plasma="" cholesterol="" of="" 8="" percent="" with="" ingestion="" of="" diets="" containing="" isp="" whether="" soy="" cotyledon="" fiber="" or="" cellulose="" was="" also="" consumed.="" the="" 8-percent="" decrease="" in="" ldl-cholesterol="" from="" baseline="" was="" statistically="" significant="" only="" when="" the="" isp="" diet="" also="" contained="" soy="" cotyledon="" fiber=""><0.05). total="" and="" ldl-cholesterol="" were="" also="" significantly="" lower=""><0.01) with="" the="" isp="" diets="" compared="" to="" the="" nonfat="" dry="" milk-cellulose="" diet.="" changes="" from="" baseline="" were="" not="" statistically="" significant="" for="" any="" of="" the="" blood="" lipids="" when="" the="" diet="" providing="" soy="" protein="" as="" sf="" was="" consumed.="" however,="" the="" difference="" in="" total="" cholesterol="" observed="" after="" ingestion="" of="" sf="" was="" 19="" mg/dl="" lower="" than="" that="" on="" the="" control="" diet="" of="" nonfat="" dry="" milk="" and="" cellulose=""><0.01). with="" diets="" providing="" either="" cow's="" milk="" (2-percent="" fat),="" or="" skim="" cow's="" milk="" (0-percent="" fat)="" plus="" soy="" oil="" (16="" g),="" or="" soybean="" milk,="" kurowska="" et="" al.="" (ref.="" 44)="" found="" no="" statistically="" significant="" changes="" from="" baseline="" in="" total="" cholesterol="" and="" ldl-cholesterol="" in="" response="" to="" any="" of="" the="" dietary="" treatments.="" in="" the="" subjects="" with="" the="" highest="" initial="" ldl-cholesterol="" levels="" and="" ldl/hdl-cholesterol="" ratios,="" ldl-="" [[page="" 62984]]="" cholesterol="" was="" reduced="" by="" 11="" percent="" by="" the="" soybean="" milk="" diet.="" holmes="" et="" al.="" (ref.="" 40)="" conducted="" two="" trials="" testing="" sf="" as="" a="" texturized="" vegetable="" protein="" product,="" with="" averages="" of="" 27="" and="" 62="" g="" of="" soy="" protein="" consumed,="" respectively,="" in="" the="" first="" and="" the="" second="" trial.="" in="" trial="" 1,="" statistically="" significant="" changes="" in="" total="" and="" ldl-cholesterol="" occurred="" during="" the="" stabilization="" period="" when="" the="" control="" diet="" was="" consumed;="" no="" further="" changes="" occurred="" after="" the="" second="" dietary="" period="" during="" which="" the="" partially="" substituted="" soy="" diet="" was="" consumed.="" in="" trial="" 2,="" both="" diets="" resulted="" in="" a="" statistically="" significant="" lowering="" of="" total="" cholesterol="" during="" the="" first="" dietary="" sequence,="" the="" animal="" protein="" diet="" by="" 18="" percent="" and="" the="" soy="" diet="" by="" 19="" percent.="" crossing="" over="" the="" diets="" had="" no="" further="" effect.="" ldl-cholesterol="" levels="" were="" not="" reduced="" by="" either="" diet.="" these="" studies="" were="" unique="" in="" the="" source="" of="" soy="" protein="" used="" and="" in="" including="" subjects="" with="" type="" iv="" hyperlipidemia.="" levels="" of="" hdl-cholesterol="" were="" also="" measured="" in="" each="" of="" these="" seven="" studies="" and="" were="" found="" either="" to="" be="" unchanged="" (refs.="" 31,="" 27,="" 51,="" and="" 40="" (2="" trials))="" or="" to="" show="" a="" slight="" but="" statistically="" significant="" increase="" (refs.="" 28="" and="" 44)="" in="" response="" to="" consumption="" of="" diets="" containing="" soy="" protein.="" levels="" of="" soy="" protein="" as="" isp="" found="" to="" be="" effective="" in="" lowering="" total="" and="" ldl-cholesterol="" levels="" ranged="" in="" these="" studies="" from="" 25="" to="" 50="" g="" (refs.="" 31,="" 28,="" 27,="" and="" 51).="" as="" whole="" soybean="" milk,="" 31="" g="" of="" soy="" protein="" lowered="" ldl-cholesterol="" only="" in="" the="" subset="" of="" subjects="" with="" the="" highest="" initial="" ldl-cholesterol="" levels="" and="" ldl/hdl-cholesterol="" levels="" (ref.="" 44).="" diets="" providing="" 50="" g="" of="" soy="" protein="" as="" sf="" did="" not="" cause="" significant="" changes="" from="" baseline="" for="" any="" of="" the="" blood="" lipids,="" but="" the="" decrease="" in="" total="" cholesterol="" observed="" after="" ingestion="" of="" sf="" was="" significantly="" greater="" than="" that="" on="" the="" control="" diet="" of="" nonfat="" dry="" milk="" and="" cellulose="" (ref.="" 51).="" diets="" providing="" 27="" g="" of="" soy="" protein="" as="" sf="" in="" a="" textured="" product="" had="" no="" significant="" effects="" on="" blood="" lipid="" levels="" compared="" to="" a="" control="" diet,="" and="" a="" higher="" level="" (62="" g)="" significantly="" lowered="" total="" cholesterol="" only="" in="" the="" experimental="" group="" fed="" the="" soy="" protein="" diet="" first="" (ref.="" 40).="" b.="" summary--hypercholesterolemic="" subjects="" consuming="" ``usual''="" diets.="" three="" studies="" reported="" on="" effects="" of="" soy="" protein="" in="" hypercholesterolemic="" subjects="" consuming="" ``usual''="" diets="" that="" were="" generally="" high="" in="" total="" fat,="" saturated="" fat,="" and="" cholesterol="" (refs.="" 37,="" 49,="" and="" 54).="" goldberg="" et="" al.="" (ref.="" 37)="" found,="" on="" the="" soy="" protein="" diet="" (with="" 99="" g="" of="" soy="" protein="" as="" isp),="" statistically="" significant="" decreases="" from="" baseline="" of="" 15="" percent="" in="" total="" cholesterol="" and="" 17="" percent="" in="" ldl-="" cholesterol.="" total="" cholesterol="" was="" 8="" mg/dl="" lower=""><0.005), and="" ldl-="" cholesterol="" was="" 10="" mg/dl="" lower=""><0.05), at="" the="" end="" of="" the="" dietary="" period="" when="" soy="" protein="" was="" ingested="" as="" compared="" to="" the="" animal="" protein="" diet.="" mercer="" et="" al.="" (ref.="" 49)="" found="" that="" a="" diet="" with="" approximately="" 17="" g="" of="" soy="" protein="" from="" isp="" did="" not="" produce="" changes="" in="" serum="" cholesterol="" that="" were="" significantly="" different="" from="" those="" of="" a="" cow's="" milk="" control="" diet.="" among="" subjects="" whose="" baseline="" total="" cholesterol="" was="" above="" the="" 90th="" percentile,="" mercer="" et="" al.="" (ref.="" 49)="" found="" that="" 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;=""><0.05) than="" the="" level="" at="" the="" end="" of="" the="" cow's="" milk="" control="" period.="" ldl-cholesterol="" did="" not="" differ="" significantly="" between="" isp="" and="" cow's="" milk="" diets="" for="" all="" subjects="" or="" for="" the="" subset="" of="" subjects="" with="" the="" highest="" initial="" total="" cholesterol="" levels.="" shorey="" et="" al.="" (ref.="" 54)="" found="" diets="" with="" 57="" g="" of="" soy="" protein="" as="" isp="" was="" associated="" with="" a="" statistically="" significant="" decrease="" from="" baseline="" in="" total="" cholesterol="" of="" 7="" percent="" (p="0.027);" however,="" these="" values="" were="" 6="" mg/dl="" higher="" than="" change="" from="" baseline="" values="" obtained="" from="" the="" control="" group.="" ldl-cholesterol="" was="" not="" measured="" in="" this="" study.="" although="" the="" two="" diets="" were="" well="" matched="" for="" saturated="" fat="" and="" cholesterol,="" interpretation="" of="" these="" findings="" is="" complicated="" by="" the="" fact="" that="" body="" weight="" was="" significantly="" decreased="" in="" both="" groups="" of="" subjects=""><0.004). subjects="" who="" showed="" a="" significant="" hypocholesterolemic="" response="" on="" either="" diet="" were="" those="" who="" substantially="" reduced="" their="" customary="" protein="" and="" fat="" intakes="" on="" the="" experimental="" diets.="" in="" contrast="" to="" other="" studies,="" subjects="" in="" this="" study="" with="" lower="" baseline="" values="" experienced="" more="" pronounced="" reductions="" in="" total="" cholesterol="" level.="" hdl-cholesterol="" was="" also="" measured="" in="" these="" three="" studies.="" changes="" were="" small="" and="" not="" statistically="" significant="" in="" two="" studies="" (refs.="" 37="" and="" 49),="" but="" hdl-cholesterol="" was="" significantly="" decreased="" from="" baseline="" values="" by="" 15="" percent="" in="" one="" study="" (ref.="" 54).="" (this="" latter="" study="" had="" a="" number="" of="" anomalous="" results.)="" each="" of="" these="" three="" studies="" fed="" soy="" protein="" in="" experimental="" diets="" as="" isp="" (refs.="" 37,="" 49,="" and="" 54).="" with="" a="" diet="" containing="" a="" very="" high="" level="" (99="" g)="" of="" soy="" protein="" from="" this="" source="" (ref.="" 37),="" statistically="" significant="" differences="" in="" both="" total="" and="" ldl-cholesterol="" were="" reported.="" results="" were="" less="" consistent="" with="" a="" relatively="" low="" level="" of="" soy="" protein="" (17="" g)="" (ref.="" 49).="" an="" intermediate="" level="" of="" soy="" protein="" (57="" g)="" was="" found="" to="" be="" ineffective="" in="" lowering="" total="" cholesterol="" in="" the="" study="" of="" shorey="" et="" al.="" (ref.="" 54).="" c.="" summary--normocholesterolemic="" subjects.="" five="" studies="" examined="" the="" effects="" of="" soy="" protein="" in="" normocholesterolemic="" subjects="" (refs.="" 30,="" 36,="" 58,="" 59,="" and="" 53).="" the="" study="" of="" carroll="" et="" al.="" (ref.="" 30)="" found="" plasma="" total="" cholesterol="" was="" significantly="" lower="" (-10="" mg/dl)="" when="" a="" soy="" protein="" diet="" (low="" in="" saturated="" fat="" and="" cholesterol="" and="" providing="" an="" estimated="" 44="" g="" soy="" protein="" as="" isp)="" was="" consumed="" as="" compared="" with="" a="" mixed="" protein="" control="" diet=""><0.05). ldl-cholesterol="" was="" not="" measured.="" giovannetti="" et="" al.="" (ref.="" 36)="" examined="" the="" effects="" of="" soy="" protein="" as="" isp="" (66="" to="" 80="" g="" of="" soy="" protein="" depending="" on="" energy="" intake)="" in="" both="" high-="" and="" low-fat="" diets.="" changes="" in="" total="" and="" ldl-cholesterol="" with="" the="" soy="" protein="" diets="" were="" not="" statistically="" significantly="" different="" from="" changes="" with="" the="" corresponding="" control="" diets,="" regardless="" of="" fat="" content.="" the="" magnitude="" of="" reduction="" in="" serum="" total="" cholesterol="" with="" soy="" protein="" was="" similar="" on="" the="" high-fat="" and="" low-fat="" diets,="" 10="" percent="" and="" 9="" percent,="" respectively.="" substitution="" of="" soy="" protein="" caused="" reductions="" in="" ldl-cholesterol="" levels="" during="" the="" high-fat="" diet="" in="" 11="" of="" 12="" subjects="" and="" during="" the="" low-fat="" diet="" in="" 9="" of="" 12="" subjects.="" van="" raaij="" et="" al.="" (ref.