[Federal Register Volume 64, Number 206 (Tuesday, October 26, 1999)]
[Rules and Regulations]
[Pages 57700-57733]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-27693]
[[Page 57699]]
_______________________________________________________________________
Part II
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 101
Food Labeling: Health Claims; Soy Protein and Coronary Heart Disease;
Final Rule
Federal Register / Vol. 64, No. 206 / Tuesday, October 26, 1999 /
Rules and Regulations
[[Page 57700]]
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: Final rule.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA) is authorizing 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). Based on its review of evidence submitted with comments
to the proposed rule, as well as evidence described in the proposed
rule, the agency has concluded that soy protein included in a diet low
in saturated fat and cholesterol may reduce the risk of CHD by lowering
blood cholesterol levels.
DATES: This regulation is effective October 26, 1999, except for
Sec. 101.82(c)(2)(ii)(B), which contains information collection
requirements that have not been approved by the Office of Management
and Budget (OMB). Upon approval, the FDA will publish a document in the
Federal Register announcing the effective date of those requirements.
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 Information
On November 8, 1990, the President signed into law the Nutrition
Labeling and Education Act of 1990 (the 1990 amendments) (Public Law
101-535). This new law amended the Federal Food, Drug, and Cosmetic Act
(the act) in a number of important ways. One notable aspect 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
rules for the authorization and use of health claims by regulation.
Additionally, Sec. 101.70 (21 CFR 101.70) establishes a process for
petitioning the agency to authorize by regulation the use of 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(f)).
In response to the 1990 amendments, FDA also conducted an extensive
review of the evidence on 10 substance-disease relationships. 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,
although 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)
(hereinafter referred to as the saturated fat/cholesterol proposed
rule), FDA set out 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
andagreement 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 tentatively
concluded that the publicly available data supported an association
between diets low in saturated fat and cholesterol and reduced risk of
CHD (56 FR 60727 at 60737), and it confirmed that conclusion in the
saturated fat/cholesterol final rule (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 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 3600, January 23, 1997, and amended at 62 FR 15344, March 31,
1997, and 62 FR 8119, February 18, 1998).
In the Federal Register of November 10, 1998 (63 FR 62977), and in
response to a petition from Protein Technologies International, Inc.
(Ref. 1 and Ref. 2), the agency proposed Sec. 101.82 to provide for
health claims on the relationship of soy protein and reduced risk of
CHD (hereinafter referred to as the soy protein proposed rule). In the
soy protein proposed rule, FDA considered the relevant scientific
studies and data presented in the petition as part of its review of the
scientific literature on soy protein and CHD. The agency summarized
this evidence in the soy protein proposed rule and presented the
rationale for a health claim on this food-disease relationship as
provided for under the significant scientific
[[Page 57701]]
agreement standard in section 403(r)(3)(B)(i) of the act and
Sec. 101.14(c) of FDA's regulations.
Proposed Sec. 101.82(c)(2)(ii)(A) identified the substance that is
the subject of the proposed claim as soy protein from the legume seed
Glycine max. The soy protein proposed rule included qualifying criteria
for the purpose of identifying soy protein-containing foods eligible to
bear the proposed health claim. The proposal also specified mandatory
content for health claim statements; identified additional, optional
information for such statements; and provided model health claims.
In its evaluation of the scientific evidence for a relationship
between consumption of soy protein and blood total and LDL-cholesterol
levels, the agency found the data suggestive but not sufficient to
establish a dose-response for this relationship. However, the agency
did find consistent, clinically significant reductions of total and
LDL-cholesterol levels in controlled trials that used at least 25 grams
(g) of soy protein per day. Thus, the agency proposed to base the
qualifying level of soy protein on a total daily intake of 25 g, as
suggested by the petitioner. Therefore, in Sec. 101.82(c)(2)(iii)(A),
FDA proposed the qualifying criterion for a food to bear the claim as
6.25 g of soy protein per reference amount customarily consumed (RACC)
(i.e., 25 g divided by 4 eating occasions per day).
In the soy protein proposed rule, FDA had tentatively indicated its
intention to use a specific analytical method to measure soy protein
for assessing compliance with the qualifying criterion. Comments
persuaded the agency that the method would be inadequate for many
products. Therefore, in the Federal Register of August 23, 1999 (64 FR
45932), FDA issued a proposed rule to provide for an alternative
procedure for assessing compliance (hereinafter referred to as the soy
protein reproposal). In the soy protein reproposal, in
Sec. 101.82(c)(2)(ii)(B) FDA proposed that it would rely on measurement
of total protein and require manufacturers, when soy is not the sole
source of protein in foods, to maintain records that document the
amount of soy protein in products and to make these records available
to appropriate regulatory officials for inspection and copying upon
request.
II. Summary of Comments and the Agency's Responses
In response to the soy protein proposed rule, the agency received
approximately 130 submissions, each containing one or more comments,
from consumers, consumer organizations, professional organizations,
government agencies, industry, trade associations, health care
professionals, and research scientists.
About half of these submissions supported the proposed rule without
providing grounds for this support other than those provided by FDA in
the preamble to the soy protein proposed rule. The majority of the
remaining comments were generally supportive, but requested
modification of one or more provisions of the proposed rule. Some
comments provided additional data on the relationship between soy
protein and CHD, including one submission, originally submitted as a
health claim petition and converted to a comment on the soy protein
proposed rule (Ref. 3), that included a comprehensive review of
available scientific evidence about the relationship. Some of the
comments that disagreed with the soy protein proposed rule provided
specific support for their positions. Some of the comments were
received after the date for submitting comments had passed. Although
the agency is not obligated to respond to late comments, in the
interest of assessing the totality of the available data, it has
considered each of these comments to the extent that it provided
complete information for review or references accessible to the agency
and addressed issues not raised in earlier comments. The agency has
summarized and addressed the relevant issues raised in the comments in
the sections of this document that follow.
In response to the soy protein reproposal, the Agency received
approximately 10 submissions, each containing one or more comments. The
agency has summarized and addressed these comments in section II.C.2 of
this document.
A. Eligibility of Soy Protein as the Subject of a Health Claim
In the soy protein proposed rule, the agency assessed whether soy
protein satisfied the preliminary requirement that a substance that is
the subject of a health claim is associated with a disease for which
the U.S. population is at risk (63 FR 62977 at 62978). Based on
analyses presented in earlier rulemakings and its review of data on the
mortality, morbidity, and costs of CHD and prevalence of ``high risk''
and ``borderline high'' total and LDL-cholesterol levels in the United
States (Refs. 4 through 8), the agency tentatively concluded that, as
required in Sec. 101.14(b)(1), CHD is a disease for which the U.S.
population is at risk. One comment reviewed additional sources of
information and reached the same conclusion.
In the soy protein proposed rule, FDA also tentatively concluded
that soy protein from Glycine max satisfied the preliminary requirement
of Sec. 101.14(b)(3)(i) that the substance be a food that contributes
taste, aroma, or nutritive value (63 FR 62977 at 62978). Sources of soy
protein identified in the soy protein proposed rule included foods
composed of or derived from whole soybeans and foods that contain
processed soy protein ingredients: Isolated soy protein (ISP), soy
protein concentrate (SPC), soy flour (SF), texturized soy protein, or
texturized vegetable protein (TVP). In addition to protein, these foods
and 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.
In assessing whether the petitioner had demonstrated that soy
protein is safe and lawful at the level necessary to justify the claim,
FDA noted that 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 (63 FR 62977
at 62978). Because the fractionation procedures used to convert
vegetable flours to vegetable protein isolates and concentrates were
commonplace prior to 1958, the petitioner also asserted that ISP and
SPC can be defined as soy flour ``subject only to conventional
processing as practiced prior to January 1, 1958.'' In addition, FDA
reviewed information submitted by the petitioner about potential risks
of consuming soy products: allergenicity (Refs. 9 and 10), exposure to
trypsin inhibitors (Refs. 11 through 16), reduced bioavailability of
minerals (Refs. 13, 17, 18, 19, and 20), and hormonal disturbances due
to soy isoflavones (Refs. 21 through 26). Based on the totality of the
evidence and, in particular, its common use in food, the agency did not
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 concluded that the petitioner provided evidence that
satisfied 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
under the applicable food safety provisions of the act (63 FR 62977 at
62979).
Several comments agreed with the agency's conclusion and some
provided the rationale for their support. A number of comments disputed
the
[[Page 57702]]
petitioner's assertion of GRAS status for soy protein and raised
questions about the safety of soy protein-containing foods. The
specific aspects of disagreement are summarized and discussed in the
following sections of this document.
1. Concerns About the Safety of Soy Protein-Based Infant Formulas
(Comment 1). Many of the comments that raised concerns about the
safety of consuming soy protein-containing foods addressed the safety
of soy protein-based infant formulas. The observed or hypothesized
detrimental effects of such formulas discussed in these comments
included: hormonal disturbances due to estrogenic effects of soy
isoflavones; thyroid abnormalities; altered mineral balance, especially
for zinc; and diabetogenic effects in infants.
FDA is aware of concerns raised about the safety of soy infant
formulas, but notes that these are speculative at this time, pending
the results of definitive research. FDA also notes that the American
Academy of Pediatrics (Ref. 73) and the New Zealand Ministry of Health
(Ref. 74) have recently issued guidelines for the safe and suitable use
of soy-based infant formulas. Some issues regarding effects of infant
formula are unique because infants may be entirely dependent on formula
as a sole source of nutrition and the relevance of such issues for soy
protein consumed as part of a mixed diet by the general U.S. population
is not clear.
In any case, concerns about effects of soy protein specific to
infant formulas are beyond the scope of the current rule, which
authorizes a health claim about the relationship of soy protein and CHD
for foods intended for use by the general population. Health claims are
not permitted on foods represented or purported for use by infants and
toddlers less than 2 years of age unless specifically provided for in
the authorizing regulation (21 CFR 101.14(e)(5)). Diets restricted in
fat, saturated fat, and cholesterol are not recommended for infants and
young children, and the current rule (Sec. 101.82) contains no
provisions for use of the health claim about the relationship between
soy protein and CHD on foods for infants and toddlers.
2. Comments on Petitioner's Self-Determination of GRAS Status for Soy
Protein
(Comment 2). One comment specifically agreed with the petitioner's
assertion that soy protein-containing food ingredients are generally
recognized as safe (GRAS) by self-determination and based on common use
in food before January 1, 1958, in conformance with Sec. 201(s) of the
act. The comment also noted that, although soy protein is not listed as
GRAS or prior sanctioned in Title 21 of the CFR, FDA has noted that
these lists ``do not include all substances generally recognized as
safe for their intended use'' and, as stated at 21 CFR 182.1, ``[i]t is
impracticable [for FDA] to list all substances that are GRAS for their
intended use.'' This comment also agreed with the petitioner's
conclusion that fractionation procedures used to convert vegetable
flours to vegetable protein concentrates and isolates were commonplace
in various sectors of the grain industry, such as corn processing, well
before 1958. Therefore, SPC and ISP can be defined as soy flour
``subject only to conventional processing as practiced prior to January
1, 1958.'' The comment concluded that SF (including steam-treated SF),
SPC, and ISP all fall within the category of ingredients that are GRAS
through experience based on their common use. Several comments objected
to the petitioner's self-determination of GRAS status, citing a variety
of reasons. As stated previously, FDA does not take issue with the
petitioner's self-determination of GRAS status, and the comments,
discussed below, have not convinced the agency to change that
conclusion.
(Comment 3). Some comments raised objections on the basis that FDA
has not approved the GRAS status of soy protein.
Although FDA has not ruled formally on the GRAS status of soy
protein ingredients, it has not challenged determinations that soy's
use as dietary protein is GRAS. Food ingredients whose use is generally
recognized as safe by qualified experts are not required by law to
receive FDA approval. Under the health claim petition process, FDA
evaluates whether the substance is ``safe and lawful'' under the
applicable food safety provisions of the act (Sec. 101.14(b)(3)(ii)).
As discussed in greater detail below, FDA did not receive sufficient
evidence from comments to challenge the petitioner's assertion that soy
protein ingredients are GRAS by self-determination. The petitioner met
the showing required by Sec. 101.14(b)(3)(ii) that the substance be
``safe and lawful.''
(Comment 4). One comment claimed that the Center for Food Safety
and Applied Nutrition recently returned a petition requesting GRAS
recognition for soy protein.
The document referred to by the comment was a notification by
Archer Daniels Midland Company (GRN 000001), rather than a petition for
FDA action, and the subject of the notification was soy isoflavone
extract, rather than soy protein. At the company's request, FDA ceased
evaluation of the GRAS Notification pending the company's updating of
the file (Ref. 75). Thus, this comment was incorrect.
(Comment 5). A comment asserted that petitioner's basis for GRAS
self-determination of the use of soy protein as a dietary protein
ingredient (i.e., common use in food before January 1, 1958) was
incorrect. Because the 1979 Select Committee on GRAS Substances (SCOGS)
report (Ref. 76) determined that, at the time of the report, likely
average dietary exposure to soy protein isolate was only about 150
milligrams (mg) from food items, the comment asserted that soy protein
isolates could not have been in common use before 1958.
FDA finds that this comment is groundless and inaccurately
characterizes the findings of the SCOGS. The 1979 SCOGS report includes
the background statement ``Edible soy protein isolates for food uses
appeared about 1957 as a major article of commerce.'' The 1979 SCOGS
Report also cited a 1972 National Research Council survey of GRAS
ingredients that listed 14 food categories in which soy protein
isolates were used and calculated an average daily intake of several
grams. Soy protein isolates represent only one of several possible
sources of soy protein in foods. In addition, for purposes of
determining if a substance is GRAS, common use is not restricted to
common use in the United States.
(Comment 6). A comment supporting the petitioner's self-
determination of GRAS status noted that use of soy as a food dates to
about the 11th century BC in the eastern half of north China. From
about the first century AD to the 15th-16th century, soybeans were
introduced in Korea, Japan, Indonesia, the Philippines, Vietnam,
Thailand, Malaysia, Burma, Nepal, and northern India. Soybeans first
grew in the United States in 1765 and were used then to manufacture soy
sauce and vermicelli (soybean paste) (Ref. 77). A comment that disputed
the petitioner's self-determination of GRAS status speculated that the
species of soybean grown early in its history in Asia may have differed
significantly in its content of nutrients and other active components
from the modern species that is cultivated in this country.
FDA does not find this comment compelling. Although the composition
of soybeans has likely changed over time, modern soybean species and
[[Page 57703]]
cultivars are, in any case, encompassed within the period of common use
of soy and soy protein in food.
(Comment 7). One comment questioned whether the Asian experience
could provide assurance that soy is safe. Drawing parallels with herbal
medicine in terms of attitudes, monitoring deficiencies, and the
general difficulty in detecting toxicities with long latency, this
comment concluded that the long history of apparent safe use of soy
products cannot assure they are without risk (Ref. 78).
The comment did not provide evidence to document that soy products,
consumed at levels necessary to justify the claim, are not generally
recognized as safe. Moreover, considerable research is underway at this
time because of the hypothesized benefits of the historical use of soy
products by certain population groups. FDA supports the ongoing
research to clarify the effects, both potentially beneficial and
potentially adverse, of soy and agrees that any effects due to changes
in the conditions of use should be monitored. However, the information
currently available does not lead FDA to object to the petitioner's
self-determination of GRAS status of soy protein.
(Comment 8). Several other comments asserted that the proposal did
not adequately establish the GRAS status of soy protein food
ingredients in that the proposal did not include a thorough evaluation
of the safety of potentially harmful components, e.g., lysinoalanine,
nitrites and nitrosamines, trypsin inhibitors, phytate, and
isoflavones.
FDA notes that the 1979 SCOGS report (Ref. 76) discussed several of
these components extensively and recommended that it would be prudent
to develop food grade specifications for soy protein isolates that
would set acceptable limits on the levels of lysinoalanine, nitrites,
and nitrosamines. But, the possible presence of these components in soy
protein isolates did not lead the SCOGS panel to recommend against GRAS
status of soy protein isolates.
As noted above, the agency finds the petitioner met the showing
required by Sec. 101.14(b)(3)(ii) that soy protein is ``safe and
lawful.'' The agency lacks documented evidence of adverse effects in
humans and has received no information about actual levels of
potentially harmful components or about threshold levels for adverse
effects in humans. Accordingly, the agency has no basis to conclude
that soy protein is not safe and lawful. The specific comments about
potentially harmful components of soy are discussed below.
3. Lysinoalanine: Potential Toxic Effects
(Comment 9). A few comments noted concerns about the presence of
lysinoalanine in soy protein isolates and cited the SCOGS report (Ref.
76), which indicated that lysinoalanine was implicated as a renal toxic
factor in rats.
FDA finds that the comments inaccurately reflected the findings of
the SCOGS report. The SCOGS report noted that the relatively severe
alkali treatment used to modify viscosity and adhesive properties of
soy protein isolates used as sizing and coating adhesives in the
production of paper and paperboard products can cause formation of
lysinoalanine. The report evaluated the risk of lysinoalanine exposure
from soy protein adhesives and binders used in paper and paperboard
food packaging. The 1979 SCOGS report noted that, ``For edible isolated
protein production, extraction is usually carried out at a pH below 9
to avoid hydrolytic or rheological changes'' and concluded that, while
relatively low levels of lysinoalanine had been reported in some
samples of food grade soy protein isolate, available information
indicated that the levels of lysinoalanine in food grade soy protein
isolates pose no hazard to the consumer (Ref. 76).
FDA notes that the comments that expressed concern about
lysinoalanine in soy protein ingredients did not provide any
information about lysinoalanine levels in food grade soy protein
ingredients nor about use of alkali-processed soy protein as a food
ingredient. FDA finds that the potential presence of lysinoalanine in
soy protein isolates used for sizing and coating adhesives in paper and
paperboard products is not relevant to the safe and lawful use of soy
protein in food. FDA also notes that the production of small amounts of
lysinoalanine during alkali processing has also been documented with
casein and lactalbumin, so it is not unique to soy. Good manufacturing
practices are and should be employed to minimize the production of
lysinoalanine because of its deleterious effects on protein quality.
4. Nitrites and Nitrosamines: Potential Carcinogenic Effects
(Comment 10). Some comments expressed concerns about the potential
presence of nitrites in soy protein and the potential their presence
poses for the in vivo formation of nitrosamines, which have been shown
to be carcinogenic in experimental animals.
FDA notes that many natural and processed foods contribute to the
total human intake of nitrite. In an appendix titled ``Health Aspects
of Nitrites in Soy Protein Isolates,'' the SCOGS report (Ref. 76)
presented an estimate of the consumer exposure to nitrite contributed
by soy protein in perspective to nitrite from other dietary sources and
that formed in the gastrointestinal tract by reduction of salivary and
dietary nitrate. The SCOGS report estimated the maximum daily nitrite
consumption for a vegetarian eating meat alternatives prepared from soy
protein to be 0.04 mg/kilogram (kg) body weight (or 2.8 mg for a 70-kg
person). The report estimated daily per capita intake of nitrite from
other foods of plant origin and cured meats to be about 2.4 mg and
daily exposure to nitrite from saliva to be 15 mg. The report estimated
that nitrite formed in the intestine from reduction of ammonia or
organic nitrogen compounds contributed about 90 mg/day. Given the
relatively minor potential contribution of soy protein to total nitrite
exposure, and the fact that no data were submitted to document the
current levels of nitrites or nitrosamines in soy protein isolates, FDA
is not persuaded of the necessity for establishing specifications for
acceptable levels of these compounds.
5. Trypsin Inhibitors: Potential Effects on Pancreatic Function
(Comment 11). A number of comments presented evidence that modern
heat treatment and other processing do not entirely eliminate the
activity of trypsin inhibitors in soy protein-containing products.
Additional references provided in comments (Refs. 79, 80, 81, and 82)
suggested that the mechanism of feedback regulation of pancreatic
enzyme secretion may be responsible for deleterious effects on the
pancreas--hyperplasia and formation of nodules--seen in animal studies.
Further, Leiner (Ref. 80) demonstrated that infusion of high levels of
isolated trypsin inhibitor in humans can evoke this mechanism but noted
that further research was needed to assess whether frequent exposures
to low levels of trypsin inhibitors consumed in the diet could have the
same effect. Other comments cited evidence for potential
anticarcinogenic effects of these and other protease inhibitors (Ref.
83). Leiner (Ref. 82) hypothesized that any anticarcinogenic effect of
protease inhibitors would likely be manifested at levels too low to
evoke their adverse effects on the pancreas.
FDA notes that the observed adverse effects have been limited to
animal
[[Page 57704]]
studies. To date, deleterious effects of consumption of low levels of
soybean trypsin inhibitors have not been documented in humans. For
example, Mills et al. (Ref. 84) conducted a prospective study of fatal
pancreas cancer among 34,000 California Seventh-day Adventists, a group
with high soy consumption. Compared to all U.S. whites, Adventists
experienced decreased risk from pancreas cancer death, which was not
statistically significant. Although there was a suggestive relationship
between increasing meat, egg, and coffee consumption and increased
pancreatic cancer risk, these variables were not significantly related
to risk after controlling for cigarette smoking. However, increasing
consumption of vegetarian protein products, beans, lentils, and peas as
well as dried fruit was associated with highly significant protective
relationships to pancreas cancer risk.
Therefore, FDA finds that the information presented in these
comments has not documented deleterious effects of dietary intake of
trypsin inhibitors from soy in humans and, thus, does not lead the
agency to take issue with the petitioner's conclusion that the use of
soy protein is safe and lawful as required by Sec. 101.14(b)(3)(iii).
6. Phytate: Effects on Mineral Balance
Comments raised concerns about the potential deleterious effect of
soy protein and its phytate content on mineral status. Phytate, the
salt of phytic acid or inositol hexaphosphate, is a natural plant
constituent containing six negatively charged phosphate groups that can
form strong complexes with divalent cations such as calcium, magnesium,
iron, zinc, and copper. Concerns relative to soy have concentrated
mainly on iron and zinc, based primarily on studies of the absorption
and bioavailability of these minerals.
(Comment 12). One comment cited a study in which a soy protein-
based purified diet induced iron deficiency in monkeys (Ref. 85). The
same comment also noted two studies in humans--one that found
inhibition of the absorption of nonheme iron from both semisynthetic
meals and meals comprising conventional foods by various soy protein-
containing ingredients (Ref. 86), and one that found increasing
inhibition of nonheme iron absorption with increasing amounts of
phytate in liquid formula meals that contained soy protein isolates
(Ref. 87). In a study cited in another comment, the substitution of
some meat in a mixed meal by soy protein caused a decrease in the
absorption of nonheme iron and an increase in the absorption of heme
iron (Ref. 88), so that overall iron absorption was not compromised.