="" 58)="" tested="" the="" effects="" of="" isp="" using="" three="" diets="" high="" in="" total="" fat,="" saturated="" fat,="" and="" cholesterol="" that="" differed="" in="" protein="" composition="" with="" 65="" percent="" of="" the="" total="" protein="" comprising="" either="" soy="" protein="" (54="" g),="" or="" casein,="" or="" an="" approximately="" 2:1="" mixture="" of="" casein="" (36="" g):soy="" (17="" g).="" in="" the="" group="" consuming="" the="" soy="" protein="" diet,="" the="" decrease="" in="" total="" serum="" cholesterol="" (-2="" percent)="" was="" not="" statistically="" significant,="" but="" the="" decrease="" in="" ldl-cholesterol="" (-8="" percent)="" was="" statistically="" significant=""><0.05). in="" addition,="" decreases="" in="" ldl-cholesterol="" were="" significantly="" greater="" with="" the="" soy="" protein="" diet="" compared="" to="" changes="" with="" the="" casein="" diet=""><0.05). in="" a="" trial="" with="" both="" normocholesterolemic="" and="" moderately="" hypercholesterolemic="" subjects,="" van="" raaij="" et="" al.="" (ref.="" 59)="" tested="" both="" isp="" and="" spc="" (each="" providing="" an="" average="" of="" 55="" g="" of="" soy="" protein)="" compared="" to="" a="" casein="" control="" in="" diets="" high="" in="" total="" fat,="" saturated="" fat,="" and="" cholesterol.="" serum="" total="" cholesterol="" was="" decreased="" from="" baseline="" by="" 4="" percent="" and="" ldl-cholesterol="" was="" decreased="" by="" 3="" percent="" on="" the="" isp="" diet.="" these="" changes="" were="" statistically="" significantly="" different="" from="" those="" on="" the="" spc="" diet=""><0.05) but="" not="" significantly="" different="" from="" those="" on="" the="" casein="" diet.="" when="" spc="" was="" used="" as="" the="" protein="" source,="" total="" cholesterol="" was="" not="" altered="" and="" ldl-cholesterol="" was="" increased="" by="" 6="" percent="" compared="" to="" [[page="" 62985]]="" baseline.="" none="" of="" these="" changes="" in="" blood="" lipids="" from="" baseline="" or="" differences="" between="" the="" casein="" and="" spc="" diets="" was="" statistically="" significant.="" interpretation="" of="" this="" study="" is="" complicated="" by="" differential="" weight="" loss="" on="" the="" experimental="" diets="" (weight="" loss="" was="" greatest="" in="" the="" casein="" group)="" and="" differential="" fiber="" intake.="" sacks="" et="" al.="" (ref.="" 53)="" studied="" the="" effects="" of="" 27="" g="" of="" protein="" consumed="" daily="" as="" isp="" or="" casein="" incorporated="" into="" muffins="" and="" oatmeal,="" in="" diets="" very="" low="" in="" saturated="" fat="" and="" cholesterol="" in="" adults="" who="" were="" strict="" vegetarians.="" not="" unexpectedly,="" given="" the="" very="" low="" baseline="" lipid="" concentrations="" and="" very="" low="" dietary="" fat="" and="" cholesterol="" intake,="" no="" statistically="" significant="" changes="" or="" differences="" in="" total="" cholesterol="" or="" ldl-cholesterol="" or="" hdl-cholesterol="" were="" observed="" from="" consumption="" of="" either="" soy="" protein="" or="" casein.="" hdl-cholesterol="" was="" measured="" in="" four="" of="" these="" studies,="" with="" statistically="" significant="" increases="" associated="" with="" soy="" protein="" intake="" found="" in="" two="" (refs.="" 58="" and="" 59)="" and="" no="" statistically="" significant="" changes="" in="" two="" (refs.="" 36="" and="" 53).="" effects="" of="" soy="" protein="" on="" total="" and="" ldl-cholesterol="" were="" less="" consistent="" in="" normocholesterolemic="" subjects="" than="" in="" moderately="" hypercholesterolemic="" subjects.="" as="" isp,="" 44="" g="" of="" soy="" protein="" was="" effective="" in="" statistically="" significantly="" lowering="" total="" cholesterol="" in="" one="" study="" (ref.="" 30),="" and="" 54="" g="" statistically="" significantly="" lowered="" ldl-="" cholesterol="" in="" one="" study="" (ref.="" 58).="" with="" very="" low="" initial="" blood="" lipid="" levels,="" the="" impact="" of="" dietary="" changes="" appears="" to="" be="" lessened.="" d.="" summary--subjects="" consuming="" hypocaloric="" diets.="" bosello="" et="" al.="" (ref.="" 29)="" and="" jenkins="" et="" al.="" (ref.="" 43)="" both="" studied="" the="" hypocholesterolemic="" effects="" of="" soy="" protein="" versus="" casein="" in="" the="" context="" of="" hypocaloric="" diets="" fed="" to="" obese="" persons="" to="" achieve="" significant="" weight="" reduction.="" in="" bosello="" et="" al.="" (ref.="" 29),="" total="" cholesterol="" and="" ldl-="" cholesterol="" in="" the="" soy="" group="" (which="" consumed="" 27="" g="" of="" soy="" protein)="" were="" both="" 16="" percent="" lower="" compared="" to="" baseline=""><0.01). compared="" to="" the="" casein="" control="" group,="" total="" cholesterol="" was="" 20="" mg/dl="" lower=""><0.01 )="" and="" ldl-cholesterol="" was="" 16="" mg/dl="" lower=""><0.01) in="" the="" soy="" protein="" group.="" jenkins="" et="" al.="" (ref.="" 43)="" found="" that="" statistically="" significant="" decreases="" from="" baseline="" in="" total="" cholesterol="" of="" 10="" percent=""><0.05) and="" in="" ldl-cholesterol="" of="" 17="" percent=""><0.05) occurred="" only="" during="" the="" period="" when="" the="" soy="" protein="" formula="" (which="" provided="" 17="" g="" of="" soy="" protein)="" was="" ingested.="" the="" levels="" of="" total="" and="" ldl-cholesterol="" achieved="" with="" ingestion="" of="" soy="" protein="" were,="" respectively,="" 10="" mg/dl="" and="" 8="" mg/dl="" lower="" with="" the="" soy="" protein="" diet="" compared="" with="" casein="" diet.="" neither="" the="" conventional="" hypocaloric="" diet="" nor="" the="" casein="" formula="" hypocaloric="" diet="" resulted="" in="" statistically="" significant="" decreases="" in="" total="" or="" ldl-="" cholesterol="" despite="" weight="" loss.="" hdl-cholesterol="" was="" decreased="" in="" both="" groups="" at="" the="" end="" of="" the="" first="" study="" (ref.="" 29);="" however,="" only="" the="" casein="" group's="" values="" were="" significantly=""><0.01) different="" from="" baseline.="" additionally,="" the="" decrease="" in="" hdl-cholesterol="" in="" the="" casein="" group="" was=""><0.01) greater="" than="" that="" observed="" in="" the="" soy="" protein="" group.="" in="" the="" second="" study="" (ref.="" 43),="" hdl-cholesterol="" levels="" were="" not="" significantly="" affected="" by="" dietary="" treatment.="" these="" two="" studies="" (refs.="" 29="" and="" 43)="" demonstrated="" decreases="" in="" both="" total="" and="" ldl-cholesterol="" levels="" during="" hypocaloric="" diets="" that="" provided="" relatively="" low="" amounts="" (27="" and="" 17="" g,="" respectively)="" of="" soy="" protein.="" 2.="" studies="" of="" subjects="" with="" type="" ii="" and="" familial="" hypercholesterolemia="" (mean="" total="" cholesterol="" level="">300 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<0.001) and="" ldl-cholesterol=""><0.01) with="" soy="" protein="" consumption="" in="" adults="" with="" type="" ii="" hyperlipoproteinemia.="" total="" intake="" of="" soy="" protein,="" as="" a="" textured="" protein="" isolate,="" was="" not="" given="" but="" was="" approximately="" 13="" percent="" of="" kcal="" or="" 60="" g.="" the="" order="" in="" which="" the="" soy="" protein="" diet="" was="" consumed="" did="" not="" affect="" the="" results="" and="" the="" changes="" in="" total="" plasma="" cholesterol="" level="" far="" exceeded="" those="" expected="" based="" on="" the="" small="" differences="" in="" ratio="" of="" polyunsaturated="" to="" saturated="" fat="" and="" cholesterol="" content="" of="" the="" diets.="" when="" the="" control="" diet="" was="" fed="" first,="" statistically="" significant="" changes="" in="" total="" and="" ldl-="" cholesterol="" were="" not="" observed;="" when="" it="" was="" fed="" second,="" total="" cholesterol="" increased="" statistically="" significantly.="" these="" investigators="" also="" reported="" that="" addition="" of="" 500="" mg="" cholesterol="" in="" a="" small,="" similar="" study="" showed="" that="" level="" of="" dietary="" cholesterol="" did="" not="" modify="" the="" cholesterol-lowering="" effect="" of="" soy="" protein="" observed.="" descovich="" et="" al.="" (ref.="" 33)="" examined="" the="" effects="" of="" soy="" protein="" replacing="" animal="" protein="" in="" adults="" with="" stable="" type="" iia="" and="" iib="" hypercholesterolemia.="" subjects="" consumed="" an="" average="" of="" 47="" g="" of="" soy="" protein="" in="" the="" form="" of="" texturized="" soy="" protein="" (from="" sf)="" mixed="" into="" main="" dishes.="" during="" the="" baseline="" control="" period="" with="" a="" lipid-lowering="" diet,="" plasma="" total="" cholesterol="" decreased="" 3="" percent="" from="" baseline="" levels.="" when="" soy="" protein="" was="" substituted="" for="" animal="" protein="" in="" the="" second="" dietary="" period,="" total="" cholesterol="" decreased="" by="" 24="" percent=""><0.001) at="" the="" end="" of="" the="" experimental="" period.="" all="" of="" the="" subjects="" demonstrated="" decreases="" in="" total="" cholesterol="" of="" at="" least="" 10="" percent.="" upon="" returning="" to="" the="" control="" diet,="" plasma="" total="" cholesterol="" increased="" 7="" percent="" in="" men="" and="" 9="" percent="" in="" women.="" ldl-cholesterol="" also="" showed="" a="" statistically="" significant="" decrease,="" by="" 31="" percent="" from="" baseline="" levels=""><0.001), while="" hdl-cholesterol="" remained="" stable="" over="" the="" course="" of="" the="" soy="" protein="" diet="" (+0.4="" mg/dl="" for="" men="" and="" +1.0="" mg/dl="" for="" women).="" wolfe="" et="" al.="" (ref.="" 64)="" tested="" the="" effects="" of="" ingesting="" 47="" g="" of="" soy="" protein="" in="" the="" form="" of="" isp="" incorporated="" into="" main="" dishes="" and="" a="" beverage,="" while="" animal="" proteins="" were="" incorporated="" into="" similar="" main="" dishes="" and="" cow's="" milk="" was="" consumed="" during="" the="" mixed="" protein="" control="" period.="" baseline="" lipid="" concentrations="" were="" not="" given;="" however,="" mean="" total="" cholesterol="" concentrations="" were="" 280="" mg/dl="" after="" the="" soy="" protein="" treatment="" and="" 321="" mg/dl="" after="" the="" control="" treatment.="" thus,="" compared="" with="" the="" control="" period,="" serum="" total="" cholesterol="" was="" 41="" mg/dl="" lower="" with="" ingestion="" of="" soy="" protein=""><0.05) and="" ldl-cholesterol="" was="" 43="" mg/dl="" lower=""><0.05). hdl-cholesterol="" was="" similar="" at="" the="" end="" of="" the="" soy="" protein="" and="" control="" dietary="" periods.="" sirtori="" et="" al.="" (ref.="" 56)="" conducted="" a="" trial="" that="" examined="" the="" effects="" of="" complete="" and="" partial="" substitution="" of="" soy="" protein="" as="" sf="" (60="" g="" or="" 30="" g="" of="" soy="" protein),="" in="" a="" lecithinated="" textured="" vegetable="" protein,="" for="" animal="" protein="" in="" adults="" with="" type="" iia="" hyperlipoproteinemia.