Another comment reported that human feeding studies with soy protein
that have examined measures of iron status have not shown detrimental
effects (Ref. 89).
A comment raised concerns about the effect of soy protein on zinc
status based on studies of absorption of zinc from soy infant formula
(Ref. 90) and a study that showed decreased serum thymulin in subjects
fed a low-zinc, soy protein-based experimental diet designed to produce
mild zinc deficiency (Ref. 91). As noted earlier, issues specific to
infant formula are outside the scope of this rulemaking and the
experimental diet in the latter study (Ref. 91) is of limited relevance
to the likely conditions of consumption of soy protein in the
population that is the target of the health claim. Another comment
cited two studies (Refs. 92 and 93) showing no adverse effects of soy
protein on absorption of zinc from meals in subjects with adequate zinc
status.
One comment provided additional information on the mechanism of
phytate interference with zinc homeostasis (Ref. 94) and characterized
the problem as more than a matter of decreased bioavailability of the
zinc consumed in a meal. The comment noted that phytate can remove from
the duodenum zinc that is mainly derived from pancreatic secretions,
that is, zinc that may have been consumed 1-2 weeks earlier. Although
these data are derived from animal studies, the comment indicated that
the physiology of zinc homeostasis is not qualitatively different
across species.
This comment expressed concern that high consumption of soy protein
might exacerbate marginal zinc deficiency, which is difficult to
diagnose, and suggested that labeling should include the content of
both zinc and phytate so consumers can be educated that a molar ratio
of phytate:zinc of less than 10 is needed to avoid detrimental effects
on zinc status, as suggested by research in animals (including Ref.
95). The comment acknowledged that education would be needed for the
public to utilize such labeling. The agency recognizes that adequacy of
iron and zinc status in largely plant-based diets is a legitimate
concern.
FDA finds that the evidence of potential adverse effects of soy
protein on iron and zinc status is equivocal. Interpretation of the
evidence is difficult because findings in human studies are often
inconsistent with results of animal studies. Moreover, many factors
affect the absorption of these minerals, including the amount consumed
in a meal, the enhancing and inhibiting effects of other components of
the meal, and the nutritional status of the subject. Animal studies
suggest that zinc status is a strong determinant of effects of phytate/
soy on zinc absorption: zinc absorption is more impaired with zinc
deficiency, in contrast to the effect of low iron status, which
enhances iron absorption. However, given the lack of documented
evidence for impaired iron and zinc status in humans consuming soy
protein as part of a mixed diet, FDA is not persuaded of the necessity
for the suggested labeling with respect to the phytate: zinc molar
ratio. Nor is it persuaded that many consumers would find the suggested
information, which is highly technical, useful at this time.
7. Soy Isoflavones: Estrogenic Effects
Many comments addressed concerns about the possible deleterious
consequences of phytoestrogen effects of the soy isoflavones, genistein
and daidzein. Most of these addressed proliferative (and potentially
carcinogenic) effects on estrogen-sensitive tissues, effects on
circulating hormone levels and potential deleterious effects on
fertility, and potentially adverse effects on sexual development.
a. Proliferative effects. (Comment 13). Several comments cited a
number of studies of in vitro effects of individual isoflavones on
proliferation of estrogen-sensitive cells. For example, Dees et al.
(Ref. 96) found that genistein increased a number of indices for
proliferative activity in MCF-7 human breast cancer cells. As the
authors noted, these findings are consistent with the conclusion that
dietary estrogens at low concentrations do not act as antiestrogens,
but act like estradiol to stimulate human breast cancer cells to enter
the cell cycle. However, many other studies (reviewed in Refs. 97 and
98) have found that the phytoestrogens present in soybeans inhibit
breast cancer cell proliferation in vitro (at lower concentrations,
closer to physiological levels) and inhibit mammary cancer development
in various animal models. FDA concludes that studies in transformed
cells cannot predict with certainty whether effects will be beneficial
or detrimental in humans consuming soy protein.
(Comment 14). Comments argued that two reports showed effects of
dietary intake of soy isoflavones on breast tissue in women. Petrakis
et al. (Ref. 99) studied 24 normal pre- and postmenopausal white women,
ages 30
[[Page 57705]]
to 58 years, who underwent monthly nipple aspiration of breast fluid
and gave blood and 24-hour urine samples for biochemical studies. The
women consumed no soy in months 1-3 and 10-12. During months 4-9 the
women ingested daily 38 grams (g) of soy protein isolate containing 38
mg of genistein (daidzein content was not reported). This study's
findings indicated that prolonged consumption of soy protein isolate
had a stimulatory effect on the breast of premenopausal women,
characterized by increased secretion of breast fluid and elevated
levels of plasma estradiol. The study also detected evidence of
epithelial proliferation (hyperplasia) in 7 of the 24 subjects during
consumption of soy. McMichael-Phillips et al. (Ref. 100) examined the
effects of dietary soy supplementation on the proliferation rate of
premenopausal, histologically normal breast epithelium and the
expression of progesterone receptor. Women (n = 48) with benign or
malignant breast disease were randomly assigned to receive their normal
diet either alone or with a 60-g soy supplement (containing 45 mg
isoflavones) taken daily for 14 days. Serum concentrations of the
isoflavones genistein and daidzein increased in the soy group at 14
days. The proliferation rate of breast lobular epithelium significantly
increased after soy supplementation when both the day of menstrual
cycle and the age of patient were accounted for. Progesterone receptor
expression increased significantly in the soy group. The authors
concluded that further studies are required to determine whether the
short-term stimulation of breast proliferation is due to estrogen
agonist activity and to examine the long-term effects of soy on both
the pituitary gland and breast.
FDA finds that the detection of proliferative effects in these two
studies suggests the need for additional research. The findings do not,
however, establish that the observed effects are detrimental and are
not supported by the findings of epidemiologic studies of soy intake
and risk of premenopausal breast cancer (Ref. 101).
b. Fertility and Hormone Levels. (Comment 15). Some comments
referenced a number of studies that reported reduced fertility in
animals exposed to phytoestrogens (including Refs. 102, 103, and 104).
Some of these studies involved phytoestrogens other than those found in
soy or consumption of soy under extreme or unusual conditions. FDA is
not convinced of the relevance of these studies to human consumption of
soy protein.
(Comment 16). Comments cited the study of Cassidy et al. 1994 (Ref.
105) as suggesting the potential for deleterious effects on human
fertility. These investigators examined the influence of a diet
containing soy protein on the hormonal status and regulation of the
menstrual cycle in six premenopausal women. Soy protein (60 g
containing 45 mg isoflavones) given daily for 1 month significantly
(p<0.01) increased="" follicular="" phase="" length="" and/or="" delayed="" menstruation.="" midcycle="" surges="" of="" luteinizing="" hormone="" (lh)="" and="" follicle-stimulating="" hormone="" (fsh)="" were="" significantly="" suppressed="" during="" dietary="" intervention="" with="" soy="" protein.="" plasma="" estradiol="" concentrations="" increased="" in="" the="" follicular="" phase="" and="" cholesterol="" concentrations="" decreased="" 9.6="" percent.="" the="" authors="" concluded="" that="" responses="" to="" soy="" protein="" are="" potentially="" beneficial="" with="" respect="" to="" risk="" factors="" for="" breast="" cancer="" and="" may="" in="" part="" explain="" the="" low="" incidence="" of="" breast="" cancer="" and="" its="" correlation="" with="" a="" high="" soy="" intake="" in="" japanese="" and="" chinese="" women.="" one="" of="" the="" comments="" that="" cited="" this="" study="" acknowledged="" that="" it="" is="" unclear="" whether="" these="" soy="" effects="" are="" beneficial="" or="" adverse.="" fda="" notes="" that="" the="" study="" found="" that="" soy="" did="" not="" interfere="" with="" ovulation="" and="" the="" study="" did="" not="" assess="" effects="" on="" fertility.="" in="" a="" similar="" study="" with="" a="" longer="" duration,="" duncan="" et="" al.="" (ref.="" 106)="" studied="" effects="" of="" isoflavone="" consumption="" in="" 14="" premenopausal="" women.="" the="" women="" consumed="" isoflavones="" in="" soy="" protein="" powders="" (control="" diet,="" 10;="" low="" isoflavone="" diet,="" 64;="" high="" isoflavone="" diet,="" 128="" mg/day)="" for="" three="" menstrual="" cycles="" plus="" 9="" days="" in="" a="" randomized="" cross-over="" design.="" the="" low="" isoflavone="" diet="" decreased="" lh="" and="" fsh="" levels="" during="" the="" periovulatory="" phase.="" the="" high="" isoflavone="" diet="" decreased="" free="" t3="" and="" dehydroepiandrosterone="" sulfate="" levels="" during="" the="" early="" follicular="" phase="" and="" estrone="" levels="" during="" the="" midfollicular="" phase.="" no="" other="" significant="" changes="" were="" observed="" in="" hormone="" concentrations="" or="" in="" the="" length="" of="" the="" menstrual="" cycle,="" follicular="" phase,="" or="" luteal="" phase.="" endometrial="" biopsies="" performed="" in="" the="" luteal="" phase="" of="" cycle="" 3="" of="" each="" diet="" period="" revealed="" no="" effect="" of="" isoflavone="" consumption="" on="" histological="" dating.="" fda="" notes="" that="" although="" this="" study's="" findings="" varied="" somewhat="" from="" those="" of="" cassidy="" et="" al.="" (ref.="" 105),="" it="" also="" did="" not="" directly="" address="" the="" effect="" of="" soy="" on="" human="" fertility.="" fda="" finds="" that="" these="" two="" studies="" do="" not="" provide="" sufficient="" evidence="" to="" address="" the="" effect="" of="" soy="" protein="" on="" human="" fertility.="" c.="" developmental="" effects.="" (comment="" 17).="" one="" comment="" cited="" the="" study="" of="" faber="" and="" hughes,="" 1993="" (ref.="" 107)="" as="" showing="" alterations="" in="" lh="" regulation="" following="" developmental="" treatment="" with="" genistein,="" suggesting="" that="" during="" pregnancy="" in="" humans,="" isoflavones="" could="" be="" a="" risk="" factor="" for="" abnormal="" brain="" and="" reproductive="" tract="" development.="" this="" study="" involved="" injection="" of="" 0,="" 1,="" 10,="" 100,="" 200,="" 400,="" 500,="" or="" 1,000="" micrograms="" of="" genistein="" into="" neonatal="" rats="" on="" days="" 1-10.="" because="" of="" the="" differences="" in="" developmental="" stages="" between="" rodents="" and="" humans,="" this="" type="" of="" experiment="" is="" used="" as="" a="" model="" for="" prenatal="" (third="" trimester)="" effects="" of="" diethylstilbestrol="" (des).="" increased="" exposure="" to="" genistein="" led="" to="" decreased="" lh="" secretion;="" the="" volume="" of="" the="" sexually="" dimorphic="" nucleus="" of="" the="" preoptic="" area="" increased="" compared="" to="" controls="" only="" in="" animals="" that="" received="" the="" two="" highest="" doses="" of="" genistein.="" an="" earlier="" paper="" by="" faber="" and="" hughes="" 1991="" (ref.="" 108)="" showed="" that="" effects="" elicited="" by="" neonatal="" injections="" of="" 1000="" micrograms="" of="" genistein="" were="" similar="" to="" those="" of="" 0.1="" micrograms="" of="" des.="" the="" comment="" also="" cited="" studies="" using="" a="" similar="" experimental="" model="" by="" medlock="" et="" al.="" (refs.="" 109="" and="" 110)="" as="" demonstrating="" that="" equol="" (a="" metabolite="" of="" daidzein="" in="" some="" individuals)="" acts="" as="" an="" endocrine="" disruptor="" during="" development.="" fda="" finds="" that="" the="" relevance="" of="" these="" studies="" to="" an="" assessment="" of="" potential="" prenatal="" effects="" of="" dietary="" soy="" protein="" during="" pregnancy="" is="" uncertain.="" (comment="" 18).="" one="" comment="" cited="" the="" study="" of="" harrison="" et="" al.="" (ref.="" 111)="" that="" showed="" pregnant="" rhesus="" monkeys="" fed="" genistein="" had="" serum="" estradiol="" levels="" 50="" to="" 100="" percent="" higher="" than="" the="" controls="" in="" three="" different="" areas="" of="" the="" maternal="" circulation.="" the="" comment="" also="" noted="" the="" finding="" that="" the="" fetuses="" of="" genistein="" fed="" monkeys="" had="" a="" 70="" percent="" higher="" serum="" estradiol="" level="" than="" did="" the="" controls.="" in="" this="" study,="" five="" monkeys="" were="" fed="" genistein="" (amount="" not="" specified)="" during="" pregnancy="" and="" compared="" to="" five="" controls.="" no="" differences="" were="" reported="" in="" maternal="" weight="" gain,="" fetal="" weights="" at="" delivery,="" or="" placental="" weights.="" significant="" differences="" in="" estradiol="" levels="" (but="" not="" progesterone)="" were="" noted="" at="" delivery="" in="" maternal="" peripheral="" blood,="" uterine="" veins,="" ovarian="" veins,="" and="" the="" fetus,="" and="" in="" maternal="" blood="" during="" pregnancy,="" but="" values="" were="" not="" reported.="" fda="" received="" only="" an="" abstract="" describing="" this="" study.="" without="" more="" complete="" documentation,="" the="" merits="" or="" weaknesses="" of="" this="" study="" cannot="" be="" evaluated.="" therefore,="" fda="" has="" not="" used="" this="" study="" to="" evaluate="" the="" concerns="" raised="" in="" this="" comment.="" fda="" notes="" that,="" in="" another="" study="" that="" examined="" dietary="" effects,="" fritz="" et="" al.="" (ref.="" 112)="" fed="" female="" rats="" genistein="" from="" [[page="" 57706]]="" conception="" to="" day="" 21="" postpartum="" in="" the="" diet="" at="" concentrations="" of="" 0,="" 25="" and="" 250="" mg="" genistein/kg="" diet.="" they="" found="" that="" genistein="" in="" the="" diet="" at="" ``physiological="" levels''="" (equivalent="" to="" those="" in="" asians="" consuming="" a="" traditional="" high="" soy="" diet)="" enhances="" cell="" differentiation,="" resulting="" in="" programming="" of="" mammary="" gland="" cells="" for="" reduced="" susceptibility="" to="" chemically="" induced="" mammary="" cancer,="" with="" no="" observed="" toxicity="" to="" the="" fertility="" of="" dams="" or="" the="" reproductive="" tract="" of="" female="" offspring.="" fda="" finds="" that="" these="" dietary="" studies="" in="" animals="" do="" not="" provide="" evidence="" for="" detrimental="" developmental="" effects="" in="" humans.="" (comment="" 19).="" another="" comment="" raised="" the="" possibility="" that="" soy="" phytoestrogens="" could="" be="" responsible="" for="" inducing="" premature="" puberty="" and="" cited="" the="" case-control="" study="" of="" estrogenic="" exposures="" by="" freni-titulaer="" et="" al.="" (ref.="" 113)="" of="" patients="" with="" premature="" thelarche="" seen="" in="" puerto="" rico="" between="" 1978="" and="" 1981.="" in="" subjects="" 2="" years="" of="" age="" or="" older="" at="" the="" onset="" of="" thelarche,="" the="" study="" found="" no="" statistically="" significant="" associations.="" in="" subjects="" with="" onset="" before="" 2="" years="" of="" age,="" statistically="" significant="" positive="" associations="" were="" found="" with="" a="" maternal="" history="" of="" ovarian="" cysts,="" consumption="" of="" soy-based="" formula,="" and="" consumption="" of="" various="" meat="" products.="" a="" statistically="" significant="" negative="" association="" was="" found="" with="" consumption="" of="" corn="" products.="" the="" authors="" concluded="" that="" these="" statistical="" associations="" were="" not="" sufficient="" to="" explain="" the="" reported="" increase="" in="" premature="" thelarche="" because="" in="" over="" 50="" percent="" of="" the="" case="" subjects="" there="" was="" no="" exposure="" to="" any="" of="" the="" risk="" factors="" for="" which="" statistical="" associations="" were="" found.="" thus,="" fda="" concludes="" that="" this="" study="" provides="" no="" convincing="" evidence="" that="" soy="" was="" responsible="" for="" premature="" thelarche.="" moreover,="" fda="" notes="" that="" the="" study="" documents="" no="" deleterious="" effects="" of="" consuming="" soy="" protein="" at="" the="" levels="" necessary="" to="" justify="" the="" health="" claim="" in="" population="" groups="" that="" are="" the="" target="" of="" the="" claim.="" d.="" other.="" (comment="" 20).="" one="" comment="" cited="" a="" study="" associating="" intake="" of="" tofu="" in="" mid-life="" by="" japanese-american="" men="" in="" hawaii="" with="" vascular="" dementia="" and="" brain="" atrophy="" in="" old="" age="" (ref.="" 114).="" this="" comment="" hypothesized="" that="" isoflavone="" inhibition="" of="" aromatase,="" which="" catalyzes="" the="" conversion="" of="" testosterone="" to="" estradiol,="" may="" provide="" a="" mechanistic="" explanation="" for="" this="" finding.="" the="" report="" cited="" (ref.="" 116)="" is="" an="" abstract="" that="" indicates="" the="" researchers="" found="" an="" association="" of="" high="" tofu="" intake="" with="" low="" cognitive="" test="" scores="" and="" with="" alzheimer's="" disease,="" rather="" than="" vascular="" dementia.="" fda="" finds="" that="" this="" abstract="" does="" not="" provide="" a="" sufficient="" basis="" to="" evaluate="" the="" merits="" and="" weaknesses="" of="" this="" study.="" as="" such,="" it="" is="" not="" useful="" in="" evaluating="" the="" safety="" concerns="" at="" issue.="" moreover,="" the="" report="" does="" not="" provide="" information="" on="" total="" soy="" intake="" or="" what="" variables="" were="" controlled="" in="" the="" analysis.="" if="" tofu="" or="" soy="" were="" implicated="" in="" alzheimer's="" disease,="" its="" prevalence="" would="" be="" expected="" to="" be="" higher="" in="" japan="" than="" in="" hawaii,="" but="" white="" et="" al.="" (ref.="" 115)="" found="" the="" prevalence="" of="" alzheimer's="" disease="" was="" higher="" in="" hawaii="" than="" in="" japan.="" therefore,="" fda="" is="" not="" persuaded="" by="" the="" comment="" raising="" concerns="" about="" potential="" adverse="" effects="" of="" soy="" protein="" in="" dementia="" and="" brain="" atrophy="" in="" older="" persons.="" (comment="" 21).="" one="" comment="" addressed="" the="" general="" issue="" of="" threshold="" effects="" for="" estrogenic="" compounds,="" citing="" a="" study="" (ref.="" 116)="" that="" showed="" no="" threshold="" dose="" for="" estradiol-induced="" sex="" reversal="" of="" turtle="" embryos.="" it="" also="" cited="" a="" study="" (ref.="" 117),="" available="" in="" abstract="" form,="" that="" reviewed="" 31="" dose-response="" curves="" for="" hormone-mimicking="" chemicals="" that="" also="" failed="" to="" show="" a="" threshold.="" the="" report="" of="" this="" study="" did="" not="" include="" mention="" of="" soy="" isoflavones="" and="" did="" not="" specify="" the="" estrogenic="" effects="" examined.="" fda="" does="" not="" find="" this="" evidence="" particularly="" useful.="" the="" relevance="" of="" the="" turtle="" model="" to="" humans="" is="" uncertain="" and="" the="" other="" cited="" evidence="" was="" available="" only="" in="" abstract="" form.="" e.="" conclusion.="" soy="" isoflavones="" and="" other="" dietary="" phytoestrogens="" are="" known="" to="" exert="" hormonal="" effects--both="" estrogenic="" and="" antiestrogenic--="" depending="" on="" the="" amount="" and="" type="" consumed="" and="" endogenous="" hormonal="" status="" of="" the="" organism="" studied;="" they="" are="" much="" less="" potent="" than="" endogenous="" estrogen="" or="" synthetic="" estrogens="" such="" as="" des.="" there="" is="" considerable="" variability="" from="" person="" to="" person="" in="" the="" absorption,="" metabolism,="" and="" disposition="" of="" the="" soy="" isoflavones,="" genistein="" and="" daidzein="" (ref.="" 118),="" and="" researchers="" have="" found="" that="" their="" metabolism="" and="" excretion="" depend="" on="" the="" duration="" of="" ingestion="" and="" the="" subject's="" sex="" (ref.="" 119).="" overall,="" the="" evidence="" for="" proliferative="" effects,="" effects="" on="" fertility="" and="" hormone="" levels,="" and="" developmental="" and="" other="" effects="" in="" humans="" due="" to="" the="" estrogenic="" effects="" of="" soy="" isoflavones="" is="" very="" limited.="" both="" possible="" beneficial="" effects="" and="" possible="" detrimental="" effects="" are="" still="" hypothetical.="" fda="" finds="" that="" the="" information="" presented="" in="" the="" comments="" has="" not="" adequately="" documented="" deleterious="" effects="" of="" dietary="" intake="" of="" soy="" isoflavones="" in="" humans.="" 8.="" soy="" isoflavones:="" goitrogenic="" effects="" (comment="" 22).="" comments="" noted="" that="" isoflavones="" are="" inhibitors="" of="" the="" enzyme="" thyroid="" peroxidase="" (tpo),="" which="" produces="" the="" thyroid="" hormones="" t3="" and="" t4,="" and="" indicated="" that="" its="" inhibition="" can="" be="" expected="" to="" generate="" thyroid="" abnormalities.="" other="" comments,="" however,="" noted="" the="" lack="" of="" evidence="" for="" consequential="" effects="" of="" tpo="" inhibition="" (i.e.,="" high="" prevalence="" of="" goiter)="" in="" populations="" with="" high="" soy="" consumption.="" one="" comment="" noted="" that="" there="" exists="" a="" body="" of="" animal="" data="" that="" demonstrates="" goitrogenic="" and="" even="" carcinogenic="" effects="" of="" soy="" products="" and="" cited="" the="" study="" by="" kimura="" et="" al.="" (ref.="" 120).="" these="" researchers="" developed="" malignant="" goiter="" in="" rats="" by="" feeding="" diets="" containing="" 40="" percent="" defatted="" soybean="" and="" no="" iodine.="" no="" deleterious="" effects="" were="" seen="" in="" controls="" fed="" the="" same="" diet="" with="" iodine="" added.="" comments="" noted="" the="" existence="" of="" a="" number="" of="" case="" reports="" in="" the="" older="" literature="" of="" soy="" inducing="" goiter="" in="" infants="" (refs.="" 121="" through="" 125).="" van="" wyk="" et="" al.="" (ref.="" 121)="" studied="" one="" infant="" who="" developed="" goiter="" on="" a="" soybean="" formula="" and="" tested="" the="" same="" product="" in="" 12="" adults.="" in="" adults,="" the="" product="" did="" not="" interfere="" with="" iodine="" absorption,="" impair="" iodine="" uptake,="" interfere="" with="" oxidation="" of="" iodine="" in="" the="" thyroid,="" or="" (in="" most="" subjects)="" interfere="" with="" the="" release="" of="" protein-bound="" iodine="" into="" the="" blood.="" hydovitz="" (ref.="" 12)="" provided="" a="" single="" case="" report;="" shepard="" et="" al.="" (ref.="" 123)="" described="" three="" cases="" and="" presented="" evidence="" that="" soybean="" goiter="" was="" caused="" by="" iodine="" deficiency.="" pinchera="" et="" al.="" (ref.="" 124)="" reported="" on="" a="" case="" of="" a="" congenitally="" hypothyroid="" infant="" and="" found="" high="" fecal="" losses="" of="" thyroxine.="" addition="" of="" adequate="" iodine="" to="" soy-based="" infant="" formulas="" in="" the="" 1960's="" generally="" resolved="" or="" prevented="" goiter.="" however,="" chorazy="" et="" al.="" (ref.="" 125)="" more="" recently="" reported="" on="" a="" hypothyroid="" infant="" who="" was="" semi-refractory="" to="" thyroid="" hormone="" therapy="" while="" consuming="" soy="" formula.="" several="" comments="" cited="" the="" study="" of="" ishizuki="" et="" al.="" (ref.="" 126)="" as="" evidence="" for="" goitrogenic="" effects="" of="" soy="" in="" adults.="" this="" study="" is="" published="" in="" japanese="" and="" the="" available="" english="" abstract="" is="" poorly="" translated.="" as="" described="" in="" that="" abstract,="" the="" design="" and="" findings="" are="" unclear:="" goiters="" were="" said="" to="" occur="" in="" half="" the="" subjects="" eating="" 30="" g="" soybeans="" daily="" for="" 3="" months,="" though="" ``various="" parameters="" of="" serum="" thyroid="" hormones="" remained="" unchanged="" by="" taking="" soybeans.''="" the="" soybean="" preparation="" used="" (reported="" in="" some="" comments="" to="" be="" roasted,="" pickled="" soybeans),="" iodine="" intake,="" and="" other="" dietary="" changes="" were="" not="" reported.="" [[page="" 57707]]="" in="" one="" comment,="" researchers="" indicated="" that="" they="" had="" identified="" genistein="" and="" daidzein="" as="" the="" goitrogenic="" isoflavonoid="" components="" of="" soy="" and="" defined="" the="" mechanisms="" for="" inhibition="" of="" tpo-catalyzed="" thyroid="" hormone="" synthesis="" using="" in="" vitro="" studies="" of="" the="" pure="" isoflavones="" (refs.="" 127="" and="" 128).="" the="" comment="" noted="" that="" the="" observed="" irreversible="" inactivation="" of="" tpo="" by="" isoflavones,="" through="" covalent="" binding="" to="" tpo,="" raises="" the="" possibility="" of="" neoantigen="" formation.="" the="" comment="" also="" noted="" that="" anti-tpo="" is="" the="" principal="" autoantibody="" present="" in="" autoimmune="" thyroid="" disease="" and="" proposed="" that="" this="" hypothetical="" mechanism="" is="" consistent="" with="" the="" reports="" of="" fort="" et="" al.="" (refs.="" 129="" and="" 130)="" of="" a="" doubling="" of="" risk="" for="" autoimmune="" thyroiditis="" in="" children="" who="" had="" received="" soy="" formulas="" as="" infants="" compared="" to="" infants="" receiving="" other="" forms="" of="" milk.="" however,="" the="" studies="" of="" fort="" et="" al.="" were="" retrospective="" case-control="" analyses="" of="" early="" feeding="" practices="" in="" children="" with="" diabetes="" (ref.="" 129)="" or="" autoimmune="" thyroid="" disease="" (ref.="" 130).="" the="" studies="" did="" not="" establish="" a="" cause-and-effect="" relationship="" or="" assess="" medical="" indications="" for="" use="" of="" soy="" formula="" in="" these="" children.="" fda="" notes="" that="" no="" data="" or="" other="" information="" presented="" in="" the="" comments="" documents="" deleterious="" effects="" on="" thyroid="" function="" of="" consuming="" soy="" protein="" at="" the="" levels="" necessary="" to="" justify="" the="" health="" claim="" in="" population="" groups="" that="" are="" the="" target="" of="" the="" claim.="" 9.="" allergenicity="" of="" soy="" protein="" (comment="" 23).="" one="" comment="" disputed="" the="" statement="" in="" the="" soy="" protein="" proposed="" rule="" that="" soy="" allergies="" are="" often="" outgrown.="" fda="" finds="" that="" the="" comment="" cited="" data="" that="" did="" not="" directly="" address="" this="" issue="" but="" documented="" the="" following="" with="" respect="" to="" soy:="" a="" case="" report="" of="" an="" anaphylactic="" reaction="" to="" soy="" in="" an="" adult="" (131);="" severe="" reactions="" to="" soy="" in="" several="" swedish="" children="" and="" adolescents,="" who="" had="" known="" severe="" reactions="" to="" peanuts="" and="" asthma="" but="" had="" not="" reacted="" previously="" to="" soy="" (refs.="" 132="" and="" 133);="" cross="" reactivity="" of="" some="" soy="" and="" peanut="" allergens="" (ref.="" 134);="" and="" an="" outbreak="" of="" gastrointestinal="" illness="" associated="" with="" consumption="" of="" an="" improperly="" processed="" soy="" protein="" tuna="" salad="" extender="" in="" which="" only="" a="" few="" individuals="" exhibited="" signs="" of="" true="" hypersensitivity="" reactions="" (ref.="" 135).="" (comment="" 24).="" one="" comment="" noted="" that="" use="" of="" soy="" protein="" health="" claims="" will="" highlight="" the="" presence="" of="" soy="" protein="" in="" foods.="" another="" comment="" noted="" that="" any="" food="" protein="" can="" stimulate="" a="" food="" allergy="" and="" that="" such="" allergies="" are="" commonly="" due="" to="" milk,="" egg,="" and="" nut="" proteins.="" this="" comment="" noted="" that="" infants="" who="" develop="" cow's="" milk="" allergies="" or="" intolerance="" are="" frequently="" prescribed="" soy="" substitutes="" and="" a="" small="" subset="" of="" these="" high-risk="" children="" also="" develop="" soy="" protein="" allergy.="" fda="" finds="" that="" the="" comments="" that="" noted="" concerns="" about="" the="" allergenicity="" of="" soy="" protein="" cited="" these="" concerns="" as="" evidence="" that="" consumption="" of="" soy="" is="" unsafe,="" but="" did="" not="" propose="" that="" any="" particular="" action="" be="" taken="" by="" the="" agency="" as="" a="" consequence="" to="" protect="" consumers="" with="" soy="" allergies.="" fda="" does="" not="" believe="" that,="" because="" some="" persons="" may="" have="" allergic="" reactions="" to="" a="" food,="" it="" is="" unsafe.="" fda="" has="" previously="" stated="" that="" the="" declaration="" of="" an="" allergenic="" substance="" in="" the="" ingredient="" statement="" on="" the="" food="" label="" provides="" adequate="" information="" for="" consumers="" regarding="" the="" presence="" of="" the="" allergenic="" ingredient="" in="" the="" product="" (63="" fr="" 8103="" at="" 8113),="" and="" sees="" no="" reason="" to="" change="" this="" view="" with="" respect="" to="" soy.="" fda="" notes,="" in="" agreement="" with="" one="" of="" the="" comments="" received,="" that="" authorization="" of="" a="" health="" claim="" for="" soy="" protein="" and="" chd="" will="" highlight="" the="" presence="" of="" soy="" protein="" in="" those="" food="" products="" that="" bear="" the="" claim.="" the="" agency,="" therefore,="" anticipates="" that="" persons="" with="" known="" soy="" allergies="" will="" be="" able="" more="" easily="" to="" avoid="" soy="" protein="" based="" products.="" b.="" updated="" review="" of="" scientific="" evidence="" and="" issues="" related="" to="" the="" evidence="" in="" the="" soy="" protein="" proposed="" rule,="" fda="" conducted="" a="" comprehensive="" review="" of="" the="" human="" studies="" submitted="" in="" the="" petition="" (refs.="" 27="" through="" 66)="" (63="" fr="" 62977="" at="" 62980).="" of="" these,="" the="" agency="" gave="" particular="" weight="" to="" 14="" clinical="" trials="" (refs.="" 27,="" 28,="" 30="" (1="" trial),="" 31,="" 36,="" 37="" (1="" trial),="" 40="" (2="" trials),="" 44,="" 49,="" 51,="" 54,="" 58,="" and="" 59).="" these="" 14="" trials="" met="" the="" criteria="" for="" selection="" set="" out="" by="" the="" agency="" (63="" fr="" 62977="" at="" 62980):="" they="" included="" subjects="" representative="" of="" the="" general="" u.s.="" population;="" were="" well="" controlled;="" reported="" information="" on="" intakes="" of="" saturated="" fat="" and="" cholesterol;="" and="" avoided="" problems="" associated="" with="" small="" sample="" size,="" lack="" of="" a="" placebo,="" and="" other="" design="" problems.="" the="" agency="" summarized="" these="" studies="" in="" table="" 1="" of="" the="" soy="" protein="" proposed="" rule="" (63="" fr="" 62977="" at="" 62998).="" the="" agency="" also="" summarized="" seven="" clinical="" trials="" in="" adults="" (refs.="" 33,="" 35,="" 46,="" 55,="" 56,="" 60,="" and="" 64)="" and="" three="" trials="" in="" children="" (refs.="" 34,="" 42/45,="" and="" 63)="" with="" type="" ii="" or="" familial="" hypercholesterolemia="" in="" table="" 2="" of="" the="" soy="" protein="" proposed="" rule="" (63="" fr="" 62977="" at="" 63011).="" in="" addition,="" fda="" reviewed="" the="" results="" of="" one="" epidemiological="" study="" (ref.="" 65="" and="" 63="" fr="" 62977="" at="" 62986)="" and="" a="" meta-="" analysis="" (ref.="" 66="" and="" 63="" fr="" 62977="" at="" 62987)="" that="" included="" a="" number="" of="" the="" soy="" protein="" studies="" submitted="" in="" the="" petition.="" based="" on="" these="" studies,="" fda="" concluded="" there="" was="" scientific="" evidence="" for="" a="" consistent,="" clinically="" significant="" effect="" of="" soy="" protein="" on="" blood="" total="" and="" ldl-cholesterol="" levels="" (63="" fr="" 62977="" at="" 62989).="" the="" hypocholesterolemic="" effect="" of="" soy="" protein="" was="" 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="" was="" 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="" caused="" only="" statistically="" nonsignificant="" effects="" or="" slight="" elevations="" in="" high="" density="" lipoprotein="" (hdl)-="" cholesterol="" levels.="" the="" intervention="" studies="" indicated="" that="" a="" minimum="" level="" of="" approximately="" 25="" g="" of="" soy="" protein="" was="" needed="" to="" have="" a="" clinically="" significant="" effect="" on="" total="" and="" ldl-cholesterol="" levels.="" 1.="" additional="" data="" submitted="" with="" comments="" and="" new="" studies="" (comment="" 25).="" several="" comments="" included="" submissions="" of="" additional="" studies="" of="" the="" effects="" of="" soy="" protein="" on="" total="" and="" ldl-cholesterol="" or="" directed="" fda="" to="" studies="" published="" since="" it="" issued="" the="" soy="" protein="" proposed="" rule.="" fda="" reviewed="" these="" studies="" and="" found="" that="" two="" (refs.="" 136="" and="" 137)="" meet="" its="" criteria="" for="" consideration.="" one="" comment="" included="" an="" unpublished="" paper="" by="" teixeira="" et="" al.,="" 1999="" (ref.="" 136)="" that="" examined="" the="" effects="" of="" feeding="" four="" graded="" levels="" of="" soy="" protein="" in="" moderately="" hypercholesterolemic="" men.="" after="" a="" three-week="" lead-in="" on="" a="" national="" cholesterol="" education="" program="" (ncep)="" step="" 1="" diet,="" subjects="" were="" randomly="" assigned="" to="" one="" of="" five="" experimental="" groups.="" each="" group="" received="" 50="" g="" protein="" daily,="" provided="" in="" a="" variety="" of="" baked="" goods="" and="" ready-to-mix="" beverages,="" from="" isp="" or="" casein="" in="" different="" proportions="" for="" 6="" weeks.="" the="" proportions="" of="" protein="" were="" 50,="" 40,="" 30,="" 20,="" and="" 0="" g="" (for="" control)="" as="" isp="" and="" 0,="" 10,="" 20,="" 30,="" and="" 50="" g="" as="" casein,="" respectively.="" at="" 3="" weeks,="" statistically="" significant=""><0.05) reductions="" in="" total="" and="" non-hdl-cholesterol="" were="" seen="" only="" in="" the="" groups="" consuming="" 40="" and="" 50="" g="" of="" soy="" protein.="" at="" 6="" weeks,="" statistically="" significant="" reductions=""><0.05) from="" baseline="" were="" found="" for="" non-hdl="" cholesterol="" levels="" in="" all="" soy="" protein-consuming="" groups="" and,="" in="" all="" except="" the="" 40="" g="" soy="" protein="" group,="" for="" total="" cholesterol="" level.="" although="" a="" reduction="" in="" total="" cholesterol="" was="" noted="" in="" this="" [[page="" 57708]]="" latter="" group,="" it="" was="" non-significant="" (p="0.07)." the="" authors="" noted="" that="" neither="" non-compliance="" with="" the="" diet="" nor="" alterations="" in="" blood="" isoflavone="" content="" could="" account="" for="" this="" result.="" the="" study="" also="" showed="" that="" levels="" of="" hdl-cholesterol="" were="" not="" affected="" by="" dietary="" treatment="" at="" any="" soy="" consumption="" level="" investigated.="" fda="" also="" noted="" the="" recently="" published="" study="" by="" wong="" et="" al.,="" 1998="" (ref.="" 137),="" who="" conducted="" a="" well="" designed="" and="" controlled="" trial="" using="" ncep="" step="" 1="" diets="" with="" most="" protein="" provided="" by="" soy="" (50="" g/day="" of="" soy="" protein)="" or="" animal="" protein.="" subjects="" were="" 13="" normocholesterolemic="" and="" 13="" hypercholesterolemic="" men="" aged="" 20-50="" years="" and="" the="" trial="" was="" a="" randomized,="" 2-part,="" crossover="" study.="" subjects="" were="" fed="" either="" an="" ncep="" step="" i="" soy="" protein-containing="" diet="" or="" an="" ncep="" step="" i="" animal="" protein="" diet="" for="" 5="" weeks.="" after="" a="" washout="" period="" of="" 10-15="" weeks,="" the="" subjects="" were="" fed="" the="" alternate="" diet="" for="" 5="" weeks.="" the="" study="" found="" the="" hypocholesterolemic="" effect="" of="" soy="" protein="" to="" be="" independent="" of="" age,="" body="" weight,="" pretreatment="" plasma="" lipid="" concentrations,="" and="" sequence="" of="" dietary="" treatment.="" regardless="" of="" plasma="" lipid="" status,="" the="" soy="" protein="" diet="" was="" associated="" with="" a="" statistically="" significant="" decrease="" in="" the="" plasma="" concentrations="" of="" ldl="" cholesterol="" (p="0.029)." fda="" finds="" these="" two="" studies="" supportive="" of="" the="" relationship="" of="" soy="" protein="" to="" reduced="" risk="" of="" chd.="" (comment="" 26).="" one="" comment="" cited="" two="" metabolic="" ward="" studies="" by="" fumagalli="" et="" al.="" 1982="" (ref.="" 138),="" designed="" to="" examine="" fecal="" steroid="" excretion="" in="" adults="" with="" familial="" type="" ii="" hypercholesterolemia,="" that="" had="" not="" been="" reviewed="" by="" fda="" in="" the="" soy="" protein="" proposed="" rule,="" as="" supportive="" of="" the="" ability="" of="" soy="" protein="" to="" lower="" total="" cholesterol="" levels.="" however,="" fda="" finds="" these="" studies="" had="" a="" very="" small="" number="" of="" subjects,="" short="" duration="" of="" treatment,="" and="" reported="" insufficient="" information="" to="" determine="" the="" amounts="" of="" soy="" protein="" in="" the="" diets="" consumed.="" these="" studies="" failed="" to="" meet="" fda's="" selection="" criteria="" for="" review="" and,="" so,="" fda="" has="" not="" considered="" them="" further.="" (comment="" 27).="" comments="" included="" information="" on="" two="" studies="" by="" jenkins="" et="" al.="" 1999="" (refs.="" 139="" and="" 140)="" that="" assessed="" the="" effects="" of="" inclusion="" of="" soy="" protein="" and="" soluble="" dietary="" fiber="" in="" an="" ncep="" step="" ii="" diet="" in="" hypercholesterolemic="" subjects="" in="" a="" randomized="" crossover="" design.="" dietary="" saturated="" fat="" (less="" than="" 7="" percent="" of="" energy)="" and="" cholesterol="" (less="" that="" 80="" mg/day)="" did="" not="" differ="" in="" the="" test="" and="" control="" metabolic="" diets="" (ref.="" 139).="" compared="" with="" the="" control="" diet,="" the="" test="" diet="" (which="" provided="" 33="" grams="" of="" soy="" protein="" from="" a="" variety="" of="" commercially="" available="" foods)="" resulted="" in="" a="" 6="" percent="" decrease="" in="" total="" cholesterol="" and="" a="" 7="" percent="" decrease="" in="" ldl-cholesterol="" levels.="" the="" second="" study="" (ref.="" 140)="" used="" a="" similar="" design="" but="" was="" only="" available="" as="" an="" abstract="" that="" contained="" too="" little="" detail="" for="" the="" agency="" to="" evaluate="" it.="" fda="" finds="" that="" neither="" of="" these="" studies="" can="" provide="" support="" for="" a="" hypocholesterolemic="" effect="" of="" soy="" protein="" per="" se="" because="" both="" soy="" protein="" and="" soluble="" fiber="" were="" varied="" concurrently.="" however,="" these="" studies="" do="" suggest="" that="" inclusion="" of="" these="" specific="" components="" can="" further="" enhance="" the="" lipid-lowering="" effect="" of="" a="" low="" saturated="" fat,="" low="" cholesterol="" diet.="" (comment="" 28).="" a="" comment="" also="" submitted="" the="" recent="" study="" by="" washburn="" et="" al.,="" 1999="" (ref.="" 141)="" for="" consideration.="" in="" this="" randomized,="" double-="" blind="" crossover="" trial,="" 51="" normocholesterolemic,="" perimenopausal="" women="" consumed="" supplements="" for="" 6-week="" periods="" of="" 20="" g="" of="" complex="" carbohydrate,="" 20="" g="" of="" soy="" protein="" containing="" 34="" mg="" of="" phytoestrogens="" given="" in="" a="" single="" dose,="" and="" 20="" g="" of="" soy="" protein="" containing="" 34="" mg="" of="" phytoestrogens="" split="" into="" two="" doses.="" significant="" declines="" in="" total="" cholesterol="" level="" (6="" percent="" lower)="" and="" ldl-="" cholesterol="" level="" (7="" percent="" lower)="" were="" observed="" with="" both="" soy="" treatments="" compared="" to="" the="" carbohydrate="" placebo="" control.="" however,="" no="" dietary="" assessments="" were="" performed;="" thus,="" fda="" cannot="" determine="" whether="" the="" women="" may="" have="" modified="" their="" usual="" dietary="" intake="" in="" response="" to="" the="" supplements="" and="" whether="" and="" how="" intake="" of="" dietary="" constituents="" may="" have="" differed="" among="" the="" treatment="" groups.="" fda="" identified="" two="" additional="" recently="" published="" studies="" for="" consideration.="" nilausen="" and="" meinertz,="" 1998="" (ref.="" 142)="" employed="" liquid="" formula="" diets="" containing="" a="" very="" high="" level="" of="" protein="" (150="" g/day)="" with="" soy="" or="" casein="" as="" the="" sole="" protein="" source="" to="" examine="" individual="" variability="" in="" lipemic="" response="" in="" a="" small="" metabolic="" study="" of="" normocholesterolemic="" men.="" in="" most="" subjects="" effects="" of="" soy="" protein="" on="" both="" ldl-="" and="" hdl-cholesterol="" levels="" were="" favorable,="" but="" considerable="" variability="" in="" response="" was="" observed.="" duane,="" 1999="" (ref.="" 143)="" also="" conducted="" a="" small="" metabolic="" ward="" study="" in="" normocholesterolemic="" men="" that="" compared="" effects="" of="" (1)="" a="" control="" diet="" with="" ``standard''="" amounts="" of="" dietary="" cholesterol,="" (2)="" a="" diet="" with="" essentially="" no="" dietary="" cholesterol="" and="" all="" animal="" sources="" of="" protein="" substituted="" by="" tvp,="" and="" (3)="" a="" diet="" similar="" to="" the="" second="" one="" with="" eggs="" isocalorically="" substituted="" for="" protein="" and="" fat="" to="" bring="" dietary="" cholesterol="" levels="" to="" the="" moderate="" range.="" diets="" containing="" soy="" protein="" decreased="" ldl-cholesterol="" but="" the="" effect="" was="" of="" borderline="" statistical="" significance.="" fda="" notes="" that="" the="" small="" number="" of="" subjects="" and="" the="" unusual="" dietary="" conditions="" employed="" in="" these="" two="" studies="" limit="" their="" usefulness="" in="" adding="" to="" the="" body="" of="" evidence="" about="" the="" effects="" of="" soy="" protein="" on="" circulating="" lipid="" levels.="" in="" summary,="" although="" most="" of="" the="" new="" studies="" considered="" had="" flawed="" or="" unusual="" designs="" that="" compromised="" their="" evaluation,="" the="" two="" better="" designed="" and="" controlled="" studies="" (ref.="" 136="" and="" ref.="" 137)="" provide="" additional="" support="" for="" the="" cholesterol="" lowering="" effects="" of="" inclusion="" of="" reasonable="" amounts="" of="" soy="" protein="" in="" diets="" low="" in="" saturated="" fat="" and="" cholesterol.="" 2.="" interpretation="" of="" the="" clinical="" trial="" data="" for="" soy="" protein="" (comment="" 29).