="" plasma="" cholesterol="" levels="" were="" not="" altered="" during="" the="" first="" control="" diet="" period.="" total="" plasma="" cholesterol="" levels="" were="" significantly=""><0.01) reduced="" in="" both="" periods="" of="" soy="" protein="" administration,="" by="" 18.6="" percent="" when="" 60="" g="" were="" consumed="" and="" by="" 13.2="" percent="" when="" 30="" g="" were="" consumed.="" serum="" cholesterol="" values="" returned="" almost="" completely="" to="" baseline="" during="" the="" second="" control="" period.="" changes="" in="" ldl-cholesterol="" levels="" were="" superimposable="" to="" those="" of="" total="" cholesterol.="" hdl-cholesterol="" levels="" tended="" to="" increase="" during="" the="" two="" soy="" periods="" and="" decline="" to="" baseline="" levels="" during="" the="" second="" control="" period,="" but="" these="" differences="" were="" not="" statistically="" significant.="" verillo="" et="" al.="" (ref.="" 60)="" compared="" the="" effects="" of="" substituting="" 31="" g="" of="" soy="" protein="" [[page="" 62986]]="" as="" sf="" for="" animal="" protein="" versus="" the="" addition="" of="" 31="" g="" of="" soy="" protein="" as="" sf="" to="" animal="" protein="" in="" adults="" with="" stable="" type="" ii="" hypercholesterolemia.="" slight,="" nonsignificant="" decreases="" in="" total="" and="" ldl-cholesterol="" levels="" were="" reported="" during="" the="" initial="" control="" period.="" among="" subjects="" who="" consumed="" the="" soy-substituted="" diet,="" serum="" total="" cholesterol="" declined="" significantly=""><0.01) from="" the="" end="" of="" the="" baseline="" diet="" by="" 35="" percent="" and="" 23="" percent="" in="" type="" iia="" and="" type="" iib="" patients,="" respectively.="" ldl-cholesterol="" declined="" significantly=""><0.01) from="" the="" end="" of="" the="" baseline="" diet="" by="" 44="" percent="" and="" 23="" percent="" in="" type="" iia="" and="" type="" iib="" patients,="" respectively.="" hdl-cholesterol="" increased="" 8="" percent,="" but="" this="" change="" did="" not="" reach="" statistical="" significance.="" the="" same="" hypocholesterolemic="" effects="" were="" also="" seen="" among="" subjects="" who="" consumed="" the="" soy-added="" diet.="" a="" comparison="" of="" results="" at="" the="" ends="" of="" the="" soy="" periods="" versus="" the="" means="" of="" final="" values="" of="" both="" control="" periods="" showed="" differences="" in="" serum="" lipids="" that="" were="" of="" similar="" magnitudes,="" but="" not="" statistically="" significantly="" different.="" the="" hypocholesterolemic="" response="" to="" soy="" was="" significantly="" related="" to="" cholesterol="" level="" at="" entry="" to="" the="" study.="" the="" study="" of="" lovati="" et="" al.="" (ref.="" 46)="" in="" adults="" with="" type="" ii="" hypercholesterolemia="" provided="" soy="" protein="" as="" sf,="" from="" textured="" vegetable="" protein,="" in="" amounts="" varying="" between="" 70="" and="" 105="" g="" depending="" upon="" total="" energy="" consumed.="" plasma="" total="" and="" ldl-cholesterol="" levels="" both="" decreased="" by="" 16="" percent=""><0.01) during="" the="" period="" when="" soy="" protein="" diet="" was="" ingested="" compared="" with="" levels="" at="" the="" start="" of="" the="" experimental="" period.="" changes="" in="" these="" parameters="" on="" the="" control="" diet="" were="" negligible.="" hdl-cholesterol="" concentrations="" were="" not="" documented="" but="" were="" reported="" to="" be="" unchanged="" on="" the="" two="" diet="" regimens.="" gaddi="" et="" al.="" (ref.="" 35)="" examined="" the="" effects="" of="" replacing="" animal="" protein="" and="" non-soy="" plant="" protein="" with="" approximately="" 75="" g="" soy="" protein="" from="" sf="" in="" a="" lecithinated="" textured="" soy="" protein,="" in="" adults="" with="" familial="" hypercholesterolemia.="" the="" control="" diet="" did="" not="" affect="" plasma="" lipid="" values="" during="" the="" initial="" experimental="" period.="" after="" ingestion="" of="" the="" soy="" protein="" diet,="" plasma="" total="" cholesterol="" decreased="" by="" 21="" percent=""><0.0l) and="" ldl-cholesterol="" decreased="" by="" 25="" percent=""><0.01) from="" levels="" measured="" after="" the="" first="" control="" diet="" period.="" hdl-cholesterol="" levels="" were="" unchanged.="" plasma="" total="" and="" ldl-cholesterol="" returned="" to="" concentrations="" close="" to="" those="" at="" baseline="" following="" resumption="" of="" the="" control="" diet="" during="" the="" third="" experimental="" period.="" b.="" studies="" in="" children.="" gaddi="" et="" al.="" (ref.="" 34)="" studied="" children="" from="" 3="" to="" 12="" years="" of="" age="" with="" familial="" hypercholesterolemia.="" after="" a="" baseline="" dietary="" period="" during="" which="" subjects="" consumed="" a="" low="" lipid="" diet,="" soy="" protein="" in="" the="" form="" of="" sf="" replaced="" a="" portion="" of="" the="" animal="" protein="" intake.="" no="" significant="" changes="" in="" plasma="" lipids="" occurred="" over="" the="" duration="" of="" the="" baseline="" dietary="" period.="" plasma="" total="" cholesterol="" at="" the="" end="" of="" the="" soy="" protein="" dietary="" period="" was="" 20="" percent="" lower="" than="" at="" the="" end="" of="" the="" baseline="" dietary="" period=""><0.001). ldl-cholesterol="" was="" 24="" percent="" lower=""><0.01) and="" hdl-cholesterol="" level="" was="" not="" affected.="" widhalm="" et="" al.="" (ref.="" 63)="" examined="" the="" lipid-lowering="" effects="" of="" incorporating="" isp="" (13.5-18="" g="" protein)="" into="" food="" and="" beverage="" recipes="" in="" children="" with="" familial="" hypercholesterolemia.="" after="" the="" soy="" protein="" dietary="" periods,="" plasma="" total="" cholesterol="" was="" 16="" percent="" lower=""><0.005) than="" baseline="" levels="" in="" the="" group="" that="" consumed="" the="" soy="" protein="" diet="" before="" the="" control="" diet="" and="" 18="" percent="" lower=""><0.001) in="" the="" group="" that="" consumed="" soy="" last.="" ldl-cholesterol="" was="" also="" statistically="" significantly="" decreased=""><0.001) by="" 22="" percent="" in="" the="" first="" group="" and="" 25="" percent="" in="" the="" second="" group.="" during="" the="" control="" diet="" periods,="" total="" and="" ldl-cholesterol="" levels="" were="" reduced="" by="" 8="" percent="" and="" 7="" percent="" in="" the="" first="" group="" and="" by="" 12="" percent="" and="" 13="" percent="" in="" the="" second="" group,="" respectively.="" hdl-cholesterol="" was="" not="" statistically="" significantly="" affected="" by="" dietary="" treatment.="" laurin="" et="" al.="" (ref.="" 45)="" and="" jacques="" et="" al.="" (ref.="" 42)="" both="" reported="" on="" a="" test="" of="" the="" lipid-lowering="" effects="" of="" isp="" (28="" g="" of="" soy="" protein)="" in="" children,="" 6="" to="" 12="" years="" of="" age,="" with="" familial="" hypercholesterolemia.="" children="" consumed="" either="" a="" conventional="" low="" fat="" diet="" with="" 2-percent="" cow's="" milk="" or="" the="" same="" low="" fat="" diet="" with="" a="" soy-based="" beverage="" made="" with="" 2-percent="" butterfat="" substituted="" for="" the="" 2-percent="" cow's="" milk.="" comparisons="" between="" the="" two="" treatment="" groups="" indicated="" that="" total="" and="" ldl-cholesterol="" levels="" were="" not="" altered.="" hdl-cholesterol="" level="" was="" increased="" 4="" percent=""><0.04) with="" soy="" protein="" compared="" to="" cow's="" milk.="" c.="" summary--subjects="" with="" type="" ii="" or="" familial="" hypercholesterolemia.="" each="" of="" the="" ten="" studies="" of="" the="" effects="" of="" soy="" protein="" in="" subjects="" with="" severe="" (type="" ii="" or="" familial)="" hypercholesterolemia="" employed="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" (refs.="" 33,="" 35,="" 46,="" 55,="" 56,="" 60,="" 64,="" 34,="" 42="" and="" 45="" (1="" trial),="" and="" 63),="" and="" most="" subjects="" had="" been="" consuming="" such="" a="" therapeutic="" diet="" prior="" to="" the="" study.="" six="" of="" the="" ten="" trials="" were="" conducted="" by="" workers="" from="" the="" same="" group="" (refs.="" 55,="" 33,="" 56,="" 46,="" 35,="" and="" 34).="" most="" used="" sf="" in="" tvp="" as="" the="" source="" of="" soy="" protein,="" in="" amounts="" ranging="" from="" 14="" to="" 105="" g="" (refs.="" 33,="" 56,="" 60,="" 46,="" 35,="" 34,="" and="" 63);="" the="" remainder="" used="" isp="" as="" the="" source="" of="" soy="" protein,="" in="" amounts="" ranging="" from="" 28="" to="" 60="" g="" (refs.="" 55,="" 64,="" and="" 42="" and="" 45="" (1="" trial)).="" in="" all="" the="" studies="" conducted="" in="" adults="" (refs.="" 33,="" 35,="" 46,="" 55,="" 56,="" 60,="" and="" 64),="" using="" both="" fixed="" sequence="" and="" crossover="" study="" designs,="" large="" and="" statistically="" significant="" decreases="" in="" both="" total="" and="" ldl-cholesterol="" levels="" were="" observed="" in="" response="" to="" consumption="" of="" diets="" containing="" soy="" protein.="" in="" the="" six="" trials="" in="" which="" they="" were="" measured,="" hdl-cholesterol="" levels="" were="" either="" not="" statistically="" significantly="" affected="" (refs.="" 33,="" 64,="" 60,="" 46,="" and="" 35)="" or="" were="" statistically="" significantly="" increased="" (ref.="" 56).="" in="" the="" studies="" conducted="" in="" children="" with="" familial="" hypercholesterolemia,="" two="" of="" the="" three="" trials="" demonstrated="" statistically="" significant="" decreases="" from="" baseline="" levels="" in="" total="" and="" ldl-cholesterol="" during="" the="" periods="" when="" soy="" protein="" diets="" were="" consumed="" (refs.="" 34="" and="" 63).="" however,="" interpretation="" of="" these="" findings="" is="" complicated="" by="" uncertainty="" about="" the="" control="" of="" intake="" of="" other="" dietary="" constituents,="" especially="" saturated="" fat="" and="" cholesterol.="" in="" the="" study="" reported="" by="" laurin="" et="" al.="" and="" jacques="" et="" al.="" (refs.="" 45="" and="" 42),="" differences="" in="" these="" dietary="" components="" were="" controlled.="" with="" diets="" providing="" 12="" percent="" of="" kcal="" from="" saturated="" fat="" and="" 163="" to="" 180="" mg="" of="" cholesterol,="" plasma="" total="" and="" ldl-cholesterol="" levels="" were="" not="" statistically="" significantly="" different,="" but="" the="" hdl-cholesterol="" level="" was="" statistically="" significantly="" higher,="" on="" the="" soy="" diet="" than="" on="" the="" cow's="" milk="" diet.="" 3.="" epidemiologic="" evidence="" on="" soy="" protein="" and="" blood="" lipids="" the="" petitioner="" also="" submitted="" one="" epidemiologic="" study="" by="" nagata="" et="" al.="" (ref.