="" one="" comment="" raised="" concerns="" about="" the="" apparent="" inconsistency="" in="" fda's="" application="" of="" its="" review="" selection="" criteria,="" especially="" with="" respect="" to="" giving="" the="" greatest="" weight="" in="" evaluation="" of="" the="" health="" claim="" to="" those="" studies="" that="" reported="" information="" about="" the="" dietary="" intake="" of="" constituents="" known="" to="" have="" the="" greatest="" influence="" on="" total="" and="" ldl-cholesterol="" levels.="" the="" comment="" noted="" that="" values="" for="" dietary="" saturated="" fat="" and="" cholesterol="" were="" not="" reported="" for="" some="" studies="" and="" that="" an="" outmoded="" description="" of="" polyunsaturated="" fatty="" acid="" to="" saturated="" fatty="" acid="" ratio="" was="" reported="" for="" some="" studies.="" fda="" agrees="" that="" values="" for="" these="" dietary="" constituents="" were="" not="" reported="" explicitly="" in="" all="" of="" the="" studies="" selected="" for="" review.="" in="" such="" cases,="" fda="" relied="" upon="" other="" documentation="" contained="" in="" the="" study="" publications="" regarding="" the="" contents="" of="" the="" test="" and="" control="" diets,="" such="" as="" sample="" menus="" and="" reported="" manipulations="" of="" sources="" of="" saturated="" fat="" and="" cholesterol,="" for="" assurance="" that="" dietary="" saturated="" fat="" and="" cholesterol="" did="" not="" differ="" significantly="" in="" the="" test="" conditions.="" (comment="" 30).="" one="" comment="" questioned="" the="" appropriateness="" of="" including="" studies="" in="" which="" only="" total="" cholesterol="" levels="" were="" measured.="" as="" noted="" above,="" in="" earlier="" rulemakings="" on="" diet="" and="" chd="" relationships,="" 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.="" fda="" notes="" that="" a="" few="" of="" the="" older="" studies="" that="" it="" considered="" and="" reviewed="" in="" the="" soy="" protein="" proposed="" rule,="" and="" in="" previous="" [[page="" 57709]]="" rulemakings,="" measured="" only="" total="" cholesterol="" levels.="" fda="" concluded="" that="" inclusion="" of="" these="" studies="" for="" review="" was="" desirable="" in="" order="" to="" assess="" the="" totality="" of="" the="" publicly="" available="" scientific="" evidence="" on="" the="" relationship="" of="" soy="" protein="" and="" risk="" of="" chd,="" even="" though="" ldl-="" cholesterol="" levels="" are="" now="" considered="" to="" be="" a="" more="" powerful="" risk="" factor="" than="" total="" cholesterol="" levels.="" (comment="" 31).="" a="" few="" comments="" disagreed="" with="" fda's="" tentative="" decision="" to="" authorize="" a="" health="" claim="" for="" the="" relationship="" between="" soy="" protein="" and="" chd="" because="" not="" all="" of="" the="" studies="" reviewed="" in="" the="" soy="" protein="" proposed="" rule="" showed="" significant="" reductions="" of="" total="" and="" plasma="" cholesterol="" levels.="" a="" recent="" review="" and="" meta-analysis="" of="" the="" effectiveness="" of="" ncep="" step="" 1="" and="" step="" 2="" dietary="" interventions="" in="" free-living="" subjects="" by="" yu-poth="" et="" al.="" (ref.="" 144)="" noted="" an="" appreciable="" range="" of="" response="" to="" the="" dietary="" interventions="" with="" the="" maximal="" effect="" being="" more="" than="" twice="" the="" average="" response="" reported="" in="" controlled="" feeding="" studies="" with="" step="" 1="" diets.="" the="" interventions="" reviewed="" were="" designed="" to="" achieve="" reduction="" of="" dietary="" saturated="" fat="" and="" cholesterol="" and="" weight="" reduction,="" factors="" known="" to="" have="" a="" major="" impact="" on="" circulating="" cholesterol="" levels.="" (the="" hypocholesterolemic="" effects="" of="" soy="" protein,="" like="" those="" of="" soluble="" fiber="" from="" whole="" oats="" and="" psyllium="" seed,="" are="" of="" a="" lesser="" magnitude="" than="" those="" of="" reduced="" dietary="" saturated="" fat="" and="" cholesterol.)="" denke="" (ref.="" 145),="" in="" an="" editorial="" comment="" on="" the="" study="" by="" yu-poth="" et="" al.,="" notes="" that="" cholesterol-lowering="" dietary="" therapy="" is="" subject="" to="" profound="" individual="" variation="" in="" response.="" in="" metabolic="" ward="" studies="" of="" subjects="" with="" unselected="" cholesterol="" levels,="" 5="" percent="" of="" individuals="" had="" no="" cholesterol-lowering="" response="" to="" dietary="" modification="" and="" the="" percentage="" of="" nonresponders="" increased="" to="" 10-25="" percent="" in="" outpatient="" studies="" (denke,="" 1995,="" ref.="" 146).="" such="" nonresponse="" can="" result="" in="" a="" significant="" underestimation="" of="" the="" effectiveness="" of="" dietary="" intervention="" when="" only="" the="" mean="" response="" is="" considered.="" the="" small="" metabolic="" ward="" study="" of="" nilausen="" and="" meinertz="" (ref.="" 142),="" described="" above,="" documented="" evidence="" for="" considerable="" inter-individual="" variability="" in="" the="" response="" of="" cholesterol="" levels="" to="" diets="" containing="" soy="" protein.="" based="" on="" the="" studies="" reviewed="" in="" the="" soy="" protein="" proposed="" rule="" and="" the="" new="" studies="" reviewed="" in="" this="" document,="" fda="" concludes="" that="" the="" totality="" of="" the="" available="" scientific="" evidence="" supports="" a="" consistent,="" if="" not="" universal,="" hypocholesterolemic="" effect="" of="" soy="" protein="" included="" in="" a="" low="" saturated="" fat="" and="" low="" cholesterol="" diet.="" the="" degree="" of="" consistency="" is="" notable="" in="" light="" of="" the="" different="" experimental="" designs="" and="" diets="" studied,="" the="" different="" forms="" and="" amounts="" of="" soy="" protein="" tested,="" and="" the="" variability="" in="" initial="" cholesterol="" levels="" of="" the="" subjects.="" the="" modest="" lowering="" of="" total="" and="" ldl-cholesterol="" levels="" generally="" observed="" in="" these="" studies="" can="" effect="" a="" significant="" reduction="" in="" chd="" risk.="" (comment="" 32).="" other="" comments="" reviewed="" various="" possible="" mechanisms="" for="" the="" cholesterol-lowering="" effects="" of="" soy="" protein="" and="" some="" argued="" that="" until="" the="" mechanism="" of="" action="" of="" soy="" protein="" is="" clearly="" established,="" no="" health="" claim="" should="" be="" authorized.="" fda="" notes,="" however,="" that="" such="" knowledge="" is="" not="" necessarily="" required="" for="" authorization="" of="" a="" health="" claim.="" 3.="" role="" of="" soy="" isoflavones="" in="" and="" effect="" of="" processing="" on="" the="" hypocholesterolemic="" effect="" of="" soy="" protein="" in="" the="" soy="" protein="" proposed="" rule,="" fda="" examined="" the="" limited="" evidence="" that="" addressed="" whether="" the="" hypocholesterolemic="" effects="" of="" soy="" protein="" intake="" were="" dependent,="" as="" suggested="" by="" the="" petitioner,="" on="" concomitant="" intake="" of="" a="" specified="" level="" of="" naturally="" occurring="" soy="" isoflavones,="" i.e.,="" 2="" mg="" isoflavones="" per="" g="" of="" soy="" protein="" (refs.="" 22,="" 28,="" 31,="" 70,="" and="" 71).="" fda="" also="" took="" note="" of="" a="" letter="" to="" the="" editor="" from="" sirtori="" et="" al.="" (ref.="" 72),="" who="" conducted="" a="" number="" of="" trials="" in="" which="" soy="" protein="" exhibited="" hypocholesterolemic="" effects="" and="" asserted="" that="" the="" products="" used="" in="" those="" trials="" were="" essentially="" devoid="" of="" isoflavones.="" given="" the="" limited="" number="" of="" studies="" and="" the="" contradictory="" outcomes,="" fda="" was="" not="" persuaded="" that="" the="" isoflavone="" component="" of="" soy="" protein="" was="" a="" relevant="" factor="" to="" the="" diet-disease="" relationship.="" rather,="" fda="" tentatively="" concluded="" that="" the="" evidence="" from="" a="" wide="" range="" of="" studies="" using="" differently="" processed="" soy="" protein="" was="" supportive="" of="" a="" relationship="" between="" soy="" protein="" per="" se="" and="" reduced="" risk="" of="" chd.="" (comment="" 33).="" several="" comments="" reviewed="" and="" discussed="" the="" animal="" and="" human="" studies="" that="" examined="" effects="" of="" isoflavones="" directly="" or="" that="" compared="" the="" effects="" of="" isp="" processed="" with="" and="" without="" alcohol="" extraction="" that="" can="" remove="" essentially="" all="" isoflavones.="" some="" of="" these="" studies="" examined="" effects="" on="" parameters="" in="" addition="" to="" cholesterol="" levels,="" such="" as="" measures="" of="" lipid-related="" gene="" expression,="" atherosclerosis,="" and="" vascular="" reactivity.="" because="" the="" health="" claim="" for="" soy="" protein="" and="" chd="" is="" based="" on="" the="" hypocholesterolemic="" effect="" of="" soy="" protein,="" only="" that="" aspect="" of="" the="" studies="" is="" summarized="" below.="" in="" one="" study,="" balmir="" et="" al.="" (ref.="" 147)="" fed="" male="" rats="" diets="" containing="" protein="" from="" ethanol-acetone="" extracted="" isp,="" nonextracted="" isp,="" casein,="" or="" casein="" to="" which="" the="" ethanol-acetone="" extract="" was="" added.="" rats="" fed="" either="" isp="" diet="" had="" lower="" serum="" total="" cholesterol="" concentrations="" compared="" with="" those="" fed="" either="" casein="" diet.="" lower="" serum="" ldl-cholesterol="" concentrations="" were="" found="" in="" rats="" fed="" either="" isp="" diet="" and="" in="" rats="" fed="" casein="" plus="" extract="" compared="" with="" those="" fed="" casein.="" sugano="" and="" koba="" (ref.="" 148)="" found="" that="" a="" methanol-extracted="" soy="" fraction="" was="" not="" as="" effective="" as="" the="" unextracted="" fraction="" in="" maintaining="" low="" plasma="" cholesterol="" levels="" in="" rats.="" kirk="" et="" al.="" (ref.="" 149)="" showed="" that="" a="" soy="" protein-based="" isoflavone-containing="" diet="" resulted="" in="" a="" reduction="" in="" cholesterol="" levels="" in="" c57bl/6="" mice="" compared="" to="" a="" diet="" containing="" alcohol-washed="" soy="" protein,="" although="" it="" had="" no="" effect="" on="" cholesterol="" levels="" in="" transgenic="" mice="" that="" lacked="" the="" ldl="" receptor.="" in="" another="" study,="" balmir="" et="" al.="" (ref.="" 147)="" fed="" male="" golden="" syrian="" hamsters="" diets="" containing="" protein="" from="" isp,="" isp="" with="" added="" ethanol-acetone="" extract,="" casein,="" or="" casein="" with="" added="" extract.="" lower="" serum="" total="" cholesterol="" and="" ldl="" cholesterol="" concentrations="" were="" observed="" in="" hamsters="" fed="" isp,="" isp="" with="" extract,="" or="" casein="" with="" extract="" compared="" with="" those="" fed="" casein.="" addition="" of="" the="" extract="" to="" casein="" at="" higher="" levels="" did="" not="" lower="" serum="" lipids="" relative="" to="" casein.="" tovar-palacio="" et="" al.="" (ref.="" 150)="" fed="" gerbils="" one="" of="" five="" experimental="" diets="" containing="" either="" casein="" or="" alcohol-="" washed="" isp="" provided="" alone,="" or="" isp="" supplemented="" with="" one="" of="" three="" different="" levels="" of="" an="" alcohol="" extract="" of="" isolated="" soy="" protein="" contributing="" either="" 2.1,="" 3.6="" or="" 6.2="" mg="" isoflavones/g="" protein.="" gerbils="" fed="" all="" of="" the="" soy-based="" diets="" had="" significantly="" lower="" total="" and="" ldl="" +="" very="" low="" density="" lipoprotein="" (vldl)-cholesterol="" levels="" than="" those="" fed="" casein.="" the="" additions="" of="" the="" alcohol="" extract="" to="" isp="" did="" not="" reduce="" serum="" cholesterol="" levels="" any="" further.="" this="" study="" suggests="" that,="" in="" gerbils,="" consumption="" of="" an="" isoflavone-containing="" extract="" does="" not="" contribute="" to="" the="" hypocholesterolemic="" effect="" of="" alcohol-extracted="" soy="" protein.="" these="" reports="" did="" not="" characterize="" the="" nature="" of="" the="" extracts="" used="" in="" the="" studies.="" overall,="" fda="" finds="" that="" studies="" in="" these="" animal="" models="" do="" not="" clarify="" the="" role="" of="" isoflavones="" in="" the="" hypocholesterolemic="" effect="" of="" soy="" protein.="" comments="" noted="" a="" series="" of="" studies="" conducted="" in="" monkeys="" that="" examined="" the="" effect="" of="" removal="" of="" isoflavones="" and="" other="" alcohol-="" extractable="" compounds="" from="" soy="" protein="" on="" its="" cholesterol-lowering="" activity.="" anthony="" et="" al.="" (ref.="" [[page="" 57710]]="" 22)="" fed="" peripubertal="" male="" and="" female="" rhesus="" monkeys="" moderately="" atherogenic="" diets="" in="" which="" the="" source="" of="" dietary="" protein="" was="" a="" soy="" protein="" isolate,="" either="" containing="" isoflavones="" or="" with="" the="" isoflavones="" removed="" by="" alcohol="" extraction,="" in="" a="" crossover="" design="" with="" each="" period="" lasting="" for="" 6="" months.="" the="" intact="" soy="" protein="" (compared="" with="" the="" extracted="" soy="" protein)="" significantly="" reduced="" ldl+vldl-cholesterol="" levels="" in="" both="" males="" and="" females="" and="" significantly="" increased="" hdl-="" cholesterol="" levels="" for="" females.="" honore="" et="" al.="" (ref.="" 23)="" fed="" young="" adult="" rhesus="" monkeys="" with="" pre-existing="" diet-induced="" atherosclerosis="" one="" of="" two="" soy-based="" diets,="" which="" were="" identical="" in="" composition="" except="" that="" the="" isoflavones="" were="" extracted="" from="" one="" and="" intact="" in="" the="" other,="" for="" 6="" months.="" total="" and="" ldl-cholesterol="" levels="" were="" significantly="" lower="" in="" females="" fed="" the="" intact="" soy="" protein="" than="" in="" those="" fed="" the="" extracted="" soy="" protein.="" the="" same="" trend="" was="" seen="" in="" males,="" but="" the="" difference="" was="" not="" statistically="" significant="" for="" total="" cholesterol.="" anthony="" et="" al.="" (ref.="" 70)="" studied="" young="" male="" cynomolgus="" macaques="" fed="" one="" of="" three="" moderately="" atherogenic="" diets="" for="" 14="" months.="" the="" groups="" differed="" only="" in="" the="" source="" of="" dietary="" protein,="" which="" was="" either="" casein/lactalbumin,="" soy="" protein="" with="" the="" isoflavones="" intact,="" or="" soy="" protein="" with="" the="" isoflavones="" mostly="" extracted.="" animals="" fed="" intact="" soy="" protein="" had="" significantly="" lower="" total="" and="" ldl+vldl-cholesterol="" levels="" compared="" with="" the="" other="" two="" groups.="" the="" animals="" fed="" intact="" soy="" protein="" had="" the="" highest="" hdl-cholesterol="" level,="" the="" casein="" group="" had="" the="" lowest="" level,="" and="" the="" group="" fed="" the="" extracted="" soy="" protein="" was="" intermediate.="" anthony="" et="" al.="" (ref.="" 151)="" randomized="" male="" and="" female="" macaques="" to="" groups="" fed="" a="" casein-containing="" diet="" or="" diets="" with="" soy="" protein="" with="" the="" isoflavones="" intact="" or="" extracted.="" fat="" and="" cholesterol="" were="" identical="" in="" all="" diets.="" the="" ldl+vldl-cholesterol="" levels="" were="" highest="" in="" the="" casein="" group,="" slightly="" lower="" in="" the="" group="" fed="" extracted="" soy="" protein,="" and="" significantly="" lower="" in="" the="" group="" fed="" intact="" soy="" protein.="" the="" hdl-cholesterol="" levels="" were="" significantly="" higher="" in="" both="" soy="" protein="" groups="" than="" in="" the="" casein="" group.="" fda="" notes="" that="" the="" alcohol="" extraction="" procedure="" used="" by="" these="" researchers,="" which="" was="" not="" characterized="" in="" the="" study="" reports,="" appeared="" to="" diminish="" the="" hypocholesterolemic="" effect="" of="" isp.="" comments="" submitted="" three="" human="" studies="" of="" isolated="" isoflavones="" that="" examined="" their="" role="" in="" cholesterol="" lowering.="" in="" a="" study="" published="" only="" as="" an="" abstract,="" colquhoun="" et="" al.="" (ref.="" 152)="" administered="" daidzein="" and="" genistein="" to="" 23="" male="" and="" female="" subjects="" with="" an="" average="" cholesterol="" level="" of="" 243="" mg/deciliter="" (dl)="" in="" a="" blinded="" crossover="" design.="" nestel="" et="" al.="" (ref.="" 52)="" studied="" 21="" women="" in="" a="" randomized="" cross-over="" design="" with="" two="" active="" treatment="" periods="" (80="" mg="" of="" isolated="" soy="" isoflavones)="" and="" one="" 5-week="" placebo="" period,="" while="" they="" consumed="" a="" soy-free="" diet.="" hodgson="" et="" al.="" (ref.="" 153)="" conducted="" a="" randomized,="" blinded,="" placebo-controlled="" trial="" of="" 8="" weeks="" duration="" and="" a="" two-way="" parallel="" design="" that="" tested="" the="" administration="" of="" 55="" mg="" of="" soy="" isoflavones="" to="" 46="" men="" and="" 13="" postmenopausal="" women.="" plasma="" lipid="" levels="" were="" not="" affected="" by="" soy="" isoflavones="" in="" any="" of="" these="" studies.="" fda="" notes="" that="" these="" studies="" do="" not="" support="" a="" role="" for="" isolated="" isoflavones="" in="" cholesterol="" lowering.="" three="" studies="" submitted="" in="" comments="" examined="" the="" effects="" of="" variation="" of="" isoflavone="" content="" in="" soy="" protein-containing="" diets="" in="" human="" subjects.="" cassidy="" et="" al.="" (ref.="" 154)="" conducted="" metabolic="" ward="" studies="" of="" the="" effects="" of="" various="" soy="" products="" with="" and="" without="" isoflavones="" in="" small="" numbers="" of="" healthy,="" nonvegetarian,="" premenopausal="" women.="" during="" one="" (control)="" menstrual="" cycle,="" the="" women="" ate="" a="" constant="" diet="" containing="" no="" soy="" products.="" then,="" over="" a="" second="" complete="" cycle="" six="" subjects="" consumed="" a="" similar="" diet="" into="" which="" 60="" g="" tvp/day,="" containing="" 45="" mg="" conjugated="" isoflavones,="" was="" incorporated.="" three="" participants="" had="" 50="" g="" miso,="" containing="" 25="" mg="" unconjugated="" isoflavones,="" added="" daily="" to="" their="" diet="" over="" a="" menstrual="" cycle,="" and="" six="" others="" consumed="" 28="" g="" tvp/day,="" containing="" 23="" mg="" conjugated="" isoflavones.="" five="" participants="" completed="" a="" third="" diet="" period="" in="" which="" they="" were="" randomly="" assigned="" to="" consume="" either="" the="" control="" diet="" over="" a="" cycle,="" or="" a="" similar="" diet="" incorporating="" 60="" g="" of="" a="" isp="" from="" which="" the="" isoflavones="" had="" been="" chemically="" extracted.="" a="" significant="" reduction="" in="" total="" cholesterol="" was="" found="" with="" 45="" mg="" conjugated="" isoflavones,="" but="" not="" with="" 23="" mg="" conjugated="" isoflavones="" or="" isoflavone-free="" isp.="" as="" previously="" reviewed="" in="" the="" soy="" protein="" proposed="" rule="" (63="" fr="" 62977="" at="" 62988),="" the="" study="" of="" baum="" et="" al.="" (ref.="" 28)="" investigated="" the="" impact="" of="" soy="" protein="" as="" isp="" containing="" different="" levels="" of="" isoflavones="" in="" hypercholesterolemic,="" postmenopausal="" women.="" 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="" 8-9="" percent="" in="" non-hdl="" (ldl+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.="" fda="" also="" previously="" reviewed="" the="" unpublished="" study="" by="" crouse="" et="" al.,="" which="" was="" subsequently="" accepted="" and="" published="" (ref.="" 31),="" in="" the="" soy="" protein="" proposed="" rule="" (63="" fr="" 62977="" at="" 62987).="" this="" study="" examined="" the="" effect="" of="" soy="" protein="" containing="" different="" levels="" of="" isoflavones="" in="" hypercholesterolemic="" men="" and="" women.="" subjects="" with="" qualifying="" serum="" lipid="" levels="" (ldl-cholesterol="" greater="" than="" 140="" mg/dl)="" after="" one="" month="" and="" who="" were="" compliant="" with="" the="" study="" regimen="" were="" randomized="" into="" one="" of="" five="" treatment="" groups.="" 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.="" results="" indicated="" that="" compared="" to="" casein="" the="" isp="" containing="" the="" highest="" level="" of="" isoflavones="" significantly="" lowered="" total=""><0.05) and="" ldl-cholesterol=""><0.05), by="" 4="" percent="" and="" 6="" percent,="" respectively,="" while="" hdl-="" cholesterol="" was="" not="" altered.="" 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.="" the="" authors="" reported="" a="" dose-response="" effect="" of="" increasing="" amounts="" of="" isoflavones="" on="" total="" and="" ldl="" cholesterol="" level.="" one="" comment="" included="" a="" reanalysis="" of="" the="" dose-response="" data="" that="" did="" not="" include="" data="" for="" the="" casein="" diet,="" in="" order="" to="" control="" for="" an="" independent="" effect="" from="" soy="" protein="" itself,="" and="" found="" no="" significant="" effect="" based="" on="" isoflavone="" content.="" a="" comment="" from="" the="" petitioner="" disagreed="" with="" this="" analysis.="" it="" also="" indicated="" that="" the="" study="" did="" not="" eliminate="" the="" possibility="" that="" isolated="" soy="" protein="" per="" se="" has="" cholesterol-lowering="" properties,="" but="" rather="" suggested="" that="" soy="" protein="" with="" higher="" levels="" of="" isoflavones="" might="" have="" even="" greater="" effects.="" fda="" finds="" that="" the="" disparity="" in="" these="" comments="" does="" not="" clarify="" the="" equivocal="" nature="" of="" the="" available="" evidence.