="" 65)="" that="" described="" the="" relationship="" between="" soy="" product="" and="" soy="" protein="" intake="" and="" serum="" total="" cholesterol="" concentrations="" in="" japanese="" men="" and="" women.="" participants="" in="" this="" study="" were="" 1,242="" men="" and="" 3,596="" women="" from="" the="" takayama="" study,="" a="" prospective="" cohort="" study="" on="" the="" impact="" of="" diet="" and="" lifestyle="" on="" cancer,="" who="" attended="" the="" annual="" health="" checkup="" program="" between="" april="" and="" october="" 1992.="" data="" regarding="" food="" intake="" were="" collected="" by="" a="" validated,="" semiquantitative="" food="" frequency="" questionnaire="" (ffq).="" blood="" samples="" were="" also="" taken="" for="" each="" subject="" and="" analyzed="" for="" total="" cholesterol="" concentrations.="" soy="" products="" identified="" in="" the="" ffq="" included="" tofu="" (plain,="" fried,="" deep-fried,="" or="" dried),="" miso,="" fermented="" soybeans,="" soy="" milk,="" and="" boiled="" soybeans.="" the="" estimated="" amount="" of="" soy="" protein="" consumed="" from="" these="" sources="" was="" 8.00=""> 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 (p<0.0001 for="" both="" men="" and="" women).="" the="" analysis="" for="" men="" was="" controlled="" for="" age,="" smoking="" status,="" and="" total="" energy,="" protein,="" and="" fat="" intake.="" the="" analysis="" for="" women="" was="" controlled="" for="" age,="" menopausal="" status,="" body="" mass="" index,="" and="" intake="" of="" energy="" and="" vitamin="" c.="" further="" adjustments="" for="" physical="" activity,="" coffee="" and="" tea="" consumption,="" and="" intakes="" of="" cholesterol,="" carbohydrates,="" fiber,="" and="" vitamin="" e="" were="" performed="" and="" results="" were="" not="" affected.="" between="" the="" 1st="" and="" 4th="" quartiles="" in="" men,="" total="" cholesterol="" was="" lower="" by="" 12="" mg/dl="" with="" a="" 9.6-g="" increase="" in="" soy="" protein="" intake.="" for="" women,="" total="" cholesterol="" was="" lower="" by="" 9="" mg/dl="" with="" a="" 7.9-g="" increase="" in="" soy="" protein="" intake.="" 4.="" meta-analysis="" of="" studies="" of="" soy="" protein="" and="" blood="" lipids="" the="" petitioner="" presented="" the="" results="" of="" a="" 1995="" meta-analysis="" (ref.="" 66)="" of="" the="" effect="" of="" soy="" protein="" on="" blood="" lipids.="" while="" the="" role="" of="" ``research="" synthesis''="" studies,="" including="" meta-analyses,="" is="" of="" interest,="" it="" is="" as="" yet="" unresolved.="" the="" appropriateness="" of="" such="" analytical="" techniques="" to="" establish="" diet/health="" relationships="" in="" particular="" is="" not="" known.="" there="" are="" on-going="" efforts="" to="" identify="" criteria="" and="" critical="" factors="" to="" consider="" in="" both="" conducting="" and="" using="" such="" analyses,="" but="" this="" science="" is="" still="" emerging.="" therefore,="" the="" meta-="" analysis="" did="" not="" weigh="" heavily="" within="" the="" body="" of="" evidence="" for="" this="" relationship.="" in="" summary,="" anderson="" et="" al.="" (ref.="" 66)="" pooled="" data="" from="" studies="" that="" were="" deemed="" comparable="" in="" methodology="" in="" order="" to="" perform="" a="" meta-="" analysis="" of="" the="" effect="" of="" soy="" protein="" on="" blood="" lipids.="" of="" the="" 37="" publications="" identified="" by="" these="" investigators="" that="" presented="" data="" on="" soy="" protein="" and="" lipid="" changes,="" 29="" met="" the="" criteria="" of="" using="" either="" isp="" or="" texturized="" soy="" protein="" as="" the="" soy="" protein="" source,="" employing="" either="" a="" parallel="" or="" crossover="" design,="" and="" providing="" initial="" or="" baseline="" cholesterol="" values="" to="" allow="" calculation="" of="" decreases.="" these="" 29="" publications="" reported="" the="" findings="" from="" 38="" separate="" trials.="" each="" of="" these="" publications="" was="" included="" in="" the="" petition="" and="" was="" considered="" for="" review="" individually="" by="" fda="" as="" described="" previously.="" thirty-four="" of="" the="" trials="" were="" conducted="" among="" adults="" and="" four="" among="" children.="" study="" samples="" included="" individuals="" with="" normal="" blood="" cholesterol="" levels="" as="" well="" as="" those="" with="" mildly="" to="" severely="" elevated="" levels.="" twelve="" of="" the="" trials="" were="" conducted="" in="" subjects="" with="" familial="" hypercholesterolemia.="" the="" specific="" analytical="" approach="" is="" described="" in="" anderson="" et="" al.="" (66).="" based="" on="" examining="" the="" difference="" from="" baseline="" between="" the="" soy="" protein="" and="" control="" protein="" groups,="" the="" analysis="" indicated="" that="" soy="" protein="" consumption="" statistically="" significantly="" decreased="" total="" cholesterol="" for="" the="" pooled="" data="" by="" 9.3="" percent="" and="" ldl-cholesterol="" by="" 12.9="" percent.="" hdl-cholesterol="" was="" increased="" by="" a="" net="" of="" 2.4="" percent="" with="" soy="" protein="" ingestion,="" but="" this="" change="" was="" not="" statistically="" significant.="" this="" analysis="" also="" suggested="" that="" the="" initial="" level="" of="" serum="" total="" cholesterol="" was="" the="" most="" important="" determinant="" of="" serum="" lipid="" response="" to="" soy="" protein.="" when="" changes="" in="" total="" and="" ldl-="" cholesterol="" were="" examined="" by="" quartile="" of="" baseline="" cholesterol="" concentration,="" a="" progressively="" greater="" magnitude="" of="" change="" was="" observed="" from="" the="" lowest="" to="" the="" highest="" quartiles.="" additional="" analyses="" indicated="" that="" the="" type="" and="" amount="" of="" soy="" protein="" consumed="" and="" type="" of="" background="" diet="" did="" not="" substantially="" influence="" the="" results.="" to="" examine="" further="" the="" effects="" of="" the="" type="" and="" amount="" of="" soy="" protein,="" an="" analysis="" was="" performed="" using="" changes="" observed="" with="" the="" soy="" diet="" alone="" instead="" of="" net="" changes="" as="" the="" outcome="" variable.="" initial="" serum="" cholesterol="" concentration="" was="" also="" the="" major="" determinant="" of="" effects="" in="" this="" model,="" but="" statistically="" significant="" effects="" (p="0.02)" were="" also="" obtained="" for="" amount="" of="" soy="" protein.="" this="" model="" predicted,="" after="" adjustment="" for="" initial="" values="" and="" other="" variables,="" serum="" total="" cholesterol="" decreases="" of="" 8.9="" mg/dl="" with="" 25="" g/day="" soy="" protein,="" 17.4="" mg/="" dl="" with="" 50="" g/day="" of="" soy="" protein,="" and="" 26.3="" mg/dl="" with="" 75="" g/day="" of="" soy="" protein.="" 5.="" studies="" of="" the="" role="" soy="" isoflavones="" isoflavones="" are="" a="" class="" of="" naturally-occurring="" compounds="" with="" weak="" estrogenic/antiestrogenic="" activities="" that="" are="" present="" in="" a="" wide="" variety="" of="" plants.="" the="" 12="" major="" isomers="" of="" naturally-occurring="" isoflavones="" in="" soybeans="" are="" genistein,="" genestin,="" 6``-o-acetylgenistin,="" 6``-o-="" malonylgenestin,="" diadzein,="" diadzin,="" 6``-o-acetyldiadzin,="" 6``-o-="" malonyldiadzin,="" glycitein,="" glycitin,="" 6``-o-acetylglycitin,="" and="" 6``-o-="" malonyglycitin.="" the="" levels="" of="" isoflavones="" in="" soybeans="" are="" known="" to="" vary="" with="" cultivar="" and="" growing="" conditions.="" soy="" isoflavones="" are="" retained="" to="" variable="" degrees="" in="" soy="" protein="" products="" and="" soy="" foods,="" depending="" on="" the="" particular="" processing="" techniques="" used.="" for="" example,="" essentially="" all="" of="" the="" isoflavones="" in="" soy="" protein="" products="" can="" be="" extracted="" by="" alcohol="" washing,="" and="" their="" levels="" can="" also="" be="" reduced="" by="" repeated="" aqueous="" washings="" and="" some="" texturization="" techniques.="" because="" of="" the="" estrogenic="" activities="" of="" the="" soy="" isoflavones,="" they="" have="" been="" hypothesized="" to="" contribute="" to="" the="" hypocholesterolemic="" effect="" of="" soy="" protein.="" the="" petitioner="" submitted="" an="" unpublished="" study="" by="" crouse="" et="" al.="" (ref.="" 31,="" documented="" in="" ref.="" 1="" with="" corrections="" noted="" in="" ref.="" 2)="" that="" examined="" the="" effect="" of="" soy="" protein="" containing="" different="" levels="" of="" isoflavones="" in="" hypercholesterolemic="" men="" and="" women="" (summarized="" in="" table="" 1="" of="" this="" document).="" potential="" subjects="" were="" provided="" instruction="" in="" an="" ncep="" step="" 1="" diet="" and="" followed="" this="" diet="" for="" 1="" month.="" subjects="" with="" qualifying="" serum="" lipid="" levels="" (ldl-cholesterol="">140 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 (p<0.05) and="" ldl-="" cholesterol=""><0.05), by="" 4="" percent="" and="" 6="" percent,="" respectively,="" while="" hdl-cholesterol="" was="" not="" altered="" (table="" 1).="" furthermore,="" in="" subjects="" with="" ldl-cholesterol="" in="" the="" top="" half="" of="" the="" study="" population,="" serum="" total="" and="" ldl-cholesterol="" were="" reduced="" by="" 9="" percent=""><0.03) and="" 12="" percent=""><0.03), respectively,="" by="" the="" isp="" with="" the="" highest="" isoflavone="" content,="" and="" by="" 8="" percent=""><0.03) and="" 9="" percent=""><0.03), respectively="" by="" the="" isp="" with="" the="" second="" highest="" isoflavone="" content,="" while="" hdl-="" cholesterol="" concentrations="" were="" maintained.="" [[page="" 62988]]="" baum="" et="" al.="" (ref.="" 28)="" also="" investigated="" the="" impact="" in="" soy="" protein="" containing="" different="" levels="" of="" isoflavones="" on="" cholesterol="" lowering="" and="" examined="" whether="" changes="" in="" blood="" lipids="" were="" lasting="" or="" transient.="" subjects="" were="" moderately="" hypercholesterolemic="" women,="" who="" were="" at="" least="" 1="" year="" since="" last="" menstrual="" period,="" and="" were="" not="" taking="" medications="" known="" to="" alter="" lipid="" or="" bone="" metabolism.="" following="" a="" 2-week="" run-in="" period="" during="" which="" subjects="" consumed="" an="" ncep="" step="" i="" diet,="" subjects="" were="" randomly="" assigned="" to="" one="" of="" three="" treatment="" groups="" consisting="" of="" 40="" g="" protein="" from="" either="" isp="" with="" 1.4="" mg="" total="" aglycone="" isoflavones/g="" protein,="" isp="" with="" 2.3="" mg="" total="" aglycone="" isoflavones/g="" protein,="" or="" casein/nonfat="" dry="" milk="" for="" the="" 24-week="" treatment="" period.="" although="" the="" adjusted="" mean="" difference="" in="" total="" serum="" cholesterol="" level="" was="" not="" statistically="" significantly="" different="" in="" the="" soy="" groups="" and="" the="" control="" group,="" there="" was="" a="" 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.="" hdl-cholesterol="" was="" also="" significantly="" increased="" in="" both="" soy="" groups="" compared="" to="" the="" control.="" body="" weight="" remained="" stable,="" and="" dietary="" intake="" was="" assessed="" and="" was="" reported="" to="" be="" similar="" among="" treatment="" groups="" although="" details="" were="" not="" reported.="" the="" petitioner="" concluded="" that="" these="" two="" studies="" (refs.="" 31="" and="" 28)="" provided="" evidence="" that="" the="" hypocholesterolemic="" effect="" of="" soy="" protein="" is="" dependent="" on="" processing="" techniques="" that="" enable="" retention="" of="" the="" naturally="" occurring="" isoflavones="" in="" conjunction="" with="" the="" soy="" protein.="" as="" additional="" supportive="" evidence="" for="" this="" conclusion,="" the="" petitioner="" cited="" studies="" of="" the="" lipid-lowering="" effects="" of="" soy="" protein="" with="" naturally="" occurring="" isoflavones="" in="" nonhuman="" primates="" (refs.="" 22="" and="" 70).="" in="" these="" experiments,="" the="" effects="" of="" diets="" including="" isp="" with="" naturally="" occurring="" isoflavones="" compared="" with="" those="" of="" diets="" containing="" either="" casein="" or="" alcohol-washed="" isp="" stripped="" of="" essentially="" all="" naturally="" occurring="" isoflavones="" were="" examined="" in="" two="" species="" of="" monkeys.="" the="" studies="" demonstrate="" significant="" depressions="" in="" total="" and="" non-hdl="" (ldl="" plus="" vldl)="" cholesterol="" levels="" in="" response="" to="" diets="" containing="" unextracted="" isp="" as="" compared="" with="" the="" diets="" containing="" casein="" or="" alcohol-washed="" isp.="" as="" evidence="" that="" soy="" isoflavones="" alone,="" in="" the="" absence="" of="" soy="" protein,="" are="" ineffective="" in="" lowering="" blood="" lipids,="" the="" petitioner="" cited="" the="" study="" of="" nestel="" et="" al.="" (ref.="" 71).="" in="" that="" study,="" consumption="" of="" a="" tablet="" containing="" 80="" mg="" of="" total="" aglycone="" isoflavones="" (mainly="" genistein="" and="" diadzein)="" had="" no="" impact="" on="" blood="" lipid="" profiles="" in="" postmenopausal="" women.="" although="" the="" petitioner="" suggested,="" based="" on="" the="" studies="" of="" crouse="" et="" al.="" (ref.="" 31)="" and="" baum="" et="" al.="" (ref.="" 28),="" that="" isoflavone="" content="" exceeding="" a="" certain="" threshold="" was="" a="" useful="" marker="" for="" soy="" protein="" that="" would="" be="" effective="" in="" lowering="" blood="" lipid="" levels,="" fda="" has="" tentatively="" concluded="" that="" the="" evidence="" is="" not="" sufficient="" to="" establish="" that="" the="" presence="" of="" isoflavones="" accounts="" for="" or="" is="" related="" to="" the="" effect="" on="" blood="" lipids.="" the="" agency="" notes="" that="" there="" are="" a="" variety="" of="" methods="" for="" processing="" soy="" that="" could="" give="" rise="" to="" variable="" amounts="" of="" naturally-="" occurring="" isoflavones="" in="" soy="" protein="" products,="" and="" this="" is="" a="" possible="" hypothesis="" for="" explaining="" some="" of="" the="" variability="" in="" the="" results="" of="" human="" intervention="" studies.="" however,="" with="" two="" exceptions="" (refs.="" 31="" and="" 28),="" the="" studies="" reviewed="" and="" described="" in="" this="" document="" did="" not="" include="" concurrent="" measures="" of="" the="" isoflavone="" content="" of="" the="" soy="" protein="" products="" studied.="" more="" importantly,="" a="" recent="" letter="" to="" the="" editor="" from="" sirtori="" et="" al.="" (ref.="" 72),="" which="" was="" not="" included="" in="" the="" petition,="" contradicts="" the="" conclusions="" of="" crouse="" et="" al.="" (ref.="" 31)="" and="" baum="" et="" al.="" (ref.="" 28).="" these="" researchers="" (ref.="" 72)="" reported="" that="" the="" tvp="" fed="" in="" their="" studies="" contained="" essentially="" no="" isoflavones="" and="" still="" considerable="" impact="" on="" ldl-cholesterol="" was="" observed.="" these="" studies="" (refs.="" 33,="" 56,="" 46,="" 35,="" and="" 34)="" were="" conducted="" in="" subjects="" with="" type="" ii="" hypercholesterolemia="" and="" all="" showed="" large="" and="" significant="" decreases="" in="" blood="" total="" and="" ldl-cholesterol="" levels.="" given="" the="" limited="" number="" of="" studies="" and="" the="" contradictory="" outcomes,="" fda="" is="" not="" persuaded="" that="" the="" isoflavone="" component="" of="" soy="" protein="" is="" a="" relevant="" factor="" to="" the="" diet-disease="" relationship.="" rather,="" fda="" tentatively="" concludes="" that="" the="" evidence="" from="" a="" wide="" range="" of="" studies="" using="" differently="" processed="" soy="" protein="" is="" supportive="" of="" a="" relationship="" between="" soy="" protein="" per="" se="" and="" reduced="" risk="" of="" chd.="" 6.="" summary="" in="" five="" (refs.="" 31,="" 28,="" 27,="" 51,="" and="" 44)="" of="" seven="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" and="" 40="" (2="" trials))="" well-controlled="" studies="" of="" hypercholesterolemic="" subjects="" consuming="" low="" saturated="" fat="" and="" low="" cholesterol="" diets,="" soy="" protein="" intake="" was="" associated="" with="" statistically="" significant="" decreases="" in="" total="" and/or="" ldl-cholesterol="" levels,="" either="" in="" the="" entire="" study="" populations="" or="" subsets="" of="" subjects="" with="" higher="" initial="" blood="" lipid="" levels.="" levels="" of="" hdl-cholesterol="" were="" found="" either="" to="" be="" unchanged="" (refs.="" 31,="" 27,="" 51,="" and="" 40="" (2="" trials))="" or="" slightly="" but="" statistically="" significantly="" increased="" (refs.="" 28="" and="" 44)="" by="" consumption="" of="" diets="" containing="" soy="" protein.="" levels="" of="" soy="" protein="" as="" isp="" found="" to="" be="" effective="" in="" lowering="" total="" and="" ldl-cholesterol="" levels,="" in="" the="" context="" of="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol,="" ranged="" in="" these="" studies="" from="" 25="" to="" 50="" g="" (refs.="" 31,="" 28,="" 27,="" and="" 51).="" as="" whole="" soybean="" milk,="" 31="" g="" of="" soy="" protein="" lowered="" ldl-cholesterol="" only="" in="" the="" subset="" of="" subjects="" with="" the="" highest="" initial="" ldl-cholesterol="" levels="" and="" ldl/hdl-cholesterol="" levels="" (ref.="" 44).="" diets="" providing="" 50="" g="" of="" soy="" protein="" as="" sf="" did="" not="" cause="" significant="" changes="" from="" baseline="" for="" any="" of="" the="" blood="" lipids,="" but="" the="" decrease="" in="" total="" cholesterol="" observed="" after="" ingestion="" of="" sf="" was="" significantly="" greater="" than="" that="" on="" the="" control="" diet="" of="" nonfat="" dry="" milk="" and="" cellulose="" (ref.="" 51).="" diets="" providing="" 27="" g="" of="" soy="" protein="" as="" sf="" in="" a="" textured="" product="" had="" no="" significant="" effects="" on="" blood="" lipid="" levels="" compared="" to="" a="" control="" diet,="" and="" a="" higher="" level="" (62="" g)="" significantly="" lowered="" total="" cholesterol="" only="" in="" the="" experimental="" group="" fed="" the="" soy="" protein="" diet="" first="" (ref.="" 40).="" three="" intervention="" studies="" reported="" on="" effects="" of="" soy="" protein="" in="" hypercholesterolemic="" subjects="" consuming="" ``usual''="" diets="" that="" were="" generally="" high="" in="" total="" fat,="" saturated="" fat,="" and="" cholesterol="" (refs.="" 37,="" 49,="" and="" 54).="" in="" each="" of="" these="" three="" studies,="" soy="" protein="" was="" fed="" in="" experimental="" diets="" as="" isp="" (refs.="" 37,="" 49,="" and="" 54).="" with="" a="" diet="" containing="" a="" very="" high="" level="" (99="" g)="" of="" soy="" protein="" from="" this="" source="" (ref.="" 37),="" statistically="" significant="" differences="" in="" both="" total="" and="" ldl-="" cholesterol="" were="" reported.="" results="" were="" less="" consistent,="" showing="" a="" significant="" decrease="" in="" total="" cholesterol="" only="" in="" subjects="" with="" the="" highest="" baseline="" levels,="" with="" a="" relatively="" low="" level="" of="" soy="" protein="" (17="" g)="" (ref.="" 49).="" an="" intermediate="" level="" of="" soy="" protein="" (57="" g)="" was="" found="" to="" be="" ineffective="" in="" lowering="" total="" cholesterol="" in="" the="" study="" of="" shorey="" et="" al.="" (ref.="" 54).="" (this="" latter="" study="" had="" a="" number="" of="" anomalous="" results.)="" hdl-cholesterol="" was="" also="" measured="" in="" these="" three="" studies.="" changes="" were="" small="" and="" not="" statistically="" significant="" in="" two="" studies="" (refs.="" 37="" and="" 49),="" but="" hdl-cholesterol="" was="" statistically="" significantly="" decreased="" from="" baseline="" values="" by="" 15="" percent="" in="" one="" study="" (ref.="" 54).="" five="" intervention="" studies="" examined="" the="" effects="" of="" soy="" protein="" in="" normocholesterolemic="" subjects="" (refs.="" 30,="" 36,="" 58,="" 59,="" and="" 53).="" effects="" of="" soy="" protein="" on="" total="" and="" ldl-cholesterol="" were="" less="" consistent="" in="" normocholesterolemic="" subjects="" than="" in="" hypercholesterolemic="" subjects.="" as="" isp,="" 44="" g="" of="" soy="" protein="" was="" effective="" in="" significantly="" lowering="" total="" cholesterol="" in="" one="" study="" (ref.="" 30)="" and="" 54="" g="" [[page="" 62989]]="" significantly="" lowered="" ldl-cholesterol="" in="" one="" study="" (ref.="" 58).="" with="" very="" low="" initial="" blood="" lipid="" levels="" seen="" in="" some="" of="" these="" studies,="" the="" impact="" of="" dietary="" changes="" is="" considerably="" lessened.="" hdl-cholesterol="" was="" measured="" in="" four="" of="" these="" studies,="" with="" statistically="" significant="" increases="" associated="" with="" soy="" protein="" intake="" found="" in="" two="" (refs.="" 58="" and="" 59)="" and="" no="" statistically="" significant="" changes="" in="" two="" (refs.="" 36="" and="" 53).="" two="" intervention="" studies="" (refs.="" 29="" and="" 43)="" examined="" the="" hypocholesterolemic="" effects="" of="" soy="" protein="" versus="" casein="" in="" the="" context="" of="" hypocaloric="" diets="" fed="" to="" obese="" persons="" to="" achieve="" significant="" weight="" reduction.="" these="" two="" studies="" (refs.="" 29="" and="" 43)="" demonstrated="" large="" decreases="" in="" both="" total="" and="" ldl-cholesterol="" levels="" during="" hypocaloric="" diets="" that="" provided="" relatively="" low="" amounts="" (27="" and="" 17="" g,="" respectively)="" of="" soy="" protein.