="" fda="" finds="" that="" these="" studies="" do="" not="" provide="" sufficiently="" consistent="" results="" to="" cause="" the="" agency="" to="" [[page="" 57711]]="" change="" the="" conclusion="" reached="" in="" the="" soy="" protein="" proposed="" rule.="" (comment="" 34).="" one="" comment="" objected="" to="" fda's="" consideration="" of="" the="" letter="" to="" the="" editor="" by="" sirtori="" et="" al.="" (ref.="" 72)="" because="" the="" reference="" substantiating="" the="" technique="" for="" processing="" the="" soy="" protein="" product="" was="" missing="" from="" the="" letter,="" the="" products="" were="" not="" tested="" for="" isoflavone="" content="" at="" the="" time="" of="" the="" studies,="" different="" soy="" products="" (isolate="" and="" flour)="" were="" used="" to="" manufacture="" the="" textured="" soy="" protein="" used="" in="" the="" studies,="" and="" the="" references="" for="" studies="" cited="" in="" the="" letter="" did="" not="" match="" the="" ones="" cited="" by="" fda="" in="" the="" soy="" protein="" proposed="" rule.="" fda="" agrees="" that="" the="" reference="" for="" the="" patented="" procedure="" for="" the="" production="" of="" the="" tvp,="" described="" as="" making="" use="" of="" rapid="" heating="" under="" high="" pressure,="" was="" omitted="" in="" the="" letter="" by="" sirtori="" et="" al.="" (ref.="" 72)="" and="" that="" the="" isoflavone="" content="" of="" the="" products="" reported="" (cholsoy="" and="" croksoy)="" was="" not="" measured="" at="" the="" time="" the="" studies="" in="" which="" they="" were="" used="" were="" conducted.="" the="" letter="" by="" sirtori="" et="" al.="" (ref.="" 72)="" cites="" two="" older="" studies--="" sirtori="" et="" al.,="" 1979="" (ref.="" 55)="" and="" sirtori="" et="" al.,="" 1979="" (ref.="" 155)--as="" well="" more="" recent="" studies--sirtori="" et="" al.,="" 1995="" (ref.="" 156)--conducted="" by="" their="" group.="" the="" five="" studies="" of="" sirtori's="" group="" that="" fda="" reviewed="" and="" cited="" in="" the="" soy="" protein="" proposed="" rule="" as="" using="" products="" that="" contained="" essentially="" no="" isoflavones="" (refs.="" 33,="" 34,="" 35,="" 46,="" and="" 56)="" are="" included="" in="" the="" reference="" list="" of="" sirtori="" et="" al.,="" 1995="" (ref.="" 156),="" which="" is="" a="" review="" article.="" the="" agency="" did="" not="" review="" sirtori="" et="" al.,="" 1979="" (ref.="" 155)="" in="" the="" soy="" protein="" proposed="" rule,="" and="" it="" did="" not="" cite="" sirtori="" et="" al.,="" 1977="" (ref.="" 55)="" because="" it="" specifically="" indicated="" use="" of="" a="" soy="" protein="" product="" different="" from="" those="" tested="" for="" isoflavone="" content.="" fda="" gives="" some="" credence="" to="" the="" knowledge="" of="" the="" investigator="" about="" the="" products="" used="" in="" his="" studies,="" but="" agrees="" that="" the="" letter="" to="" the="" editor="" does="" not="" provide="" sufficient="" documentation="" to="" permit="" an="" unequivocal="" conclusion="" that="" the="" products="" found="" to="" be="" devoid="" of="" isoflavones="" were="" identical="" to="" those="" used="" in="" the="" clinical="" studies.="" (comment="" 35).="" one="" comment="" asserted="" that="" most="" of="" the="" studies="" reported="" by="" sirtori's="" group="" were="" performed="" using="" a="" textured="" soy="" protein="" based="" on="" steam-treated="" soy="" flour;="" this="" treatment="" would="" be="" expected="" to="" remove="" isoflavones.="" the="" comment="" also="" included="" a="" letter="" from="" sirtori="" (ref.="" 157)="" stating="" that="" essentially="" all="" of="" his="" group's="" studies="" beginning="" in="" 1980="" were="" with="" products="" without="" isoflavones.="" however,="" the="" patent="" referenced="" in="" this="" letter="" was="" not="" included="" with="" this="" submission.="" thus,="" fda="" cannot="" verify="" that="" the="" process="" used="" to="" produce="" the="" products="" used="" in="" sirtori's="" studies="" over="" time="" was="" the="" same="" used="" to="" produce="" the="" products="" analyzed="" recently="" for="" isoflavone="" content.="" (comment="" 36).="" the="" interpretation="" of="" the="" data="" available="" on="" the="" role="" of="" soy="" isoflavones="" in="" and="" the="" effects="" of="" processing="" on="" the="" hypocholesterolemic="" effect="" of="" soy="" protein="" varied="" widely="" in="" the="" comments.="" several="" comments="" agreed="" with="" fda's="" conclusion="" that="" the="" evidence="" did="" not="" support="" a="" significant="" role="" for="" soy="" isoflavones="" in="" cholesterol-lowering="" effects="" of="" soy="" protein.="" one="" comment="" supported="" the="" petitioner's="" original="" conclusion="" that="" a="" level="" of="" 2="" mg="" aglycone="" isoflavones="" per="" g="" soy="" protein="" was="" necessary="" for="" cholesterol="" lowering.="" in="" a="" comment,="" the="" petitioner="" agreed="" with="" fda="" ``that="" a="" relationship="" exists="" between="" soy="" protein="" per="" se="" and="" reduced="" risk="" of="" chd.''="" the="" additional="" evidence="" about="" the="" role="" of="" isoflavones="" is="" contradictory="" and="" inconclusive="" and="" has="" not="" persuaded="" fda="" to="" alter="" its="" original="" conclusion="" about="" the="" inability="" to="" identify="" a="" specific="" contribution="" of="" soy="" isoflavones="" to="" the="" cholesterol-lowering="" effects="" of="" soy="" protein.="" at="" the="" same="" time,="" the="" evidence="" shows="" a="" clear="" relationship="" between="" soy="" protein="" and="" reduced="" risk="" of="" chd="" despite="" lack="" of="" a="" clearly="" defined="" mechanism="" for="" its="" effect.="" (comment="" 37).="" several="" comments="" interpreted="" the="" evidence="" as="" showing="" that="" alcohol="" extraction="" used="" in="" the="" processing="" of="" certain="" soy="" protein="" ingredients="" (to="" the="" extent="" that="" they="" are="" rendered="" essentially="" devoid="" of="" isoflavones)="" impairs="" or="" eliminates="" the="" hypocholesterolemic="" effects="" of="" soy="" protein="" and="" recommended="" that="" the="" health="" claim="" not="" be="" allowed="" for="" alcohol-washed="" products.="" comments="" also="" raised="" some="" questions="" about="" the="" extent="" to="" which="" extensively="" alcohol-washed="" products,="" such="" as="" those="" used="" in="" the="" animal="" studies,="" are="" available="" commercially.="" one="" comment="" asserted="" that="" some="" of="" isp="" products="" used="" in="" the="" primate="" studies="" were="" subjected="" to="" additional="" alcohol="" extraction="" by="" the="" investigators,="" but="" the="" agency="" could="" not="" independently="" verify="" this="" assertion.="" this="" comment="" also="" stated="" that="" all="" commercial="" sources="" of="" soy="" protein="" contain="" some="" isoflavones.="" fda="" examined="" the="" recently="" compiled="" usda-iowa="" state="" university="" isoflavone="" database="" (ref.="" 158),="" which="" documents="" the="" following="" ranges="" of="" total="" isoflavone="" content="" for="" various="" soy="" protein-containing="" ingredients,="" and="" found="" that="" most,="" but="" not="" all,="" contained="" levels="" of="" isoflavones="" higher="" than="" those="" that="" would="" result="" from="" harsh="" alcohol="" extraction="" procedures:="" table="" 1="" ------------------------------------------------------------------------="" aglycone="" isoflavones="" product="" (mg/100="" g="" edivle="" portion="" ------------------------------------------------------------------------="" soy="" flour,="" textured...............................="" 4.40-295.55="" soy="" flour,="" defatted...............................="" 73.72-168.09="" soy="" flour,="" full-fat,="" raw..........................="" 59.80-264.84="" soy="" flour,="" full-fat,="" roasted......................="" 131.70-260.50="" soy="" protein="" concentrate,="" aqueous="" washed...........="" 61.23-167.00="" soy="" protein="" concentrate="" produced="" by="" alcohol="" 2.08-31.82="" extraction.......................................="" soy="" protein="" isolate...............................="" 46.50-199.25="" instant="" beverage,="" soy="" powder......................="" 100.10-125.00="" ------------------------------------------------------------------------="" fda="" agrees="" that="" the="" data="" from="" the="" animal="" studies="" reviewed="" suggest="" that="" alcohol="" washing="" of="" soy="" protein="" can="" reduce="" its="" hypocholesterolemic="" effects.="" with="" respect="" to="" human="" studies,="" fda="" finds="" the="" available="" evidence="" is="" insufficient="" to="" permit="" any="" conclusions="" about="" the="" impact="" of="" processing="" by="" alcohol="" extraction="" on="" the="" hypocholesterolemic="" effect="" of="" soy="" protein.="" thus,="" fda="" concludes="" it="" would="" be="" premature="" to="" exclude="" alcohol-washed="" products="" from="" eligibility="" to="" bear="" the="" health="" claim.="" (comment="" 38).="" one="" comment="" noted="" that="" several="" clinical="" trials="" designed="" to="" resolve="" questions="" about="" the="" impact="" of="" processing="" and="" isoflavone="" content="" are="" [[page="" 57712]]="" currently="" in="" progress.="" many="" of="" the="" comments="" on="" these="" issues="" urged="" that="" fda="" proceed="" with="" the="" health="" claim="" regulation="" as="" proposed,="" but="" monitor="" research="" developments="" and="" make="" changes="" in="" the="" regulation="" as="" warranted="" by="" the="" results.="" as="" noted="" above,="" fda="" finds="" that,="" in="" light="" of="" the="" evidence="" that="" soy="" protein="" processed="" in="" various="" ways,="" containing="" unknown="" amounts="" of="" isoflavones,="" has="" hypocholesterolemic="" effects,="" fda="" is="" not="" applying="" any="" criteria="" for="" inclusion="" of="" naturally="" occurring="" isoflavones="" or="" excluding="" alcohol-washed="" products="" from="" eligibility="" to="" bear="" the="" health="" claim="" on="" soy="" protein="" and="" chd.="" (comment="" 39).="" a="" few="" comments="" suggested="" that,="" regardless="" of="" the="" conclusions="" about="" the="" significance="" of="" soy="" isoflavones="" to="" the="" reduction="" of="" chd="" risk,="" food="" products="" that="" bear="" the="" soy="" protein="" health="" claim="" be="" allowed="" or="" required="" to="" state="" the="" isoflavone="" content="" of="" the="" product="" on="" the="" label.="" the="" comments="" did="" not="" provide="" any="" evidence="" that="" persuaded="" the="" agency="" that="" consumers="" would="" find="" this="" information="" helpful="" in="" making="" healthful="" dietary="" choices.="" accordingly,="" the="" agency="" is="" not="" adopting="" this="" suggestion.="" 4.="" amount="" of="" soy="" protein="" required="" for="" significant="" effect="" on="" cholesterol="" levels="" based="" on="" the="" limited="" data="" reviewed="" that="" supported="" a="" dose-response="" and="" the="" data="" that="" showed="" clinically="" significant="" reductions="" in="" total="" and="" ldl-cholesterol="" with="" soy="" protein="" ingestion="" in="" the="" range="" of="" 17-31="" g/day,="" and="" recognizing="" that="" the="" hypocholesterolemic="" effects="" of="" soy="" protein="" were="" dependent="" on="" initial="" blood="" lipid="" levels,="" the="" agency="" tentatively="" concluded="" that="" 25="" g/day="" represented="" a="" reasonable,="" effective="" amount="" of="" soy="" protein="" (63="" fr="" 62977="" at="" 62992).="" in="" addition,="" the="" agency="" noted="" that="" 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="" concluded="" that="" the="" amount="" of="" soy="" protein="" associated="" with="" reduction="" in="" total="" and="" ldl-cholesterol="" levels="" and,="" thus,="" with="" reduced="" risk="" of="" chd="" was="" 25="" g="" or="" more="" of="" soy="" protein="" per="" day="" (63="" fr="" 62977="" at="" 62992).="" (comment="" 40).="" many="" comments="" agreed="" with="" the="" agency's="" conclusion="" that="" 25="" g="" or="" more="" of="" soy="" protein="" per="" day="" was="" associated="" with="" reduction="" in="" total="" and="" ldl-cholesterol="" levels.="" several="" comments="" raised="" concerns="" about="" the="" adequacy="" of="" the="" available="" data="" to="" support="" an="" assessment="" of="" dose-response.="" one="" comment="" expressed="" concern="" that="" higher="" levels="" of="" soy="" protein="" are="" needed="" to="" modify="" cholesterol="" levels="" in="" normocholesterolemic="" individuals="" and="" that="" this="" should="" be="" indicated="" as="" part="" of="" the="" claim.="" fda="" agrees="" that="" the="" available="" data="" on="" the="" hypocholesterolemic="" effects="" of="" soy="" protein="" do="" not="" permit="" a="" dose-response="" assessment.="" however,="" fda="" notes="" that="" dose-response="" data="" are="" not="" required="" to="" establish="" the="" qualifying="" criteria="" for="" a="" substance="" that="" is="" the="" subject="" of="" a="" health="" claim.="" under="" sec.="" 101.70,="" which="" describes="" the="" requirements="" for="" health="" claim="" petitions,="" the="" petition="" must="" address="" whether="" there="" is="" an="" optimum="" level="" of="" the="" particular="" substance="" to="" be="" consumed="" beyond="" which="" no="" benefit="" would="" be="" expected="" (sec.="" 101.70(f)(b)(1)).="" this="" information="" may="" or="" may="" not="" be="" based="" on="" dose-response="" data.="" for="" example,="" in="" its="" evaluation="" of="" the="" scientific="" evidence="" for="" a="" relationship="" between="" consumption="" of="" soluble="" fiber="" from="" psyllium="" seed="" husk="" and="" blood="" total="" and="" ldl-cholesterol="" levels,="" the="" agency="" found="" no="" reliable="" data="" to="" establish="" a="" dose-response="" for="" this="" relationship="" (62="" fr="" 28234="" at="" 28240).="" however,="" the="" agency="" did="" find="" that,="" in="" placebo-controlled="" studies="" that="" tested="" an="" intake="" of="" 10.2="" g="" of="" psyllium="" seed="" husk="" per="" day="" as="" a="" part="" of="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol,="" there="" were="" consistently="" significant="" effects="" of="" psyllium="" husk="" on="" blood="" total="" and="" ldl-cholesterol="" levels.="" therefore,="" the="" agency="" based="" the="" qualifying="" level="" of="" soluble="" fiber="" from="" psyllium="" seed="" husk="" on="" a="" total="" daily="" intake="" of="" 10.2="" g="" husk="" or="" about="" 7="" g="" of="" soluble="" fiber.="" the="" qualifying="" level="" of="" 25="" g/day="" has="" been="" demonstrated="" to="" have="" a="" consistent,="" clinically="" significant="" effect="" on="" total="" and="" ldl-cholesterol="" levels.="" this="" 25="" g/day="" level="" of="" intake="" for="" cholesterol="" lowering="" is="" confirmed="" by="" the="" new="" study="" of="" teixeira="" et="" al.="" (ref.="" 136),="" which="" showed="" significant="" hypocholesterolemic="" effects="" of="" 20="" g/day="" of="" soy="" protein.="" therefore,="" the="" agency="" disagrees="" with="" the="" comments="" suggesting="" that="" dose-="" response="" data="" are="" needed="" before="" the="" agency="" can="" authorize="" a="" health="" claim.="" the="" totality="" of="" scientific="" data,="" which="" establish="" a="" clinically="" significant="" reduction="" in="" blood="" cholesterol="" based="" on="" an="" intake="" of="" at="" least="" 25="" g/day="" of="" soy="" protein,="" provides="" an="" adequate="" basis="" for="" establishing="" a="" qualifying="" level="" for="" soy="" protein-containing="" products.="" the="" agency="" agrees="" that="" the="" available="" data="" indicate="" that="" the="" hypocholesterolemic="" effect="" of="" soy="" protein="" may="" be="" dependent="" on="" initial="" cholesterol="" levels,="" but="" notes="" that="" moderately="" hypercholesterolemic="" individuals="" are="" generally="" more="" responsive="" to="" dietary="" interventions="" than="" normocholesterolemic="" individuals.="" 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.="" 37).="" the="" public="" health="" policy="" articulated="" by="" the="" 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="" 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.="" the="" agency="" is="" persuaded="" by="" the="" evidence="" it="" has="" reviewed="" in="" this="" rulemaking="" that="" the="" consumption="" of="" soy="" protein,="" as="" part="" of="" a="" low="" saturated="" fat="" and="" cholesterol="" diet,="" can="" be="" a="" useful="" public="" health="" measure="" to="" assist="" in="" the="" national="" policy="" of="" promoting="" eating="" patterns="" that="" will="" help="" in="" achieving="" or="" maintaining="" desirable="" blood="" cholesterol="" levels="" in="" the="" general="" population.="" therefore,="" it="" concludes="" that="" the="" health="" claim="" need="" not="" indicate="" that="" hypercholesterolemic="" individuals="" may="" be="" more="" responsive="" to="" consumption="" of="" soy="" protein="" than="" normocholesterolemic="" individuals.="" in="" addition,="" consistent="" with="" the="" agency's="" conclusions="" in="" rulemaking="" on="" the="" dietary="" saturated="" fat="" and="" cholesterol/chd="" claim="" (58="" fr="" 2739="" at="" 2745,="" january="" 6,="" 1993),="" the="" wording="" of="" the="" health="" claim="" as="" ``="" `may'="" or="" `might'="" reduce="" the="" risk="" of="" heart="" disease''="" adequately="" represents="" the="" fact="" that="" not="" all="" persons="" will="" realize="" the="" same="" magnitude="" of="" benefit="" from="" adopting="" the="" dietary="" change.="" 5.="" summary="" of="" the="" scientific="" evidence="" fda="" reviewed="" human="" studies="" submitted="" by="" the="" petitioner="" and="" in="" comments="" that="" evaluated="" the="" effects="" on="" serum="" cholesterol="" and="" ldl-="" cholesterol="" levels="" of="" dietary="" interventions="" with="" soy="" protein="" in="" subjects="" with="" normal="" to="" elevated="" serum="" cholesterol="" levels="" and="" that="" met="" the="" agency's="" criteria="" for="" selection.="" most="" intervention="" trials="" in="" subjects="" with="" total="" cholesterol="" levels="" less="" than="" 300="" mg/dl="" found="" that="" soy="" protein="" [[page="" 57713]]="" reduced="" total="" and/or="" ldl-cholesterol="" levels="" to="" a="" clinically="" significant="" degree="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" 37,="" 49,="" 30,="" 58,="" 29,="" 43,="" 136,="" and="" 137.).="" moreover,="" hdl-cholesterol="" levels="" were="" unchanged="" (refs.="" 31,="" 27,="" 51,="" 40,="" 37,="" 49,="" 36,="" 53,="" 136,="" and="" 137)="" 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="" those="" in="" hypercholesterolemic="" subjects="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" 40,="" 37,="" 49,="" 54,="" 29,="" 43,="" and="" 136)="" except="" in="" the="" study="" of="" wong="" et="" al.="" (ref.="" 137),="" in="" which="" normocholesterolemic="" and="" moderately="" hypercholesterolemic="" subjects="" were="" equally="" responsive.="" 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="" cholesterol="" levels="" less="" than="" 300="" mg/dl="" used="" low="" saturated="" fat="" and="" low="" cholesterol="" diets="" (refs.="" 31,="" 28,="" 27,="" 51,="" 44,="" 30,="" 36,="" 53,="" 29,="" 43,="" 136,="" and="" 137),="" 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.="" given="" the="" variability="" of="" amounts="" and="" forms="" in="" which="" soy="" protein="" was="" provided="" in="" the="" diets,="" the="" response="" of="" blood="" lipid="" levels="" appears="" robust="" and="" notably="" consistent,="" particularly="" in="" subjects="" with="" moderate="" hypercholesterolemia.="" 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="" also="" consistent="" 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="" foods="" but="" produced="" fairly="" consistent="" results="" regardless="" of="" the="" food="" form="" fed="" and="" apparent="" differences="" in="" processing="" techniques.="" the="" fda="" 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="" concludes="" that="" the="" effect="" is="" due="" to="" soy="" protein="" per="" se="" and="" is="" not="" consistently="" related="" to="" the="" presence="" or="" absence="" of="" isoflavones.="" the="" evidence="" currently="" available,="" as="" reviewed="" in="" section="" ii.b.3="" of="" this="" document,="" does="" not="" permit="" a="" conclusion="" regarding="" how="" significantly="" alcohol="" processing="" may="" affect="" the="" hypocholesterolemic="" effects="" of="" soy="" protein.="" the="" intervention="" studies="" reviewed="" indicate="" that="" a="" minimum="" level="" of="" approximately="" 25="" g="" of="" soy="" protein="" per="" day="" results="" in="" a="" clinically="" significant="" effect="" on="" total="" and="" ldl-cholesterol="" levels.="" with="" respect="" to="" the="" scientific="" data="" and="" information="" about="" the="" relationship="" of="" soy="" protein="" and="" chd,="" the="" relevant="" data="" are="" provided="" by="" well="" controlled="" and="" well="" designed="" studies.="" soy="" protein,="" the="" food="" substance="" that="" is="" the="" subject="" of="" the="" claim,="" is="" measured="" in="" those="" studies.="" the="" relationship="" of="" the="" biomarkers="" evaluated--total="" and="" ldl-="" cholesterol--to="" the="" risk="" of="" chd="" is="" validated="" and="" the="" studies="" measured="" the="" biomarkers="" appropriately.="" finally,="" a="" consistent="" body="" of="" evidence="" from="" a="" variety="" of="" studies="" is="" available.