="" hdl-cholesterol="" was="" decreased="" in="" both="" soy="" and="" casein="" groups="" at="" the="" end="" of="" the="" first="" study="" (ref.="" 29);="" however,="" only="" the="" casein="" group's="" values="" were="" significantly="" different=""><0.01) from="" baseline.="" additionally,="" the="" decrease="" in="" hdl-cholesterol="" in="" the="" casein="" group="" was="" significantly="" greater=""><0.01) than="" that="" observed="" in="" the="" soy="" protein="" group.="" in="" the="" second="" study="" (ref.="" 43),="" hdl-cholesterol="" levels="" were="" not="" significantly="" affected="" by="" dietary="" treatment.="" in="" all="" seven="" intervention="" studies="" conducted="" in="" adults="" with="" type="" ii="" or="" familial="" hypercholesterolemia="" (refs.="" 33,="" 35,="" 46,="" 55,="" 56,="" 60,="" and="" 64),="" large="" and="" statistically="" significant="" decreases="" in="" both="" total="" and="" ldl-cholesterol="" levels="" were="" observed="" in="" response="" to="" consumption="" of="" diets="" containing="" soy="" protein.="" in="" the="" six="" trials="" in="" which="" they="" were="" measured,="" hdl-cholesterol="" levels="" were="" either="" not="" statistically="" significantly="" affected="" (refs.="" 33,="" 64,="" 60,="" 46,="" and="" 35)="" or="" statistically="" significantly="" increased="" (ref.="" 56).="" each="" of="" these="" studies="" in="" adults="" with="" severe="" (type="" ii="" or="" familial)="" hypercholesterolemia="" employed="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" (refs.="" 33,="" 35,="" 46,="" 55,="" 56,="" 60,="" and="" 64)="" and="" most="" subjects="" had="" been="" consuming="" such="" a="" therapeutic="" diet="" prior="" to="" the="" study.="" most="" trials="" used="" sf="" in="" tvp="" as="" the="" source="" of="" soy="" protein,="" in="" amounts="" ranging="" from="" 31="" to="" 105="" g="" (refs.="" 33,="" 56,="" 60,="" 46,="" and="" 35);="" the="" remainder="" used="" isp="" as="" the="" source="" of="" soy="" protein,="" in="" amounts="" ranging="" from="" 28="" to="" 60="" g="" (refs.="" 55="" and="" 64).="" two="" of="" the="" three="" trials="" conducted="" in="" children="" with="" familial="" hypercholesterolemia="" demonstrated="" significant="" decreases="" from="" baseline="" levels="" in="" total="" and="" ldl-cholesterol="" during="" the="" periods="" when="" soy="" protein="" diets="" were="" consumed="" (refs.="" 34="" and="" 63).="" evidence="" from="" one="" epidemiologic="" study="" (ref.="" 65)="" supported="" a="" significant="" negative="" trend="" for="" lower="" serum="" total="" cholesterol="" concentrations="" with="" higher="" levels="" of="" soy="" protein="" intake=""><0.0001 for="" both="" men="" and="" women).="" between="" the="" first="" and="" fourth="" quartiles="" in="" men="" total="" cholesterol="" was="" lower="" by12="" mg/dl="" with="" a="" 9.6-g="" increase="" in="" soy="" protein="" intake.="" for="" women,="" total="" cholesterol="" was="" lower="" by="" 9="" mg/dl="" with="" a="" 7.9-g="" increase="" in="" soy="" protein="" intake.="" based="" on="" these="" studies,="" fda="" tentatively="" finds="" there="" is="" scientific="" evidence="" for="" a="" consistent,="" clinically="" significant="" effect="" of="" soy="" protein="" on="" blood="" total="" and="" ldl-cholesterol.="" the="" hypocholesterolemic="" effect="" of="" soy="" protein="" is="" seen="" in="" addition="" to="" the="" effects="" of="" a="" low="" saturated="" fat="" and="" low="" cholesterol="" diet.="" the="" degree="" of="" lowering="" of="" blood="" total="" and="" ldl-cholesterol="" is="" consistently="" and="" highly="" dependent="" on="" initial="" levels,="" within="" and="" across="" studies="" of="" subjects="" with="" normal,="" moderately="" elevated,="" and="" severely="" elevated="" blood="" lipid="" levels,="" with="" persons="" having="" higher="" blood="" lipid="" levels="" showing="" greater="" effects.="" soy="" protein="" consistently="" causes="" only="" statistically="" nonsignificant="" effects="" or="" slight="" elevations="" in="" hdl-cholesterol="" levels.="" the="" intervention="" studies="" suggest="" that="" a="" minimum="" level="" of="" approximately="" 25="" g="" of="" soy="" protein="" is="" needed="" to="" have="" a="" clinically="" significant="" effect="" on="" total="" and="" ldl-cholesterol="" levels.="" these="" conclusions,="" drawn="" from="" the="" review="" of="" the="" individual,="" well="" controlled="" studies,="" are="" also="" supported="" by="" the="" meta-analysis="" of="" anderson="" et="" al.="" (66).="" iv.="" decision="" to="" propose="" a="" health="" claim="" relating="" soy="" protein="" to="" reduction="" in="" risk="" of="" chd="" the="" petition="" provided="" and="" fda="" reviewed="" information="" on="" pertinent="" human="" studies="" that="" evaluated="" the="" effects="" on="" serum="" cholesterol="" and="" ldl-="" cholesterol="" levels="" from="" dietary="" intervention="" with="" soy="" protein="" in="" subjects="" with="" normal="" to="" elevated="" serum="" cholesterol="" levels.="" fda="" tentatively="" concludes="" that,="" based="" on="" the="" totality="" of="" publicly="" available="" scientific="" evidence,="" there="" is="" significant="" scientific="" agreement="" to="" support="" the="" relationship="" between="" consumption="" of="" soy="" protein="" included="" in="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol="" and="" the="" risk="" of="" chd.="" the="" strongest="" evidence="" for="" the="" effect="" of="" soy="" protein="" on="" the="" risk="" of="" chd="" is="" provided="" by="" studies="" that="" measured="" the="" effect="" of="" dietary="" soy="" protein="" consumption="" on="" the="" two="" major="" risk="" factors="" for="" chd,="" total="" and="" ldl-cholesterol.="" in="" most="" intervention="" trials="" in="" subjects="" with="" total=""><300 mg/dl,="" soy="" protein="" was="" found="" to="" reduce="" total="" and/or="" ldl-cholesterol="" levels="" to="" a="" clinically="" significant="" degree="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" 37,="" 49,="" 30,="" 58,="" 29,="" and="" 43).="" moreover,="" hdl-cholesterol="" levels="" were="" unchanged="" (refs.="" 31,="" 27,="" 51,="" 40,="" 37,="" 49,="" 36,="" and="" 53)="" or="" slightly="" increased="" (refs.="" 28,="" 44,="" 58,="" and="" 59).="" in="" some="" cases="" (refs.="" 27,="" 44,="" and="" 49),="" decreases="" in="" total="" and="" ldl-cholesterol="" were="" statistically="" significant="" only="" in="" subsets="" of="" subjects="" with="" the="" higher="" initial="" blood="" lipid="" levels.="" results="" in="" normocholesterolemic="" subjects="" (refs.="" 30,="" 36,="" 58,="" 59,="" and="" 53)="" were="" more="" variable="" than="" in="" hypercholesterolemic="" subjects="" (31,="" 28,="" 27,="" 51,="" 44,="" 40,="" 37,="" 49,="" 54,="" 29,="" and="" 43).="" the="" outcome="" of="" an="" epidemiologic="" study="" (ref.="" 65)="" also="" supported="" a="" relationship="" between="" higher="" levels="" of="" soy="" protein="" intake="" and="" lower="" blood="" lipid="" levels.="" most="" of="" the="" studies="" in="" subjects="" with="" total=""><300 mg/dl="" used="" low="" saturated="" fat="" and="" low="" cholesterol="" diets="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" 30,="" 36,="" 53,="" 29,="" and="" 43),="" but="" some="" used="" ``usual''="" diets="" (refs.="" 37,="" 49,="" 54,="" 36,="" 58,="" and="" 59).="" although="" soy="" protein="" was="" found="" to="" lower="" blood="" lipid="" levels="" in="" some="" of="" the="" studies="" using="" ``usual''="" diets,="" hypocholesterolemic="" effects="" of="" soy="" protein="" were="" more="" consistently="" observed="" with="" diets="" low="" in="" saturated="" fat="" and="" cholesterol.="" in="" some="" studies="" (especially="" those="" without="" run-in="" periods)="" (refs.="" 40="" and="" 54),="" the="" control="" low="" saturated="" fat="" and="" low="" cholesterol="" diets="" induced="" significant="" decreases="" in="" blood="" lipid="" levels="" making="" it="" difficult="" to="" detect="" any="" additional="" effect="" of="" soy="" protein.="" at="" the="" same="" time,="" in="" two="" studies="" in="" which="" soy="" protein="" containing="" hypocaloric="" diets="" were="" compared="" to="" similar="" diets="" without="" soy="" (refs.="" 29="" and="" 43),="" only="" the="" soy="" protein="" containing="" diets="" induced="" significant="" changes="" in="" blood="" lipid="" levels.="" given="" the="" variability="" of="" amounts="" and="" forms="" in="" which="" soy="" protein="" was="" provided="" in="" the="" diets,="" the="" response="" of="" blood="" lipid="" levels="" appears="" robust.="" data="" from="" studies="" of="" adults="" with="" type="" ii="" and="" familial="" forms="" of="" hypercholesterolemia="" (and="" total="" cholesterol="" levels="" in="" excess="" of="" 300="" mg/="" dl)="" (refs.="" 55,="" 33,="" 64,="" 56,="" 64,="" 46,="" and="" 35)="" were="" more="" consistent="" than="" studies="" in="" persons="" with="" lower="" blood="" lipid="" levels="" in="" showing="" large="" and="" statistically="" significant="" decreases="" in="" total="" and="" ldl-cholesterol,="" accompanied="" by="" no="" changes="" or="" slight="" increases="" in="" hdl-cholesterol="" levels.="" nearly="" all="" of="" the="" subjects="" in="" these="" trials="" consumed="" low="" saturated="" fat="" and="" low="" cholesterol="" diets="" during="" the="" studies="" and="" had="" consumed="" such="" diets="" prior="" to="" studies="" with="" soy="" protein.="" soy="" protein="" was="" tested="" in="" a="" variety="" of="" food="" forms="" (as="" soy="" beverages,="" formulated="" into="" meat="" and="" dairy="" product="" analogs,="" added="" to="" soups,="" or="" baked="" into="" foods,="" such="" as="" muffins="" and="" breads)="" but="" produced="" fairly="" consistent="" results="" [[page="" 62990]]="" regardless="" of="" the="" food="" form="" fed="" and="" apparent="" differences="" in="" processing="" techniques.="" fda="" tentatively="" concludes,="" based="" on="" the="" evidence="" submitted="" and="" reviewed,="" that="" soy="" protein,="" included="" in="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol,="" can="" lower="" blood="" total="" and="" ldl-cholesterol="" levels,="" without="" adversely="" affecting="" hdl-cholesterol="" levels.="" the="" agency="" also="" tentatively="" concludes="" that="" the="" effect="" is="" due="" to="" soy="" protein="" per="" se="" and="" is="" not="" consistently="" related="" to="" the="" presence="" or="" absence="" of="" isoflavones.="" the="" intervention="" studies="" suggest="" that="" a="" minimum="" level="" of="" approximately="" 25="" g="" of="" soy="" protein="" is="" needed="" to="" have="" a="" clinically="" significant="" effect="" on="" total="" and="" ldl-cholesterol="" levels.