="" accordingly,="" the="" agency="" is="" able="" to="" conclude,="" based="" on="" the="" totality="" of="" the="" publicly="" available="" scientific="" evidence,="" that="" there="" is="" significant="" scientific="" agreement="" that="" soy="" protein,="" included="" at="" a="" level="" of="" 25="" g/day="" in="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol,="" can="" help="" reduce="" total="" and="" ldl-cholesterol="" levels,="" and="" that="" such="" reductions="" may="" reduce="" the="" risk="" of="" chd.="" c.="" nature="" of="" the="" food="" eligible="" to="" bear="" the="" claim="" 1.="" the="" qualifying="" amount="" of="" soy="" protein="" 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.,="" one="" racc)="" should="" provide="" \1/4\="" of="" this="" amount="" (based="" on="" four="" 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="" was="" 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).="" the="" agency="" tentatively="" concluded="" in="" the="" soy="" protein="" proposed="" rule="" that="" the="" assumption="" of="" four="" servings="" per="" day="" of="" soy="" protein-containing="" foods="" was="" reasonable.="" therefore,="" the="" agency="" found="" that="" use="" of="" the="" qualifying="" criterion="" set="" forth="" in="" the="" petition="" would="" be="" appropriate="" (63="" fr="" 62977="" at="" 62992).="" most="" comments="" agreed="" that="" the="" qualifying="" level="" of="" 6.25="" g="" soy="" protein="" per="" racc="" was="" appropriate.="" many="" of="" these="" comments="" also="" indicated="" that="" a="" sufficient="" number="" and="" variety="" of="" soy="" protein-containing="" foods="" are="" available="" to="" enable="" consumers="" to="" select="" suitable="" products="" to="" consume="" a="" total="" of="" 25="" g="" soy="" protein="" per="" day.="" (comment="" 41).="" several="" comments="" suggested="" rounding="" the="" qualifying="" level="" to="" 6="" or="" 7="" g="" of="" soy="" protein="" per="" racc,="" in="" keeping="" with="" the="" requirements="" for="" the="" labeling="" of="" protein="" in="" the="" nutrition="" facts="" panel.="" fda,="" however,="" notes="" that="" the="" nutrition="" facts="" panel="" contains="" the="" amount="" of="" total="" protein="" per="" serving="" of="" the="" product,="" regardless="" of="" the="" source="" ingredient.="" for="" many="" products="" that="" may="" bear="" the="" claim,="" soy="" protein="" may="" not="" be="" the="" sole="" contributor="" to="" total="" protein.="" therefore,="" fda="" finds="" that="" the="" amount="" of="" soy="" protein="" in="" a="" serving="" of="" a="" food="" that="" may="" bear="" the="" health="" claim="" will="" neither="" be="" required="" nor="" permitted="" to="" appear="" in="" the="" nutrition="" facts="" panel.="" the="" qualifying="" level="" need="" not="" conform="" to="" requirements="" specific="" to="" the="" nutrition="" facts="" panel.="" (comment="" 42).="" one="" comment="" received="" in="" response="" to="" the="" soy="" protein="" reproposal="" indicated="" that="" food="" processors="" will="" be="" required="" to="" declare="" the="" corrected="" amount="" of="" protein="" and="" the="" percent="" daily="" value="" of="" protein="" on="" the="" nutrition="" facts="" panel,="" in="" accordance="" with="" 21="" cfr="" 101.9(c)(7)(i).="" this="" comment="" noted="" that,="" in="" nearly="" all="" cases,="" the="" amount="" of="" protein="" declared="" will="" be="" lower="" than="" the="" quantity="" of="" protein="" present="" in="" the="" product="" and="" may,="" in="" some="" instances,="" be="" lower="" than="" the="" qualifying="" amount="" of="" soy="" protein.="" fda="" notes="" that="" compliance="" with="" the="" requirements="" of="" this="" regulation="" will="" be="" based="" on="" the="" actual="" amount="" of="" soy="" protein="" present="" in="" the="" food="" and="" not="" on="" the="" amount="" of="" protein="" declared="" on="" the="" nutrition="" label.="" (comment="" 43).="" one="" comment="" suggested="" that="" the="" qualifying="" level="" should="" be="" increased="" to="" 12.5="" g="" soy="" protein="" per="" racc="" because="" of="" concerns="" that="" consumers="" would="" not="" choose="" soy="" protein-containing="" foods="" frequently="" enough="" during="" a="" day="" to="" reach="" a="" total="" of="" 25="" g="" and="" might="" believe="" that="" the="" health="" benefit="" may="" be="" attained="" by="" eating="" a="" single="" serving="" of="" a="" food="" that="" provided="" no="" more="" than="" 6.25="" g="" soy="" protein.="" several="" [[page="" 57714]]="" other="" comments="" also="" raised="" concerns="" that="" consuming="" soy="" protein-="" containing="" foods="" up="" to="" four="" times="" daily="" would="" represent="" a="" significant="" change="" from="" the="" typical="" american="" diet="" that="" might="" not="" be="" selected="" by="" many="" consumers.="" fda="" cannot="" assess="" how="" many="" consumers="" would="" be="" interested="" in="" making="" such="" a="" change,="" but="" it="" is="" persuaded="" that="" it="" will="" be="" feasible="" for="" motivated="" consumers="" to="" do="" so.="" doubling="" the="" qualifying="" level="" of="" soy="" protein="" per="" racc="" would="" greatly="" and="" unnecessarily="" restrict="" the="" number="" of="" foods="" potentially="" eligible="" to="" bear="" the="" health="" claim.="" because="" sec.="" 101.82(c)(2)(i)(g)="" requires="" that="" the="" claim="" specify="" both="" the="" daily="" dietary="" intake="" of="" soy="" protein="" that="" is="" necessary="" to="" reduce="" the="" risk="" of="" coronary="" heart="" disease="" and="" the="" contribution="" that="" one="" serving="" of="" the="" product="" makes="" to="" the="" specified="" daily="" dietary="" intake,="" consumers="" will="" not="" be="" misled="" about="" the="" amount="" of="" soy="" protein="" needed="" for="" the="" health="" effect.="" (comment="" 44).="" a="" number="" of="" comments="" suggested="" that="" greater="" flexibility="" in="" meeting="" the="" recommended="" total="" daily="" intake="" of="" 25="" g="" soy="" protein="" per="" day="" could="" be="" achieved="" by="" permitting="" a="" lower="" qualifying="" level="" on="" the="" basis="" of="" increasing="" the="" number="" of="" servings="" or="" eating="" occasions="" per="" day="" from="" four="" to="" five="" or="" six="" or="" more.="" several="" of="" these="" comments="" proposed="" that="" the="" qualifying="" level="" of="" soy="" protein="" should="" be="" reduced="" to="" 4="" g="" per="" racc;="" one="" suggested="" lowering="" the="" qualifying="" level="" to="" 2.5="" g="" per="" racc.="" most="" of="" these="" comments="" indicated="" that="" 4="" g="" soy="" protein="" per="" racc="" is="" the="" maximum="" amount="" of="" soy="" protein="" from="" soy="" flour="" that="" can="" be="" incorporated="" in="" baked="" products="" that="" consumers="" find="" palatable="" and="" acceptable.="" these="" comments="" suggested="" that="" lowering="" the="" qualifying="" level="" would="" stimulate="" manufacturers="" to="" develop="" a="" wider="" range="" of="" products="" and="" indicated="" that="" use="" of="" isp="" in="" baked="" products="" would="" be="" prohibitively="" expensive.="" one="" comment="" challenged="" fda's="" assertion="" that="" consumers="" would="" be="" able="" to="" consume="" an="" effective="" amount="" of="" soy="" protein="" from="" a="" variety="" of="" products,="" including="" baked="" goods.="" fda="" based="" the="" assertion="" on="" its="" observation="" that="" baked="" products="" had="" been="" used="" to="" provide="" soy="" protein="" in="" some="" studies="" the="" agency="" relied="" upon="" to="" justify="" authorization="" of="" the="" health="" claim="" (refs.="" 27,="" 28,="" and="" 51);="" in="" one="" study="" (ref.="" 27),="" the="" authors="" indicated="" that="" 25="" g="" soy="" protein="" daily="" was="" provided="" in="" four="" muffins.="" isp="" was="" the="" source="" of="" soy="" protein="" in="" the="" baked="" products="" used="" in="" these="" studies.="" some="" comments="" stated="" that="" fda="" need="" not="" base="" the="" qualifying="" level="" on="" four="" eating="" occasions="" per="" day="" as="" the="" agency="" had="" done="" for="" other="" health="" claims="" for="" substances="" (beta-glucan="" soluble="" fiber="" from="" whole="" oats="" and="" soluble="" fiber="" from="" psyllium="" seed="" husks).="" fda="" finds="" that="" these="" comments="" did="" not="" provide="" a="" compelling="" rationale="" for="" selecting="" an="" appropriate="" number="" of="" eating="" occasions="" on="" any="" other="" basis.="" the="" agency="" has="" not="" limited="" its="" previous="" determinations="" of="" an="" appropriate="" qualifying="" level="" of="" a="" substance="" that="" does="" not="" have="" a="" daily="" value="" in="" a="" food="" to="" be="" eligible="" to="" bear="" a="" health="" claim="" to="" consideration="" of="" the="" number="" of="" individual="" foods="" or="" classes="" of="" food="" products="" then="" available="" that="" might="" bear="" the="" claim.="" rather,="" in="" determining="" what="" constitutes="" a="" level="" of="" the="" substance="" sufficiently="" high="" to="" justify="" the="" claim,="" fda="" considers="" factors="" such="" as="" the="" number="" of="" servings="" likely="" to="" be="" consumed="" and="" the="" feasibility="" of="" developing="" a="" variety="" of="" foods="" that="" contain="" a="" significant="" proportion="" of="" the="" total="" daily="" intake="" needed="" for="" the="" claimed="" benefit.="" for="" example,="" when="" the="" psyllium="" claim="" was="" authorized,="" fda="" was="" aware="" of="" only="" one="" conventional="" food="" product="" that="" would="" have="" been="" eligible="" to="" bear="" the="" claim="" and="" concluded="" that,="" if="" various="" psyllium-containing="" foods="" were="" available,="" consumption="" of="" four="" servings="" daily="" could="" be="" achieved.="" based="" on="" experience="" with="" that="" claim="" and="" other="" health="" claims,="" fda="" believes="" that="" manufacturers="" will="" be="" encouraged="" by="" the="" availability="" of="" a="" health="" claim="" for="" soy="" protein="" and="" chd="" to="" develop="" new="" products="" that="" will="" be="" eligible="" to="" bear="" the="" claim.="" the="" agency="" is="" not="" persuaded="" by="" the="" comments="" received="" that="" it="" should="" abandon="" its="" assumption="" that="" a="" daily="" food="" consumption="" pattern="" includes="" three="" meals="" and="" a="" snack="" (see="" 58="" fr="" 2302="" at="" 2379,="" january="" 6,="" 1993)="" and="" that="" one="" serving="" of="" a="" soy="" protein-containing="" product="" could="" reasonably="" be="" consumed="" at="" each="" eating="" occasion.="" as="" noted="" in="" the="" discussion="" above="" of="" the="" comments="" that="" expressed="" concerns="" about="" the="" willingness="" of="" consumers="" to="" select="" soy="" protein-containing="" foods="" as="" many="" as="" four="" times="" a="" day,="" such="" an="" eating="" pattern="" represents="" a="" considerable="" change="" from="" a="" typical="" american="" diet.="" although="" one="" of="" the="" comments="" included="" detailed="" menus="" that="" illustrated="" the="" possibility="" of="" consuming="" more="" than="" one="" soy="" protein-containing="" product="" per="" eating="" occasion,="" fda="" has="" concluded="" that="" it="" should="" not="" lower="" the="" amount="" of="" soy="" protein="" required="" for="" a="" food="" to="" be="" eligible="" to="" bear="" the="" health="" claim.="" (comment="" 45).="" one="" comment="" suggested="" that="" the="" amount="" of="" soy="" protein="" required="" for="" eligibility="" to="" bear="" the="" health="" claim="" be="" permitted="" to="" be="" determined="" on="" the="" basis="" of="" serving="" size="" as="" well="" as="" racc.="" this="" comment="" is="" outside="" the="" scope="" of="" this="" rulemaking.="" current="" regulations="" (21="" cfr="" 101.12(g))="" require="" that,="" ``the="" reference="" amount="" [i.e.,="" the="" reference="" amount="" customarily="" consumed]="" *="" *="" *="" shall="" be="" used="" in="" determining="" whether="" a="" product="" meets="" the="" criteria="" *="" *="" *="" for="" health="" claims.''="" in="" a="" previous="" rulemaking,="" fda="" had="" considered="" permitting="" this="" option,="" but="" comments="" persuaded="" the="" agency="" that="" the="" most="" reasonable="" approach="" was="" to="" base="" claim="" evaluations="" on="" the="" reference="" amount="" (58="" fr="" 2229="" at="" 2287).="" fda="" agreed="" with="" the="" comments="" that="" claims="" should="" reflect="" the="" true="" characteristics="" of="" a="" product,="" and="" that="" those="" characteristics="" do="" not="" change="" if="" the="" product="" is="" packaged="" in="" a="" different="" size="" container.="" the="" comment="" received="" in="" response="" to="" the="" soy="" protein="" proposed="" rule="" did="" not="" provide="" a="" convincing="" rationale="" to="" justify="" a="" change="" in="" this="" decision.="" 2.="" method="" for="" determining="" qualifying="" amount="" of="" soy="" protein="" in="" foods="" in="" the="" soy="" protein="" proposed="" rule="" (63="" fr="" 62977="" at="" 62992),="" fda="" proposed="" use="" of="" the="" association="" of="" official="" analytical="" chemists="" (aoac)="" official="" method="" of="" analysis="" no.="" 988.10="" to="" measure="" soy="" protein="" in="" foods.="" as="" described="" in="" the="" soy="" protein="" reproposal="" (64="" fr="" 45932="" at="" 45933),="" each="" of="" the="" comments="" on="" this="" proposed="" analytical="" method="" disagreed="" with="" its="" use="" and="" concluded="" that="" the="" method="" was="" unlikely="" to="" produce="" a="" reliable="" measure="" of="" the="" soy="" protein="" content="" in="" every="" food.="" the="" comments="" noted="" a="" variety="" of="" problems="" with="" the="" assay.="" these="" comments="" persuaded="" the="" agency="" that="" aoac="" official="" method="" of="" analysis="" no.="" 988.10="" was="" not="" an="" appropriate="" method="" for="" the="" quantitation="" of="" soy="" protein="" in="" many="" of="" the="" products="" that="" may="" be="" eligible="" to="" bear="" the="" health="" claim.="" in="" the="" soy="" protein="" reproposal,="" fda="" discussed="" the="" alternative="" approaches="" suggested="" in="" comments="" for="" assessing="" compliance="" with="" the="" qualifying="" level="" of="" soy="" protein="" in="" products="" that="" bear="" the="" health="" claim.="" based="" on="" this="" information,="" the="" agency="" provided="" its="" tentative="" rationale="" for="" a="" procedure="" employing="" measurement="" of="" total="" protein="" and,="" for="" products="" containing="" sources="" of="" protein="" other="" than="" soy,="" calculation="" of="" the="" soy="" protein="" content="" based="" on="" information="" contained="" in="" manufacturers'="" records="" (64="" fr="" 45932="" at="" 45934).="" thus,="" in="" the="" soy="" protein="" reproposal,="" fda="" modified="" previously="" proposed="" sec.="" 101.82(c)(2)(ii)(b)="" to="" provide="" for="" this="" alternative="" approach="" for="" compliance="" assessment="" that="" relied,="" in="" some="" cases,="" on="" records="" that="" the="" agency="" could="" inspect.="" the="" agency="" received="" approximately="" 10="" comments="" in="" response="" to="" the="" soy="" protein="" reproposal.="" one="" of="" the="" comments="" did="" not="" address="" the="" proposed="" [[page="" 57715]]="" procedure="" for="" compliance="" assessment="" but,="" rather,="" reiterated="" concerns="" raised="" in="" comments="" on="" the="" soy="" protein="" proposed="" rule="" about="" the="" safety="" of="" soy="" isoflavones.="" among="" the="" materials="" it="" referenced="" were="" two="" documents="" authored="" by="" fda="" staff="" that="" the="" comment="" characterized="" as="" ``reports.''="" fda="" could="" not="" identify="" one="" of="" these="" documents="" from="" the="" citation="" given="" and="" the="" other="" was="" a="" letter="" submitted="" as="" a="" comment="" to="" docket="" 98p-0683="" in="" response="" to="" the="" soy="" protein="" proposed="" rule.="" another="" comment="" raised="" concerns="" about="" the="" gras="" status="" of="" soy="" protein.="" fda="" has="" addressed="" the="" issues="" raised="" in="" the="" earlier="" comments="" regarding="" gras="" status="" and="" safety="" in="" section="" ii.a="" of="" this="" document.="" in="" addition="" to="" commenting="" about="" the="" reproposal,="" one="" comment="" raised="" a="" technical="" issue="" about="" the="" nutrition="" labeling="" declaration="" of="" protein="" that="" is="" addressed="" in="" section="" ii.c.1.="" (comment="" 46).="" two="" comments="" objected="" to="" the="" 30-day="" comment="" period="" allowed="" for="" the="" soy="" protein="" reproposal.="" fda="" stated="" its="" rationale="" and="" authority="" for="" selecting="" this="" period="" in="" the="" soy="" protein="" reproposal="" (64="" fr="" 45932="" at="" 45936="" and="" 45937)="" and="" notes="" that="" these="" comments="" were="" submitted="" and="" received="" in="" timely="" fashion.="" one="" of="" these="" comments="" asserted="" that="" after="" the="" comment="" period="" for="" the="" soy="" protein="" proposed="" rule="" had="" passed,="" no="" new="" submissions="" or="" evidence="" after="" that="" date="" other="" than="" that="" of="" fda="" origin="" (or="" from="" published="" scientific="" documents="" accessed="" by="" fda)="" was="" acceptable.="" as="" noted="" in="" the="" introduction="" of="" section="" ii="" of="" this="" document,="" fda="" disagrees="" with="" this="" assertion.="" fda="" considered="" comments="" received="" after="" the="" initial="" comment="" period,="" regardless="" of="" source,="" to="" the="" extent="" that="" each="" provided="" complete="" information="" for="" review="" or="" references="" accessible="" to="" the="" agency="" and="" addressed="" issues="" not="" raised="" in="" earlier="" comments.="" (comment="" 47).="" a="" comment="" asserted="" that="" the="" issue="" of="" the="" method="" fda="" will="" use="" to="" verify="" that="" foods="" contain="" the="" qualifying="" amount="" of="" soy="" protein="" is="" irrelevant="" because="" fda="" was="" required="" to="" consider="" and="" evaluate="" only="" the="" claims="" made="" for="" the="" substance="" identified="" in="" the="" petition,="" soy="" protein="" with="" naturally="" occurring="" isoflavones.="" this="" comment="" misunderstands="" fda's="" responsibility="" to="" review="" and="" evaluate="" the="" available="" scientific="" evidence="" and="" reach="" appropriately="" supported="" conclusions="" about="" the="" substance-disease="" relationship="" based="" on="" information="" provided="" in="" the="" petition,="" accessed="" in="" the="" public="" scientific="" literature,="" and="" received="" in="" comments.="" fda="" notes,="" for="" example,="" that="" in="" response="" to="" a="" petition="" for="" oat="" bran="" and="" oatmeal,="" it="" proposed="" to="" authorize="" a="" health="" claim="" on="" the="" relationship="" of="" those="" foods="" and="" chd="" (61="" fr="" 296).="" comments="" received="" in="" response="" to="" that="" proposal="" persuaded="" fda="" to="" change="" the="" substance="" of="" its="" final="" rule="" to="" beta-glucan="" soluble="" fiber="" from="" whole="" oats="" (62="" fr="" 3584).="" the="" agency="" has="" addressed="" the="" earlier="" comments="" on="" the="" role="" of="" isoflavones="" in="" the="" hypocholesterolemic="" effect="" of="" soy="" protein="" in="" section="" ii.b.3="" of="" this="" document.="" (comment="" 48).="" two="" comments="" objected="" to="" any="" use="" of="" recordkeeping="" for="" compliance="" assessment,="" questioning="" whether="" it="" could="" be="" an="" appropriate="" substitute="" for="" analytical="" methods="" to="" assess="" the="" truthfulness="" of="" health="" claims.="" one="" of="" these="" comments="" also="" reiterated="" objections="" to="" authorization="" of="" the="" health="" claim,="" because="" of="" concerns="" about="" incomplete="" scientific="" understanding="" of="" the="" biological="" activity="" of="" soy="" components,="" in="" terms="" of="" both="" safety="" and="" contribution="" to="" the="" protective="" effect="" of="" soy="" protein="" in="" chd.="" the="" agency="" has="" addressed="" these="" concerns,="" which="" were="" raised="" in="" comments="" on="" the="" soy="" protein="" proposed="" rule,="" in="" sections="" ii.a="" and="" ii.b.3,="" respectively,="" of="" this="" document.="" the="" other="" comment="" asserted="" that="" an="" approved,="" scientifically="" accurate="" methodology="" is="" needed="" for="" any="" health="" claim.="" however,="" it="" also="" indicated="" that="" fda="" should="" finalize="" its="" regulation="" as="" originally="" proposed,="" but="" did="" not="" propose="" an="" alternative="" for="" compliance="" verification="" other="" than="" suggesting="" that="" a="" manufacturer="" might="" voluntarily="" share="" analytical="" data="" with="" the="" agency="" if="" questions="" about="" compliance="" were="" raised.="" fda="" does="" not="" agree="" with="" the="" contention="" that="" an="" analytical="" method="" is="" an="" absolute="" requirement="" for="" a="" health="" claim,="" even="" though="" it="" is="" the="" preferred="" means="" for="" verifying="" compliance="" with="" the="" requirements="" of="" a="" health="" claim="" regulation="" and="" substantiating="" the="" truthfulness="" of="" all="" label="" statements.="" (comment="" 49).="" many="" other="" comments="" supported="" continued="" work="" to="" develop="" appropriate="" analytical="" methodology="" for="" measuring="" the="" content="" of="" soy="" protein="" in="" foods,="" and="" urged="" fda,="" in="" collaboration="" with="" other="" government="" agencies,="" industry,="" and="" scientific="" organizations,="" to="" pursue="" this="" effort.="" as="" noted="" in="" the="" soy="" protein="" reproposal,="" fda="" intends="" to="" do="" so,="" to="" the="" extent="" that="" resources="" permit.="" also,="" as="" noted="" in="" the="" soy="" protein="" reproposal,="" and="" as="" urged="" in="" a="" number="" of="" comments,="" fda="" would="" propose="" to="" amend="" its="" regulation="" to="" provide="" for="" compliance="" verification="" based="" on="" one="" or="" more="" analytical="" methodologies="" when="" such="" methods="" have="" been="" validated.="" (comment="" 50).="" several="" of="" the="" comments="" specifically="" addressed="" the="" method="" for="" assessing="" compliance="" set="" out="" in="" the="" soy="" protein="" reproposal.="" none="" of="" these="" comments="" objected="" to="" use="" of="" an="" analytical="" method="" for="" measuring="" total="" protein="" as="" a="" measure="" of="" soy="" protein="" in="" foods="" that="" contain="" soy="" as="" the="" only="" source="" of="" protein.="" absent="" an="" appropriate="" analytical="" methodology,="" each="" of="" these="" comments="" supported="" the="" need="" for="" manufacturers="" to="" have="" and="" keep="" records="" to="" substantiate="" the="" amount="" of="" soy="" protein="" in="" a="" food="" that="" bears="" the="" health="" claim="" and="" contains="" sources="" of="" protein="" other="" than="" soy,="" and="" to="" make="" such="" records="" available="" to="" appropriate="" regulatory="" officials="" upon="" request.="" these="" comments="" noted="" that="" in="" cases="" where="" records="" are="" needed="" to="" substantiate="" label="" claims,="" food="" manufacturers="" have="" historically="" provided="" such="" records="" voluntarily="" upon="" request="" to="" the="" fda="" and="" could="" be="" expected="" to="" continue="" to="" do="" so="" in="" the="" future.="" they="" argued="" that="" fda="" need="" not="" assert="" broad="" records="" inspection="" authority="" in="" order="" to="" obtain="" the="" information="" needed="" for="" compliance="" assessment.="" they="" noted="" 21="" cfr="" 101.13(j)(ii)(a),="" which="" requires="" firms="" to="" have="" substantiation="" for="" the="" basis="" of="" nutrient="" reference="" values="" in="" comparative="" nutrient="" content="" claims="" and="" to="" make="" such="" substantiation="" available="" to="" appropriate="" regulatory="" officials="" upon="" request,="" as="" a="" model="" for="" requests="" of="" records.="" fda="" agrees="" that="" a="" manufacturer="" must="" have="" substantiation="" that="" a="" qualifying="" amount="" of="" soy="" protein="" is="" present="" in="" a="" product="" that="" bears="" the="" health="" claim="" and="" that="" such="" records="" can="" serve="" as="" the="" basis="" for="" substantiation="" of="" use="" of="" the="" health="" claim.="" fda="" noted="" in="" the="" federal="" register="" of="" february="" 2,="" 1996="" (61="" fr="" 3885="" at="" 3886)="" several="" examples="" of="" regulations="" that="" implemented="" the="" 1990="" amendments="" in="" which="" the="" agency="" could="" not="" independently,="" using="" analytical="" methodology,="" verify="" the="" basis="" for="" statements="" on="" the="" food="" label,="" but="" instead="" would="" rely="" on="" access="" to="" a="" manufacturers'="" information="" supporting="" its="" labeling="" claims.="" these="" include="" access="" to:="" (1)="" a="" detailed="" protocol="" and="" records="" of="" all="" data="" used="" to="" derive="" a="" density-adjusted="" reference="" amount="" for="" aerated="" foods="" (58="" fr="" 2229="" at="" 2272="" and="" sec.="" 101.12(e));="" (2)="" information="" that="" provides="" the="" basis="" for="" deriving="" reference="" nutrient="" values="" for="" comparative="" nutrient="" content="" claims="" such="" as="" ``light''="" (58="" fr="" 2302="" at="" 2365="" and="" sec.="" 101.13(j)(1)(ii)(a));="" (3)="" specific="" information="" with="" respect="" to="" the="" caloric="" content="" of="" new="" products="" with="" reduced="" digestibility="" (58="" fr="" 2079="" at="" 2087="" and="" 2111="" and="" sec.="" 101.9(c)(1)(i)(d));="" and="" (4)="" information="" supporting="" nutrient="" content="" claims="" for="" restaurant="" foods="" (58="" fr="" 2302="" at="" 2388="" and="" sec.="" 101.13(q)(5)(ii)).="" [[page="" 57716]]="" in="" each="" of="" these="" cases,="" verification="" of="" the="" truthfulness="" of="" a="" label="" claim="" can="" be="" assessed="" by="" fda="" only="" with="" access="" to="" information="" known="" only="" by="" the="" manufacturer.="" the="" same="" is="" true,="" in="" the="" absence="" of="" a="" validated="" analytical="" method="" to="" measure="" the="" amount="" of="" soy="" protein="" in="" the="" presence="" of="" other="" proteins,="" for="" verifying="" that="" the="" qualifying="" amount="" of="" soy="" protein="" to="" bear="" the="" health="" claim="" is="" present="" in="" a="" food="" that="" contains="" sources="" of="" protein="" in="" addition="" to="" soy.="" thus,="" the="" agency="" concludes,="" in="" agreement="" with="" these="" comments,="" that="" it="" is="" appropriate="" to="" require="" access="" to="" manufacturers'="" records="" substantiating="" the="" ratio="" of="" soy="" protein="" to="" total="" protein="" for="" foods="" that="" contain="" sources="" of="" protein="" in="" addition="" to="" soy="" to="" assess="" their="" compliance="" with="" this="" regulation.="" also,="" in="" agreement="" with="" these="" comments,="" the="" agency="" concludes="" that="" it="" need="" not="" assert="" broad="" records="" inspection="" authority="" to="" have="" access="" to="" appropriate="" records.="" the="" agency="" disagrees,="" however,="" with="" comments="" that="" indicate="" that="" reliance="" on="" the="" voluntary="" provision="" of="" records="" by="" manufacturers="" is="" sufficient="" to="" meet="" the="" agency's="" need="" to="" verify="" compliance.="" rather,="" the="" agency="" is="" taking="" the="" approach="" of="" codifying="" a="" requirement="" for="" the="" manufacturer="" to="" provide="" appropriate="" records,="" on="" request,="" as="" the="" agency="" has="" done="" previously.="" although="" most="" of="" the="" comments="" supported="" the="" use="" of="" records,="" in="" principle,="" for="" compliance="" assessment,="" they="" also="" raised="" concerns="" about="" the="" types="" of="" records="" that="" fda="" might="" request,="" the="" circumstances="" under="" which="" fda="" would="" request="" records,="" and="" the="" legal="" authority="" of="" the="" fda="" to="" require="" records="" and="" records="" inspection.="" (comment="" 51).="" several="" comments="" indicated="" that="" fda="" had="" used="" overly="" broad="" and="" imprecise="" language="" in="" the="" soy="" protein="" reproprosal="" to="" describe="" the="" types="" of="" records="" that="" fda="" would="" request.="" they="" indicated="" that="" a="" manufacturer="" is="" best="" able="" to="" determine="" the="" nature="" of="" the="" records="" that="" would="" be="" needed="" to="" substantiate="" the="" amount="" of="" soy="" protein="" in="" its="" own="" products="" and="" urged="" that="" manufacturers="" be="" allowed="" the="" flexibility="" to="" determine="" how="" to="" document="" substantiation.="" one="" comment="" argued="" that="" a="" recipe-based="" system="" would="" be="" too="" complex="" and="" burdensome="" for="" baked="" goods="" in="" particular.="" other="" comments="" expressed="" concern="" that="" fda="" would,="" in="" all="" cases,="" require="" inspection="" of="" a="" wide="" variety="" of="" records,="" including="" nutrient="" data="" bases="" or="" analyses,="" recipes="" or="" formulations,="" purchase="" orders="" for="" ingredients,="" and="" others.="" fda="" agrees="" that="" the="" manufacturer="" will="" be="" in="" the="" best="" position="" to="" know="" which="" of="" its="" records="" provide="" documentation="" of="" the="" amount="" of="" soy="" protein="" in="" its="" products,="" and="" specifically="" the="" ratio="" of="" soy="" protein="" to="" total="" protein.="" by="" listing="" the="" types="" of="" records="" that="" could="" provide="" such="" documentation="" in="" the="" soy="" protein="" reproposal,="" fda="" did="" not="" intend="" to="" indicate="" that="" it="" would="" request="" all="" of="" these="" records="" and="" subject="" them="" to="" inspection,="" or="" even="" that="" it="" would="" specify="" any="" particular="" records="" when="" it="" requests="" them.="" instead,="" fda="" intended="" to="" suggest="" the="" types="" of="" records="" a="" manufacturer="" might="" use="" to="" substantiate="" the="" levels="" of="" soy="" protein="" in="" its="" foods.="" accordingly,="" fda="" has="" modified="" sec.="" 182(c)(2)(ii)(b)="" to="" clarify="" that="" the="" manufacturer="" is="" to="" identify="" these="" materials.="" (comment="" 52).="" one="" comment="" questioned="" whether="" fda="" might="" request="" records="" for="" products="" in="" which="" soy="" is="" the="" only="" source="" of="" protein="" and="" urged="" fda="" to="" specify="" that="" it="" would="" not="" request="" records="" for="" such="" products.="" fda="" agrees="" that,="" because="" measurement="" of="" total="" protein="" provides="" adequate="" assessment="" of="" compliance="" for="" products="" in="" which="" soy="" is="" the="" sole="" source="" of="" protein,="" that="" it="" would="" not,="" under="" the="" regulation,="" request="" records="" for="" substantiation="" of="" the="" amount="" of="" soy="" protein="" in="" such="" products.="" the="" agency="" believes="" that="" the="" proposed="" language="" adequately="" communicates="" this="" point="" and="" has="" made="" no="" changes="" to="" the="" regulatory="" language="" in="" response="" to="" this="" comment.="" (comment="" 53).="" one="" comment="" requested="" that="" fda="" identify="" what="" circumstances="" would="" precipitate="" a="" request="" for="" records.="" although="" fda="" cannot="" specify="" all="" such="" circumstances,="" it="" notes,="" as="" did="" another="" of="" the="" comments,="" that="" a="" substantial="" proportion="" of="" its="" enforcement="" actions="" are="" undertaken="" in="" response="" to="" trade="" complaints.="" (comment="" 54).="" one="" comment="" asked="" that="" the="" agency="" specify="" that="" any="" records="" requested="" could="" be="" provided="" on="" site="" without="" the="" need="" for="" reproduction="" or="" duplication="" by="" the="" investigator.="" another="" comment,="" however,="" objected="" to="" fda="" making="" requests="" for="" information="" on="" site,="" arguing="" that="" most="" companies="" would="" have="" the="" necessary="" information="" at="" headquarters="" rather="" than="" at="" production="" facilities.="" this="" comment="" urged="" that="" fda="" make="" any="" such="" requests="" in="" writing="" and="" allow="" the="" manufacturers="" to="" provide="" appropriate="" substantiation="" within="" a="" reasonable="" period="" of="" time.="" as="" fda="" will="" not="" require="" inspection="" of="" records="" on="" site,="" the="" concern="" about="" reproduction="" or="" duplication="" is="" moot.="" fda="" agrees="" that="" making="" a="" request="" for="" records="" in="" writing="" is="" appropriate="" and="" has="" modified="" the="" regulation="" accordingly.="" (comment="" 55).="" some="" comments="" objected="" to="" the="" alternative="" offered="" in="" the="" soy="" protein="" reproposal="" that="" fda="" would="" authorize="" the="" claim="" only="" for="" products="" that="" contain="" soy="" as="" the="" sole="" source="" of="" protein,="" if="" it="" could="" not="" proceed="" with="" a="" regulation="" to="" provide="" access="" to="" records="" for="" compliance="" verification.="" these="" comments="" noted="" that="" such="" an="" action="" would="" give="" unfair="" advantage="" to="" certain="" products,="" unfairly="" penalize="" products="" that="" were="" equally="" beneficial,="" and="" dilute="" the="" potential="" benefit="" of="" the="" health="" claim="" to="" consumers.="" because="" the="" agency="" has="" authorized="" the="" claim="" for="" any="" food="" that="" contains="" adequate="" amounts="" of="" soy="" protein,="" without="" regard="" to="" other="" sources="" of="" protein,="" these="" comments="" are="" moot.="" (comment="" 56).="" one="" comment="" noted="" that,="" in="" addition="" to="" providing="" fda,="" upon="" request,="" information="" regarding="" substantiation="" of="" the="" claim,="" food="" processors="" may,="" on="" a="" voluntary="" basis,="" present="" information="" on="" the="" food="" label="" or="" in="" labeling="" that="" may="" support="" the="" eligibility="" of="" the="" product="" to="" bear="" the="" claim="" and="" facilitate="" an="" fda="" compliance="" review.="" such="" information="" might="" take="" the="" form="" of="" statements="" about="" the="" percentage="" composition="" of="" soy="" protein="" in="" a="" serving="" of="" food.="" the="" agency="" agrees="" that="" manufacturers="" may="" voluntarily="" provide="" such="" truthful="" and="" not="" misleading="" information="" and="" that="" the="" provision="" of="" such="" information="" may="" aid="" consumer="" understanding="" of="" the="" claim.="" (comment="" 57).="" several="" of="" the="" comments="" strongly="" objected="" to="" the="" proposal="" for="" records="" inspection="" on="" the="" basis="" that="" fda="" lacks="" the="" statutory="" authority="" to="" require="" access="" to="" records="" for="" foods.="" another="" comment="" argued="" that,="" once="" the="" agency="" determined="" that="" a="" substance-="" disease="" relationship="" meets="" the="" standard="" of="" significant="" scientific="" agreement,="" the="" act="" requires="" the="" agency="" to="" authorize="" a="" claim,="" and="" the="" agency="" may="" not="" require="" that="" manufacturers="" maintain="" records="" or="" that="" fda="" be="" able="" to="" request="" or="" inspect="" them.="" this="" comment="" also="" asserted="" that,="" were="" fda="" to="" require="" recordkeeping,="" record="" production,="" or="" records="" inspection,="" it="" would="" violate="" the="" first="" amendment="" by="" conditioning="" the="" exercise="" of="" speech="" rights="" on="" the="" recordkeeping,="" record="" production,="" or="" records="" inspection="" requirement.="" fda="" disagrees="" with="" these="" comments.="" other="" comments="" have="" convinced="" the="" agency="" that,="" in="" this="" instance,="" it="" need="" not="" assert="" its="" rulemaking="" authority="" to="" provide="" for="" inspection="" of="" records.="" this="" issue="" is="" therefore="" moot.="" the="" agency="" maintains,="" however,="" that="" it="" has="" the="" legal="" authority,="" using="" section="" 701(a)="" of="" the="" act,="" to="" promulgate="" record="" inspection="" requirements="" for="" the="" efficient="" enforcement="" of="" the="" act.="" the="" requirements="" that="" records="" be="" maintained="" and="" submitted="" to="" the="" agency="" upon="" request="" pass="" the="" test="" in="" national="" confectioners="" association="" v.="" califano,="" 569="" f.2d="" 690,="" 693="" &="" n.9="" (d.c.="" cir.="" 1979).="" first,="" these="" requirements="" are="" limited="" to="" those="" records="" that="" the="" manufacturer="" [[page="" 57717]]="" reasonably="" determines="" substantiate="" the="" level="" of="" soy="" protein="" in="" its="" food,="" and="" only="" with="" respect="" to="" foods="" that="" contain="" a="" source="" of="" protein="" in="" addition="" to="" soy.="" second,="" the="" requirements="" assist="" in="" the="" efficient="" enforcement="" of="" the="" act.="" they="" focus="" only="" on="" those="" foods="" for="" which="" an="" adequate="" analytical="" method="" is="" not="" available.="" they="" allow="" fda="" to="" verify="" that="" the="" authorized="" soy="" health="" claim="" is="" truthful="" and="" not="" misleading="" when="" it="" is="" used="" on="" such="" foods.="" the="" requirements,="" therefore,="" assist="" in="" the="" effective="" and="" efficient="" enforcement="" of="" the="" act.="" third,="" these="" requirements="" are="" not="" unduly="" burdensome.="" they="" require="" maintenance="" of="" records="" that="" manufacturers="" should="" already="" have="" to="" validate="" that="" their="" food="" product="" may="" lawfully="" bear="" the="" claim,="" and="" they="" permit="" them="" to="" identify="" the="" records="" that="" substantiate="" their="" claim.="" fda="" requests="" copies="" of="" the="" records="" in="" writing="" without="" inspection.="" these="" burdens="" are="" not="" unreasonably="" onerous.="" with="" respect="" to="" significant="" scientific="" agreement,="" the="" comment="" misreads="" the="" statute.="" under="" section="" 403(r)(3)(b)(i)="" of="" the="" act,="" fda="" authorizes="" a="" claim="" about="" a="" substance-disease="" relationship="" only="" if="" the="" standard="" of="" significant="" scientific="" agreement="" is="" met.="" under="" that="" section,="" significant="" scientific="" agreement="" is="" a="" necessary="" condition,="" but="" not="" a="" sufficient="" one,="" for="" fda="" to="" authorize="" a="" health="" claim.="" fda="" may="" impose="" other="" requirements="" in="" accordance="" with="" section="" 403(r)="" of="" the="" act.="" the="" agency="" also="" disagrees="" that="" the="" recordkeeping="" and="" record="" access="" provisions="" violate="" the="" first="" amendment.="" under="" section="" 201(g)(1)="" of="" the="" act,="" a="" food="" is="" not="" a="" drug="" solely="" because="" its="" labeling="" contains="" a="" health="" claim="" authorized="" and="" made="" in="" accordance="" with="" the="" requirements="" of="" section="" 403(r)="" of="" the="" act.="" section="" 201(g)(1)="" provides="" no="" such="" provision="" for="" a="" food="" whose="" labeling="" contains="" a="" health="" claim="" that="" is="" not="" authorized="" and="" made="" in="" accordance="" with="" the="" requirements="" of="" section="" 403(r)="" of="" the="" act.="" congress="" provided="" for="" the="" use="" on="" foods="" of="" health="" claims="" authorized="" under="" and="" made="" in="" accordance="" with="" the="" requirements="" of="" section="" 403(r)="" of="" the="" act="" to="" promote="" the="" public="" health="" by,="" in="" part,="" helping="" consumers="" maintain="" balanced="" and="" healthful="" diets="" (58="" fr="" at="" 2514).="" fda="" has="" required="" that="" foods="" whose="" labels="" contain="" an="" authorized="" health="" claim="" must="" contain="" a="" sufficiently="" high="" level="" of="" the="" substance="" that="" is="" the="" subject="" of="" the="" claim="" in="" question="" (see="" 21="" cfr="" 101.14(d)(2)(vii)).="" this="" provision="" assures="" that="" a="" food="" bearing="" the="" claim="" in="" fact="" contributes="" to="" the="" claimed="" effect="" (56="" fr="" at="" 60553)="" and="" so="" may="" help="" consumers="" to="" maintain="" a="" balanced="" and="" healthful="" diet.="" absent="" the="" recordkeeping="" and="" access="" provisions,="" fda="" could="" not="" assure="" that,="" when="" the="" soy="" protein="" health="" claim="" appears="" on="" foods,="" they="" will,="" in="" fact,="" contain="" sufficiently="" high="" levels="" of="" soy="" protein.="" these="" provisions,="" therefore,="" directly="" advance="" congress'="" substantial="" interest="" in="" permitting="" the="" use="" of="" health="" claims="" on="" foods="" and="" they="" are="" narrowly="" tailored="" to="" do="" so.="" in="" addition,="" when="" used="" on="" a="" food,="" the="" authorized="" soy="" protein="" health="" claim="" must="" identify="" the="" amount="" of="" soy="" protein="" in="" a="" serving="" of="" food.="" accordingly,="" the="" provisions="" also="" permit="" fda="" to="" assure="" that="" the="" claim="" as="" it="" appears="" on="" a="" food="" is="" not="" false="" and="" misleading.="" 3.="" requirement="" that="" food="" meets="" the="" criterion="" for="" low="" fat="" in="" sec.="" 101.82(c)(2)(iii)(b),="" the="" agency="" proposed,="" consistent="" with="" other="" authorized="" heart="" disease="" health="" claims,="" that="" foods="" bearing="" the="" health="" claim="" meet="" the="" requirements="" for="" ``low="" saturated="" fat,''="" ``low="" cholesterol,''="" and="" ``low="" fat.''="" in="" the="" preamble="" to="" the="" final="" rule="" authorizing="" the="" fruits,="" vegetables,="" and="" grain="" products="" and="" heart="" disease="" claim="" (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="" saturated="" fat/="" cholesterol="" proposed="" rule="" (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="" concluded="" that="" proposed="" sec.="" 101.82(c)(2)(iii)(b)="" set="" forth="" appropriate="" requirements="" for="" foods="" to="" be="" eligible="" to="" bear="" the="" soy="" protein="" and="" chd="" claim.="" (comment="" 58).="" no="" comments="" objected="" to="" the="" requirements="" that="" a="" food="" meet="" the="" criteria="" for="" ``low="" saturated="" fat''="" and="" ``low="" cholesterol''="" in="" order="" to="" bear="" a="" health="" claim="" about="" the="" relationship="" of="" soy="" protein="" and="" chd.="" however,="" many="" comments="" objected="" to="" the="" requirement="" that="" a="" food="" meet="" the="" criterion="" for="" ``low="" fat,''="" mainly="" on="" the="" basis="" that="" all="" foods="" made="" from="" whole="" soybeans="" would="" be="" disqualified="" by="" virtue="" of="" the="" inherent="" ratio="" of="" protein="" to="" fat="" (approximately="" 2="" to="" 1)="" in="" soybeans.="" several="" of="" these="" comments="" noted="" that="" makers="" of="" such="" foods="" would="" have="" to="" use="" soy="" protein="" isolates="" to="" develop="" qualifying="" products.="" the="" comments="" that="" provided="" additional="" rationale="" argued="" that="" saturated="" fat="" and="" cholesterol="" were="" properly="" restricted="" for="" a="" chd="" claim,="" but="" that="" total="" fat="" need="" not="" be="" restricted="" to="" the="" same="" degree="" because="" it="" is="" not="" directly="" related="" to="" risk="" of="" chd.