="" based="" on="" the="" totality="" of="" the="" scientific="" evidence="" presented="" in="" the="" petition,="" the="" agency="" tentatively="" concludes="" that="" there="" is="" significant="" scientific="" evidence="" to="" show="" that="" soy="" protein,="" included="" in="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol,="" will="" help="" reduce="" serum="" lipids,="" and="" that="" such="" reductions="" may="" reduce="" the="" risk="" of="" chd.="" in="" the="" majority="" of="" clinical="" studies="" evaluating="" soy="" products,="" total="" and="" ldl-cholesterol="" were="" the="" lipid="" fractions="" shown="" to="" be="" the="" most="" affected="" by="" soy="" protein="" intervention.="" as="" part="" of="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol,="" regular="" consumption="" of="" soy="" protein,="" in="" an="" amount="" to="" provide="" 25="" g/day,="" resulted="" in="" reduced="" total="" and="" ldl-cholesterol="" levels="" in="" subjects="" with="" normal="" and="" elevated="" serum="" cholesterol="" levels.="" as="" stated="" in="" section="" iii.a="" of="" this="" document,="" federal="" government="" and="" other="" reviews="" have="" concluded="" that="" there="" is="" substantial="" epidemiologic="" and="" clinical="" evidence="" that="" high="" blood="" levels="" of="" total="" cholesterol="" and="" ldl-cholesterol="" represent="" major="" contributors="" to="" chd="" (56="" fr="" 60727="" at="" 60728,="" and="" refs.="" 4="" through="" 7).="" dietary="" factors="" that="" decrease="" total="" cholesterol="" and="" ldl-="" cholesterol="" will="" affect="" the="" risk="" of="" chd="" (refs.="" 4="" through="" 7).="" given="" all="" of="" this="" evidence,="" the="" agency="" is="" proposing="" a="" health="" claim="" on="" the="" relationship="" between="" soy="" protein="" and="" reduced="" risk="" of="" chd.="" v.="" description="" and="" rationale="" for="" components="" of="" health="" claim="" a.="" relationship="" between="" soy="" protein="" and="" chd="" and="" the="" significance="" of="" the="" relationship="" proposed="" sec.="" 101.82(a)="" describes="" the="" relationship="" between="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" containing="" soy="" protein="" and="" the="" risk="" of="" chd.="" in="" proposed="" sec.="" 101.82(a)(1),="" the="" agency="" recounts="" that="" chd="" is="" the="" most="" common="" and="" serious="" form="" of="" cvd,="" and="" that="" chd="" refers="" to="" diseases="" of="" the="" heart="" muscle="" and="" supporting="" blood="" vessels.="" the="" proposed="" section="" also="" notes="" that="" high="" blood="" total="" and="" ldl-cholesterol="" levels="" are="" associated="" with="" increased="" risk="" of="" developing="" chd="" and="" identifies="" the="" levels="" of="" total="" cholesterol="" and="" ldl-cholesterol="" that="" would="" put="" an="" individual="" at="" high="" risk="" of="" developing="" chd,="" as="" well="" as="" those="" serum="" lipid="" levels="" that="" are="" associated="" with="" borderline="" high="" risk.="" this="" information="" will="" assist="" consumers="" in="" understanding="" the="" seriousness="" of="" chd.="" in="" proposed="" sec.="" 101.82(a)(2),="" the="" agency="" recounts="" that="" populations="" with="" a="" low="" incidence="" of="" chd="" tend="" to="" have="" low="" blood="" total="" and="" ldl-="" cholesterol="" levels.="" it="" states="" that="" these="" populations="" also="" tend="" to="" have="" dietary="" patterns="" that="" are="" low="" in="" total="" fat,="" saturated="" fat,="" and="" cholesterol="" and="" high="" in="" plant="" foods="" that="" contain="" fiber="" and="" other="" components.="" this="" information="" is="" consistent="" with="" that="" provided="" in="" the="" authorized="" health="" claim="" for="" fruits,="" vegetables,="" and="" grain="" products="" and="" chd="" (sec.="" 101.77)="" and="" so="" the="" agency="" believes="" that="" this="" information="" provides="" a="" basis="" for="" a="" better="" understanding="" of="" the="" numerous="" factors="" that="" contribute="" to="" the="" risk="" of="" chd="" and="" the="" relationship="" with="" soy="" protein="" and="" diets="" low="" in="" saturated="" fat="" and="" cholesterol.="" proposed="" sec.="" 101.82(a)(3)="" states="" that="" diets="" low="" in="" saturated="" fat="" and="" cholesteral="" may="" reduce="" the="" risk="" of="" chd.="" the="" paragraph="" further="" states="" that="" soy="" protein,="" when="" added="" to="" such="" a="" diet,="" may="" also="" help="" reduce="" the="" risk="" of="" chd.="" proposed="" sec.="" 101.82(b)="" describes="" the="" significance="" of="" the="" diet-="" disease="" relationship.="" in="" proposed="" sec.="" 101.82(b)(1),="" the="" agency="" recounts="" that="" chd="" remains="" a="" major="" public="" health="" concern="" in="" the="" united="" states="" because="" the="" disease="" accounts="" for="" more="" deaths="" than="" any="" other="" disease="" or="" group="" of="" diseases.="" the="" claim="" states="" that="" early="" management="" of="" modifiable="" risk="" factors="" for="" chd="" is="" a="" major="" public="" health="" goal="" that="" can="" assist="" in="" reducing="" the="" risk="" of="" chd.="" this="" information="" is="" consistent="" with="" the="" evidence="" that="" lowering="" blood="" total="" and="" ldl-cholesterol="" levels="" reduces="" the="" risk="" of="" chd="" (56="" fr="" 60727,="" 58="" fr="" 2739,="" and="" refs.="" 4="" through="" 8).="" in="" proposed="" sec.="" 101.82(b)(2),="" the="" significance="" of="" the="" relationship="" between="" soy="" protein="" and="" chd="" risk="" factors="" in="" context="" of="" the="" total="" diet="" is="" discussed.="" the="" agency="" recounts="" that="" many="" americans'="" intakes="" of="" saturated="" fat="" and="" cholesterol="" exceed="" recommended="" levels,="" and="" it="" summarizes="" public="" health="" recommendations="" for="" the="" diet="" (56="" fr="" 60727="" at="" 60738="" and="" sec.="" 101.75(b)(3)).="" this="" paragraph="" also="" states="" that="" scientific="" evidence="" demonstrates="" that="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" and="" that="" contain="" soy="" protein="" are="" associated="" with="" reduced="" blood="" lipids.="" fda="" tentatively="" concludes="" that="" the="" latter="" statement="" is="" scientifically="" valid="" based="" on="" the="" evidence="" that="" it="" has="" reviewed="" on="" this="" nutrient-disease="" relationship.="" b.="" nature="" of="" the="" claim="" in="" proposed="" sec.="" 101.82(c)(1),="" fda="" is="" proposing="" to="" require="" that="" all="" of="" the="" general="" requirements="" for="" health="" claims="" set="" out="" in="" sec.="" 101.14="" be="" met.="" this="" provision="" is="" consistent="" with="" the="" provisions="" of="" the="" other="" specific="" health="" claim="" regulations="" in="" 21="" cfr="" part="" 101,="" subpart="" e.="" in="" proposed="" sec.="" 101.82(c)(2)(i),="" fda="" is="" proposing="" to="" authorize="" a="" health="" claim="" on="" the="" relationship="" between="" diets="" that="" contain="" soy="" protein="" and="" are="" low="" in="" saturated="" fat="" and="" cholesterol="" and="" the="" risk="" of="" chd.="" the="" agency="" is="" proposing="" to="" do="" so="" based="" on="" its="" review="" of="" the="" scientific="" evidence="" on="" this="" nutrient-disease="" relationship,="" which="" shows="" that="" diets="" that="" contain="" soy="" protein="" and="" are="" low="" in="" saturated="" fat="" and="" cholesterol="" help="" to="" reduce="" total="" and="" ldl-cholesterol="" levels,="" especially="" in="" individuals="" with="" elevated="" blood="" total="" cholesterol="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" 37,="" 49,="" 30,="" 58,="" 29,="" 43,="" 55,="" 33,="" 64,="" 56,="" 64,="" 46,="" and="" 35).="" this="" result="" is="" significant="" for="" the="" risk="" of="" heart="" disease="" because="" elevated="" levels="" of="" total="" and="" ldl-cholesterol="" are="" associated="" with="" increased="" risk="" of="" chd="" (refs.="" 4="" through="" 7).="" most="" of="" the="" scientific="" evidence="" for="" an="" effect="" of="" soy="" protein="" on="" blood="" lipid="" levels="" was="" provided="" by="" studies="" that="" used="" diets="" low="" in="" saturated="" fat="" and="" cholesterol.="" although="" soy="" protein="" was="" found="" to="" lower="" blood="" lipid="" levels="" in="" some="" of="" the="" studies="" using="" ``usual''="" diets="" (refs.="" 37,="" 49,="" and="" 58),="" hypocholesterolemic="" effects="" of="" soy="" protein="" were="" more="" consistently="" observed="" with="" diets="" low="" in="" saturated="" fat="" and="" cholesterol.="" moreover,="" as="" stated="" in="" section="" v.a="" of="" this="" document,="" chd="" is="" a="" major="" public="" health="" concern="" in="" the="" united="" states,="" and="" the="" totality="" of="" the="" scientific="" evidence="" provides="" strong="" and="" consistent="" support="" that="" diets="" high="" in="" saturated="" fat="" and="" cholesterol="" are="" associated="" with="" elevated="" levels="" of="" blood="" total="" and="" ldl-cholesterol="" and,="" thus,="" chd="" (56="" fr="" 60727="" at="" 60737).="" dietary="" estimates="" for="" american="" adults="" show="" that="" the="" average="" saturated="" fat="" intakes="" of="" american="" adults="" are="" about="" 13="" percent="" of="" calories,="" total="" fat="" intakes="" are="" about="" 37="" percent="" of="" calories,="" and="" average="" cholesterol="" intakes="" range="" from="" 300="" to="" over="" 400="" mg="" daily="" for="" adult="" men="" and="" women="" (56="" fr="" 60727="" at="" 60738).="" the="" current="" intakes="" of="" saturated="" fat="" and="" total="" fat="" are="" thus="" well="" in="" excess="" of="" recommended="" goals="" of="" less="" than="" 10="" percent="" and="" 30="" percent="" of="" calories.="" [[page="" 62991]]="" dietary="" guidelines="" from="" both="" government="" and="" private="" scientific="" bodies="" conclude="" that="" the="" majority="" of="" the="" american="" population="" would="" benefit="" from="" decreased="" consumption="" of="" dietary="" saturated="" fat="" and="" cholesterol="" (refs.="" 4="" through="" 7).="" the="" results="" of="" several="" studies="" showed="" that="" daily="" consumption="" of="" soy="" protein="" lowered="" total="" cholesterol="" and="" ldl-="" cholesterol,="" and="" the="" effects="" of="" dietary="" intake="" of="" soy="" protein="" were="" evident="" when="" the="" diets="" were="" low="" in="" saturated="" fat="" and="" cholesterol="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" 30,="" 29,="" and="" 43).="" thus,="" the="" agency="" tentatively="" finds="" that="" it="" will="" be="" more="" helpful="" to="" americans'="" efforts="" to="" maintain="" healthy="" dietary="" practices="" if="" the="" effect="" of="" soy="" protein="" on="" serum="" lipids="" is="" characterized="" in="" the="" context="" of="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol.="" in="" sec.="" 101.82(c)(2)(i)(a),="" the="" agency="" is="" proposing="" to="" require,="" consistent="" with="" other="" health="" claims,="" that="" the="" relationship="" be="" qualified="" with="" the="" terms="" ``may''="" or="" ``might.''="" these="" terms="" are="" used="" to="" make="" clear="" that="" not="" all="" persons="" can="" necessarily="" expect="" to="" benefit="" from="" these="" dietary="" changes="" (56="" fr="" 60727="" at="" 60740="" and="" 58="" fr="" 2552="" at="" 2573).="" the="" requirement="" that="" the="" claim="" use="" the="" term="" ``may''="" or="" ``might''="" to="" relate="" the="" ability="" of="" soy="" protein="" to="" reduce="" the="" risk="" of="" heart="" disease="" is="" also="" intended="" to="" reflect="" the="" multifactorial="" nature="" of="" the="" disease.="" in="" sec.="" 101.82(c)(2)(i)(b),="" the="" agency="" is="" proposing="" to="" require,="" consistent="" with="" other="" authorized="" health="" claims,="" that="" the="" terms="" ``coronary="" heart="" disease''="" or="" ``heart="" disease''="" be="" used="" in="" specifying="" the="" disease.="" these="" terms="" are="" commonly="" used="" in="" dietary="" guidance="" materials,="" and="" therefore="" they="" should="" be="" readily="" understandable="" to="" the="" consumer="" (56="" fr="" 60727="" at="" 60740="" and="" 58="" fr="" 2552="" at="" 2573).="" in="" sec.="" 101.82(c)(2)(i)(c),="" the="" agency="" is="" proposing="" that="" the="" claim="" specify="" the="" substance="" as="" ``soy="" protein.''="" based="" on="" its="" review="" of="" the="" scientific="" evidence="" submitted="" with="" the="" petition,="" the="" agency="" tentatively="" concludes="" that="" there="" is="" significant="" scientific="" agreement="" that="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" that="" contain="" soy="" protein="" may="" help="" to="" reduce="" blood="" total="" and="" ldl-cholesterol="" levels,="" the="" major="" modifiable="" risk="" factors="" for="" chd="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" 37,="" 49,="" 30,="" 58,="" 29,="" 43,="" 55,="" 33,="" 64,="" 56,="" 64,="" 46,="" and="" 35).="" as="" discussed="" in="" section="" iii.c.5="" of="" this="" document,="" fda="" did="" not="" find="" persuasive="" the="" limited="" and="" contradictory="" evidence="" that="" soy="" isoflavones="" are="" a="" relevant="" factor="" in="" the="" diet-disease="" relationship="" persuasive.="" therefore,="" fda="" has="" tentatively="" concluded="" that="" evidence="" from="" a="" wide="" range="" of="" studies="" supports="" a="" relationship="" between="" soy="" protein="" per="" se="" and="" reduced="" risk="" of="" chd.="" as="" discussed="" previously,="" the="" agency="" tentatively="" finds="" that="" for="" the="" public="" to="" understand="" fully,="" in="" the="" context="" of="" the="" total="" daily="" diet,="" the="" significance="" of="" consumption="" of="" soy="" protein="" on="" the="" risk="" of="" chd="" (see="" section="" 403(r)(3)(b)(iii)="" of="" the="" act),="" information="" about="" the="" total="" diet="" must="" be="" included="" as="" part="" of="" the="" claim.="" therefore,="" in="" sec.="" 101.82(c)(2)(i)(d),="" the="" agency="" is="" proposing="" to="" require="" that="" the="" claim="" include="" the="" fact="" that="" the="" effect="" of="" dietary="" consumption="" of="" soy="" protein="" on="" the="" risk="" of="" chd="" is="" evident="" when="" it="" is="" consumed="" as="" part="" of="" a="" healthy="" diet="" and="" that,="" consistent="" with="" other="" authorized="" health="" claims,="" the="" fat="" component="" of="" the="" diet="" be="" specified="" as="" ``saturated="" fat''="" and="" ``cholesterol.''="" based="" on="" its="" review="" of="" the="" scientific="" evidence="" submitted="" with="" the="" petition,="" the="" agency="" tentatively="" concludes="" that="" there="" is="" significant="" scientific="" agreement="" that="" diets="" containing="" soy="" protein="" and="" low="" in="" saturated="" fat="" and="" cholesterol="" are="" associated="" with="" reduced="" blood="" total="" and="" ldl-cholesterol="" levels.="" proposed="" sec.="" 101.82(c)(2)(i)(e),="" consistent="" with="" other="" authorized="" health="" claims,="" requires="" that="" the="" claim="" not="" attribute="" any="" degree="" of="" risk="" reduction="" of="" chd="" to="" consumption="" of="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" that="" contain="" soy="" protein.="" none="" of="" the="" studies="" that="" the="" agency="" reviewed="" provide="" a="" basis="" for="" determining="" the="" percent="" reduction="" in="" risk="" of="" chd="" likely="" from="" consuming="" diets="" that="" contain="" soy="" protein="" and="" are="" low="" in="" saturated="" fat="" and="" cholesterol.="" also="" consistent="" with="" other="" authorized="" claims,="" proposed="" sec.="" 101.82(c)(2)(i)(f)="" requires="" that="" the="" claim="" not="" imply="" that="" consumption="" of="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" and="" that="" contain="" soy="" protein="" is="" the="" only="" recognized="" means="" of="" reducing="" chd="" risk.="" proposed="" sec.="" 101.82(c)(2)(i)(g)="" requires="" that="" the="" claim="" specify="" the="" daily="" dietary="" intake="" of="" soy="" protein="" needed="" to="" reduce="" the="" risk="" of="" chd="" and="" the="" contribution="" one="" serving="" of="" the="" product="" makes="" to="" achieving="" the="" specified="" daily="" dietary="" intake.="" this="" requirement="" is="" consistent="" with="" requirements="" set="" forth="" in="" sec.="" 101.81.="" in="" the="" studies="" showing="" a="" statistically="" significant="" effect="" of="" soy="" protein="" on="" total="" or="" ldl-cholesterol,="" the="" amounts="" fed="" ranged="" from="" 17="" to="" 105="" g/day="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" 37,="" 49,="" 30,="" 58,="" 29,="" 43,="" 55,="" 33,="" 64,="" 56,="" 64,="" 46,="" and="" 35).="" in="" proposing="" 25="" g/day="" as="" an="" effective="" daily="" intake="" of="" soy="" protein,="" the="" petitioner="" relied="" on="" the="" meta-analysis="" by="" anderson="" et="" al.="" (ref.="" 65)="" and="" noted="" that="" the="" estimate="" suggested="" by="" the="" meta-analysis="" was="" confirmed="" by="" the="" recent="" study="" of="" crouse="" et="" al.="" (ref.="" 31)="" that="" found="" reductions="" in="" total="" and="" ldl-cholesterol="" of="" 4="" and="" 6="" percent,="" respectively,="" with="" ingestion="" of="" 25="" g/day="" of="" soy="" protein="" containing="" high="" levels="" of="" isoflavones.="" fda="" notes="" that,="" although="" none="" of="" the="" studies="" reviewed="" attempted="" to="" determine="" an="" effective="" or="" optimal="" amount="" of="" soy="" protein,="" the="" study="" by="" sirtori="" et="" al.="" (ref.="" 56)="" suggests="" the="" existence="" of="" a="" dose-response.="" in="" that="" study="" of="" subjects="" with="" type="" ii="" hypercholesterolemia,="" total="" cholesterol="" levels="" were="" reduced="" by="" 13="" and="" 19="" percent,="" and="" ldl-="" cholesterol="" levels="" were="" reduced="" by="" 18="" and="" 23="" percent,="" compared="" to="" control="" by="" ingestion="" of="" 30="" and="" 60="" g/day="" of="" soy="" protein,="" respectively.="" with="" levels="" of="" soy="" protein="" intake="" lower="" than="" the="" proposed="" effective="" amount,="" findings="" have="" been="" variable.="" mercer="" et="" al.="" (ref.="" 49)="" found="" a="" statistically="" significant="" reduction="" in="" total="" cholesterol="" in="" response="" to="" 17="" g/day="" of="" soy="" protein="" only="" in="" those="" subjects="" with="" high="" initial="" values.="" feeding="" the="" same="" amount="" (17="" g/day)="" of="" soy="" protein="" in="" a="" hypocaloric="" diet,="" however,="" jenkins="" et="" al.="" (ref.="" 43)="" found="" statistically="" significant="" reductions="" of="" 10="" and="" 17="" percent="" in="" total="" and="" ldl-="" cholesterol,="" respectively.="" with="" 25="" g/day="" of="" soy="" protein,="" bakhit="" et="" al.="" (ref.="" 27)="" found="" a="" statistically="" significant="" reduction="" in="" total="" cholesterol="" (about="" 8="" percent)="" in="" subjects="" with="" blood="" cholesterol="" levels="" greater="" than="" 220="" mg/dl.="" crouse="" et="" al.="" (ref.="" 31)="" found="" that="" 25="" g="" of="" soy="" protein="" that="" contained="" a="" high="" level="" of="" isoflavones="" significantly="" lowered="" total=""><0.05) and="" ldl-cholesterol=""><0.05), by="" 4="" percent="" and="" 6="" percent,="" respectively.="" furthermore,="" in="" subjects="" with="" ldl-cholesterol="" in="" the="" top="" half="" of="" the="" study="" population,="" serum="" total="" and="" ldl-cholesterol="" were="" reduced="" by="" 9="" percent=""><0.03) and="" 12="" percent=""><0.03), respectively,="" by="" soy="" protein="" with="" the="" highest="" isoflavone="" content,="" and="" by="" 8="" percent=""><0.03) and="" 9="" percent=""><0.03), respectively,="" by="" soy="" protein="" with="" the="" second="" highest="" isoflavone="" content.="" although="" holmes="" et="" al.="" (ref.="" 40)="" did="" not="" find="" statistically="" significant="" changes="" in="" blood="" lipids="" with="" 27="" g="" of="" soy="" protein,="" using="" 28="" g="" of="" soy="" protein="" in="" a="" hypocaloric="" diet,="" bosello="" et="" al.="" (ref.="" 29)="" observed="" decreases="" of="" 16="" percent="" from="" baseline="" in="" both="" total="" and="" ldl-cholesterol=""><0.01). with="" 31="" g="" of="" soy="" protein,="" kurowska="" et="" al.="" (ref.="" 44)="" found="" an="" 11-percent="" reduction="" in="" ldl-cholesterol="" in="" subjects="" with="" the="" highest="" initial="" ldl-="" cholesterol="" levels="" and="" ldl/hdl-cholesterol="" ratios.="" as="" a="" substitution="" or="" as="" an="" addition,="" verillo="" et="" al.="" (ref.="" 60)="" found="" 31="" g="" of="" soy="" protein="" produced="" large="" (="">20 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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G. Avellone, L. Colombo, C. Fragiacomo, G. Noseda, and S. Lenzi,
``Cholesterol-lowering and HDL-raising Properties of Lecithinated Soy
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Metabolism, 29:348-357, 1985.
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
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59. Van Raaij, J. M. A., M. B. Katan, C. E. West, and J. G. A. J.
Hautvast, ``Influence of Diets Containing Casein, Soy Isolate, and Soy
Concentrate on Serum Cholesterol and Lipoproteins in Middle-aged
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60. Verrilo, A., A. de Teresa, P. C. Giarrusso, and S. La Rocca,
``Soybean Protein Diets in the Management of Type II
Hyperlipoproteinaemia,'' Atherosclerosis, 54:321-331, 1985.
61. Vessby, B., B. Karlstrom, H. Lithell, I. B. Gustafsson, and I.
Werner, ``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,
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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93-3046, Bethesda, MD, 1993.
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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]
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