="" these="" comments="" noted="" that="" products="" derived="" from="" whole="" soybeans="" that="" contain="" 6.25="" g="" of="" protein="" per="" racc="" would="" just="" exceed="" the="" criterion="" for="" ``low="" fat''="" of="" 3="" g="" fat="" per="" racc.="" however,="" these="" products="" would="" not="" lead="" to="" an="" increase="" in="" the="" intake="" of="" saturated="" fat="" or="" cholesterol="" and,="" thus,="" negate="" the="" health="" benefits="" of="" soy="" protein.="" in="" addition,="" they="" would="" serve="" as="" sources="" of="" the="" essential="" fatty="" acids,="" linoleic="" acid="" and="" linolenic="" acid.="" as="" noted="" above,="" the="" fda="" has="" required="" that="" foods="" bearing="" any="" of="" the="" previously="" authorized="" chd="" health="" claims="" meet="" the="" requirements="" for="" ``low="" saturated="" fat,''="" ``low="" cholesterol,''="" and="" ``low="" fat.''="" in="" the="" saturated="" fat/cholesterol="" proposed="" rule,="" fda="" proposed="" that="" in="" order="" for="" a="" food="" to="" bear="" the="" health="" claim,="" the="" food="" must="" also="" meet="" the="" requirements="" for="" a="" ``low''="" claim="" relative="" to="" total="" fat="" content="" (56="" fr="" 60727="" at="" 60739).="" the="" agency="" noted="" that,="" while="" total="" fat="" is="" not="" directly="" related="" to="" increased="" risk="" for="" chd,="" it="" may="" have="" significant="" indirect="" effects.="" low="" fat="" diets="" facilitate="" reductions="" in="" the="" intake="" of="" saturated="" fat="" and="" cholesterol="" to="" recommended="" levels.="" furthermore,="" the="" agency="" noted="" that="" obesity="" is="" a="" major="" risk="" factor="" for="" chd,="" and="" dietary="" fats,="" which="" have="" more="" than="" twice="" as="" many="" calories="" per="" gram="" as="" proteins="" and="" carbohydrates,="" are="" major="" contributors="" to="" total="" calorie="" intakes.="" for="" many="" adults,="" maintenance="" of="" desirable="" body="" weight="" is="" more="" readily="" achieved="" with="" moderation="" of="" intake="" of="" total="" fat.="" the="" agency="" also="" concluded="" that="" this="" approach="" would="" be="" most="" consistent="" with="" the="" u.s.="" dietary="" guidelines="" and="" other="" dietary="" guidance="" that="" recommends="" diets="" low="" in="" saturated="" fat,="" total="" fat,="" and="" cholesterol.="" in="" the="" saturated="" fat/cholesterol="" final="" rule="" (58="" fr="" 2739="" at="" 2742),="" fda="" reiterated="" the="" requirement="" for="" ``low="" fat,''="" but="" allowed="" for="" the="" exception="" that="" fish="" and="" game="" meats="" could="" meet="" the="" requirement="" for="" ``extra="" lean,''="" because="" these="" foods="" are="" appropriately="" included="" in="" a="" diet="" low="" in="" fat,="" saturated="" fat,="" and="" cholesterol.="" fda="" also="" noted="" that="" the="" ``low="" fat''="" requirement="" for="" foods="" to="" make="" the="" saturated="" fat/="" cholesterol="" and="" heart="" disease="" health="" claim="" would="" limit="" a="" manufacturer's="" ability="" to="" increase="" trans-fatty="" acid="" levels="" in="" foods,="" since="" any="" substitution="" of="" trans-fatty="" acids="" for="" saturated="" fatty="" acids="" would="" have="" to="" be="" accomplished="" within="" the="" 3="" g="" per="" racc="" or="" per="" 50="" g="" limit="" for="" total="" fat.="" the="" agency="" considered="" this="" approach="" unlikely="" to="" result="" in="" significantly="" increased="" levels="" of="" trans-fatty="" acids="" in="" foods="" bearing="" the="" health="" claim="" (58="" fr="" 2739="" at="" 2744).="" the="" latter="" consideration="" is="" not="" applicable="" to="" the="" case="" of="" foods="" made="" from="" whole="" soybeans.="" no="" substitution="" of="" one="" type="" of="" fatty="" acid="" for="" another="" is="" [[page="" 57718]]="" contemplated="" for="" these="" products.="" the="" amount="" by="" which="" foods="" made="" from="" whole="" soybeans="" that="" are="" otherwise="" eligible="" to="" bear="" the="" soy="" protein="" health="" claim="" would="" exceed="" the="" ``low="" fat''="" criterion="" due="" to="" the="" inherent="" fat="" content="" of="" soybeans="" is="" small="" and="" well="" below="" the="" disqualifying="" level="" for="" total="" fat="" that="" a="" food="" bearing="" any="" health="" claim="" must="" meet="" (sec.="" 101.14="" (a)(4)).="" fda="" is="" persuaded="" that="" products="" derived="" from="" whole="" soybeans="" are="" useful="" sources="" of="" soy="" protein="" that="" they,="" like="" fish="" and="" game="" meats="" that="" are="" ``extra="" lean,''="" can="" be="" appropriately="" incorporated="" in="" a="" diet="" that="" is="" low="" in="" fat,="" saturated="" fat,="" and="" cholesterol.="" thus,="" fda="" is="" modifying="" sec.="" 101.82(c)(2)(iii)(b)="" to="" require="" that="" all="" products="" meet="" the="" criteria="" for="" ``low="" saturated="" fat''="" and="" ``low="" cholesterol''="" and="" adding="" sec.="" 101.82(c)(2)(iii)(c)="" to="" require="" that="" a="" food="" meet="" the="" criterion="" for="" ``low="" fat''="" in="" order="" to="" bear="" the="" soy="" protein="" health="" claim,="" except="" for="" products="" consisting="" of="" or="" derived="" from="" whole="" soybeans="" without="" additional="" fat.="" d.="" required="" elements="" for="" the="" claim="" 1.="" context="" of="" the="" total="" daily="" diet="" in="" the="" soy="" protein="" proposed="" rule="" (63="" fr="" 62977="" at="" 62991),="" the="" agency="" tentatively="" found="" 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="" proposed="" 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="" related="" to="" chd,="" the="" fat="" component="" of="" the="" diet="" be="" specified="" as="" ``saturated="" fat''="" and="" ``cholesterol.''="" (comment="" 59).="" one="" comment="" objected="" to="" this="" requirement="" on="" several="" grounds:="" that="" fda="" has="" been="" inconsistent="" in="" requiring="" specification="" of="" the="" need="" to="" consume="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" in="" previously="" authorized="" chd="" health="" claims;="" that="" the="" effect="" of="" soy="" protein="" on="" blood="" cholesterol="" levels="" is="" independent="" of="" a="" low="" fat,="" low="" saturated="" fat,="" and="" low="" cholesterol="" diet;="" that="" the="" statutory="" requirement="" to="" place="" the="" claim="" in="" the="" context="" of="" the="" total="" daily="" diet="" need="" only="" relate="" the="" labeled="" product="" to="" the="" rest="" of="" the="" day's="" diet;="" and="" that="" consumers="" will="" conclude="" that="" soy="" protein="" will="" be="" of="" no="" benefit="" to="" them="" if="" they="" cannot="" reduce="" saturated="" fat="" and="" cholesterol="" in="" their="" diets.="" other="" comments="" raised="" similar="" objections="" to="" the="" requirement.="" this="" comment="" and="" others="" proposed="" that="" fda="" allow="" a="" variety="" of="" shortened="" claims="" that="" would="" effectively="" render="" this="" requirement="" an="" optional="" element="" of="" the="" claim="" or="" that="" fda="" permit="" the="" information="" in="" this="" requirement="" to="" be="" presented="" in="" a="" split="" claim.="" fda="" disagrees="" with="" some="" of="" the="" characterizations="" of="" fda's="" requirements="" for="" currently="" authorized="" heart="" disease="" claims.="" the="" comment="" notes="" that="" the="" agency="" requires="" a="" statement="" of="" the="" role="" of="" low="" saturated="" fat="" and="" cholesterol="" diets="" in="" the="" reduction="" of="" risk="" of="" heart="" disease="" in="" three="" of="" the="" authorized="" claims'the="" dietary="" lipids="" claim="" (21="" cfr="" 101.75),="" the="" claim="" for="" fruits,="" vegetables,="" and="" grain="" products="" that="" contain="" dietary="" fiber,="" particularly="" soluble="" fiber="" (21="" cfr="" 101.77),="" and="" the="" claim="" for="" soluble="" fiber="" from="" psyllium="" seed="" husks="" (21="" cfr="" 101.81)--="" because="" the="" effect="" of="" the="" subject="" food="" substances="" had="" been="" established="" only="" in="" the="" context="" of="" such="" a="" diet.="" however,="" the="" comment="" maintained="" that="" evidence="" for="" the="" hypocholesterolemic="" effect="" of="" soluble="" fiber="" from="" whole="" oats="" showed="" it="" to="" be="" independent="" of="" other="" dietary="" changes.="" thus,="" in="" requiring="" that="" the="" claim="" for="" this="" substance="" be="" stated="" in="" the="" context="" of="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol="" (21="" cfr="" 101.81),="" the="" comment="" asserted="" that="" fda="" had="" failed="" to="" provide="" a="" claim="" that="" accurately="" and="" truthfully="" reflected="" the="" underlying="" science.="" fda="" disagrees="" with="" this="" characterization.="" the="" petition="" for="" a="" health="" claim="" for="" oat="" products="" stated="" that="" there="" was="" significant="" scientific="" evidence="" to="" show="" that="" the="" effect="" of="" oats="" on="" lowering="" serum="" lipids="" is="" independent="" of="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol.="" in="" light="" of="" this="" evidence,="" the="" petitioner="" argued="" that="" any="" health="" claim="" that="" is="" authorized="" need="" not="" refer="" to="" such="" a="" diet.="" in="" the="" proposed="" rule="" for="" a="" health="" claim="" for="" oat="" products,="" the="" agency="" acknowledged="" that="" there="" were="" a="" number="" of="" studies="" that="" showed="" that="" high="" intakes="" of="" oat="" bran="" and="" oatmeal="" lowered="" blood="" total="" and="" ldl-cholesterol="" in="" subjects="" that="" otherwise="" consumed="" a="" typical="" american="" diet="" (61="" fr="" 296="" at="" 305).="" however,="" the="" agency="" also="" recognized="" that="" chd="" is="" a="" major="" public="" health="" concern="" in="" the="" united="" states,="" and="" that="" 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="" 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.="" although="" the="" results="" of="" several="" studies="" showed="" that="" daily="" consumption="" of="" oat="" bran="" or="" oatmeal="" lowered="" total="" cholesterol="" and="" ldl-cholesterol="" levels,="" the="" agency="" noted="" that="" the="" effects="" of="" dietary="" intake="" of="" oat="" bran="" or="" oatmeal="" were="" particularly="" evident="" when="" the="" diets="" were="" low="" in="" saturated="" fat="" and="" cholesterol="" (61="" fr="" 296="" at="" 306).="" thus,="" the="" agency="" tentatively="" found="" it="" would="" be="" more="" helpful="" to="" americans'="" efforts="" to="" maintain="" healthy="" dietary="" practices="" if="" the="" effect="" of="" oats="" on="" serum="" lipids="" were="" described="" in="" the="" context="" of="" a="" healthy="" diet="" (61="" fr="" 296="" at="" 306).="" this="" tentative="" conclusion="" was="" supported="" by="" many="" of="" the="" comments="" received="" in="" response="" to="" the="" proposed="" rule="" and="" described="" in="" the="" final="" rule="" authorizing="" a="" health="" claim="" for="" soluble="" fiber="" from="" whole="" oats="" (62="" fr="" 3584="" at="" 3594).="" in="" the="" final="" rule,="" the="" agency="" noted="" that="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" are="" considered="" by="" expert="" groups="" to="" be="" the="" most="" effective="" dietary="" means="" of="" reducing="" heart="" disease="" risk,="" and="" that="" while="" soluble="" fiber="" from="" whole="" oats="" can="" contribute="" to="" this="" effect,="" its="" role="" is="" generally="" recognized="" as="" being="" of="" smaller="" magnitude="" (ref.="" 5).="" further,="" expert="" groups="" saw="" selection="" of="" foods="" with="" soluble="" fiber="" from="" whole="" oats="" as="" a="" useful="" adjunct="" to="" selection="" of="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" (ref.="" 5).="" the="" agency="" concluded="" that="" it="" would="" not="" be="" in="" the="" best="" interest="" of="" public="" health="" or="" consistent="" with="" the="" scientific="" evidence="" to="" imply="" that="" selecting="" diets="" with="" soluble="" fiber="" from="" whole="" oats="" is="" a="" substitute="" for="" consuming="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" (62="" fr="" 3584="" at="" 3594).="" therefore,="" fda="" emphasized="" the="" importance="" of="" the="" dietary="" component="" of="" the="" health="" claim,="" i.e.,="" the="" necessity="" for="" soluble="" fiber="" from="" whole="" oats="" to="" be="" consumed="" as="" part="" of="" a="" low="" saturated="" fat,="" low="" cholesterol="" diet,="" for="" a="" complete="" understanding="" of="" the="" claim="" (62="" fr="" 3584="" at="" 3594).="" the="" comment="" also="" characterized="" the="" claim="" for="" sodium/salt="" and="" hypertension="" (21="" cfr="" 101.74)="" as="" a="" claim="" about="" risk="" of="" heart="" disease="" and="" indicated="" that="" fda="" was="" not="" consistent="" because="" this="" claim="" is="" not="" required="" to="" be="" stated="" in="" the="" context="" of="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol.="" fda="" disagrees="" with="" this="" characterization="" of="" the="" claim="" and="" the="" conclusion="" that="" follows="" from="" it.="" this="" claim="" does="" not="" address="" the="" risk="" of="" heart="" disease,="" but="" rather="" is="" a="" claim="" specific="" for="" hypertension.="" the="" scientific="" evidence="" does="" not="" suggest="" that="" dietary="" saturated="" fat="" and="" cholesterol="" have="" a="" significant="" effect="" on="" blood="" pressure;="" thus,="" no="" mention="" of="" that="" dietary="" context="" is="" required.="" in="" addition,="" fda="" has="" stated="" (58="" fr="" 2739="" at="" 2746)="" that="" it="" has="" not="" been="" presented="" with="" data="" that="" sodium="" intake="" [[page="" 57719]]="" is="" a="" risk="" factor="" for="" heart="" disease="" and="" that="" a="" claim="" characterizing="" the="" relationship="" between="" sodium="" and="" heart="" disease="" would="" misbrand="" a="" food="" under="" section="" 403(r)(1)(b)="" of="" the="" act="" unless="" it="" were="" specifically="" authorized="" by="" the="" agency.="" the="" agency="" does="" agree="" with="" the="" comment="" that="" it="" has="" not="" found="" that="" all="" the="" risk="" factors="" for="" chd="" must="" be="" stated="" in="" order="" to="" ensure="" that="" a="" heart="" disease="" health="" claim="" is="" truthful="" and="" not="" misleading.="" in="" fact,="" for="" chd="" claims="" authorized="" more="" recently="" (21="" cfr="" 101.81),="" fda="" has="" not="" required="" that="" chd="" be="" characterized="" in="" the="" claim="" as="" a="" disease="" caused="" by="" many="" factors,="" in="" contrast="" to="" the="" claims="" that="" fda="" authorized="" earlier="" as="" part="" of="" the="" initial="" nlea="" reviews="" (21="" cfr="" 101.75="" and="" 21="" cfr="" 101.77).="" in="" addition,="" fda="" disagrees="" with="" the="" assertion="" that="" the="" cholesterol="" lowering="" effect="" of="" soy="" protein="" is="" independent="" of="" other="" dietary="" changes;="" the="" agency="" interprets="" the="" data="" differently.="" as="" noted="" in="" the="" discussion="" above,="" most="" of="" the="" scientific="" evidence="" for="" an="" effect="" of="" soy="" protein="" on="" blood="" lipid="" levels="" is="" 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,="" hypocholesterolemic="" effects="" of="" soy="" protein="" were="" more="" consistently="" observed="" with="" diets="" low="" in="" saturated="" fat="" and="" cholesterol.="" the="" agency="" concludes="" that="" the="" data="" supporting="" an="" independent="" effect="" for="" soy="" protein="" are="" more="" limited="" than="" those="" supporting="" an="" independent="" effect="" of="" soluble="" fiber="" from="" whole="" oats="" in="" reducing="" cholesterol="" levels.="" moreover,="" because="" the="" hypocholesterolemic="" effects="" of="" soy="" protein="" are="" seen="" in="" addition="" to="" the="" effects="" of="" a="" low="" saturated="" fat,="" low="" cholesterol="" diet,="" combining="" the="" two="" practices="" will="" provide="" enhanced="" benefits.="" nor="" does="" fda="" agree="" with="" the="" comment's="" assertion="" that="" the="" statutory="" requirement="" to="" place="" the="" claim="" in="" the="" context="" of="" the="" total="" daily="" diet="" need="" only="" relate="" the="" labeled="" product="" to="" the="" rest="" of="" the="" day's="" diet.="" in="" the="" 1993="" health="" claims="" final="" rule="" (58="" fr="" 2478="" at="" 2513),="" the="" agency="" disagreed="" with="" comments="" that="" proposed="" that="" the="" requirement="" to="" enable="" the="" public="" to="" understand="" the="" significance="" of="" the="" claim="" in="" the="" context="" of="" the="" total="" daily="" diet="" would="" be="" fulfilled="" if="" a="" health="" claim="" merely="" characterized="" the="" level="" of="" a="" substance="" vis-a-vis="" a="" disease,="" provided="" that="" there="" was="" significant="" scientific="" agreement="" that="" that="" level="" of="" intake="" of="" the="" substance="" was="" beneficial="" in="" reducing="" the="" risk="" of="" disease.="" rather,="" fda="" found="" that="" section="" 403(r)(3)(b)(iii)="" of="" the="" act="" requires="" that="" a="" regulation="" that="" authorizes="" a="" health="" claim="" provide="" that="" the="" claim="" be="" stated="" in="" a="" manner="" that="" enables="" the="" public="" to="" comprehend="" the="" information="" in="" the="" claim="" and="" to="" understand="" the="" relationship="" of="" the="" substance="" to="" the="" disease,="" the="" significance="" of="" the="" substance="" in="" affecting="" the="" disease,="" and="" the="" significance="" of="" the="" information="" in="" the="" context="" of="" the="" total="" daily="" diet.="" thus,="" a="" claim="" may="" need="" to="" address="" a="" wide="" variety="" of="" factors="" to="" fulfill="" these="" requirements,="" and="" the="" agency="" is="" not="" limited="" to="" requiring="" only="" that="" information="" that="" is="" necessary="" to="" prevent="" a="" claim="" from="" being="" misleading.="" finally,="" the="" agency="" is="" not="" persuaded="" that="" requiring="" the="" soy="" protein="" claim="" to="" be="" stated="" in="" the="" context="" of="" a="" total="" daily="" diet="" low="" in="" saturated="" fat="" and="" cholesterol="" will="" deter="" consumers="" who="" are="" interested="" in="" dietary="" control="" of="" cholesterol="" levels,="" and="" who="" have="" made="" unsuccessful="" attempts="" to="" lower="" dietary="" intake="" of="" saturated="" fat="" and="" cholesterol,="" from="" incorporating="" soy="" protein="" into="" their="" diets.="" consumers="" now="" have="" had="" experience="" with="" the="" claims="" for="" soluble="" fiber="" from="" whole="" oats="" and="" psyllium="" seed="" husks.="" these="" claims,="" like="" the="" soy="" protein="" claim,="" accurately="" draw="" the="" consumer's="" attention="" to="" the="" dietary="" pattern="" associated="" most="" strongly="" with="" reduction="" of="" risk="" from="" heart="" disease--a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol--and="" offer="" choices="" of="" specific="" foods="" that="" can="" be="" incorporated="" into="" this="" dietary="" pattern="" to="" enhance="" its="" beneficial="" effects.="" thus,="" fda="" is="" not="" modifying="" the="" requirement="" that="" the="" health="" claim="" for="" soy="" protein="" be="" stated="" in="" the="" context="" of="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol.="" 2.="" daily="" dietary="" intake="" of="" soy="" protein="" and="" contribution="" of="" one="" serving="" in="" the="" soy="" protein="" proposed="" rule="" (63="" fr="" 62977="" at="" 62991),="" the="" agency="" proposed="" that="" sec.="" 101.82(c)(2)(i)(g)="" require="" 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.="" the="" agency="" noted="" this="" requirement="" was="" consistent="" with="" requirements="" set="" forth="" in="" sec.="" 101.81="" for="" claims="" about="" soluble="" fiber="" from="" whole="" oats="" and="" psyllium="" seed="" husks,="" food="" substances="" that="" (like="" soy="" protein)="" do="" not="" have="" daily="" values="" that="" can="" serve="" as="" a="" guide="" to="" consumers="" for="" appropriate="" levels="" of="" intake.="" it="" is="" also="" required="" by="" sec.="" 101.14(d)(2)(vii).="" (comment="" 60).="" almost="" all="" of="" the="" comments="" that="" addressed="" these="" requirements="" supported="" the="" need="" for="" the="" claim="" to="" contain="" this="" information.="" some="" comments="" expressed="" concern="" that="" even="" with="" this="" information="" some="" consumers="" might="" be="" misled="" into="" believing="" that="" a="" single="" serving="" of="" a="" soy="" protein-containing="" food="" would="" contribute="" the="" full="" daily="" amount="" needed="" for="" the="" claimed="" health="" benefit.="" fda="" notes="" that="" these="" comments="" did="" not="" suggest="" what="" additional="" information="" might="" be="" helpful="" to="" consumers="" in="" understanding="" the="" claim.="" (comment="" 61).="" several="" comments="" suggested="" that="" the="" daily="" dietary="" intake="" of="" soy="" protein="" needed="" to="" reduce="" the="" risk="" of="" chd="" be="" required="" to="" be="" described="" as="" ``at="" least="" 25="" g/day="" of="" soy="" protein''="" or="" ``a="" minimum="" of="" 25="" g/day="" of="" soy="" protein.''="" fda="" is="" not="" persuaded="" to="" require="" that="" such="" statements="" be="" used="" because="" it="" is="" concerned="" about="" the="" need="" to="" balance="" informing="" consumers="" about="" the="" effective="" level="" of="" soy="" protein="" intake="" needed="" to="" provide="" the="" claimed="" health="" benefit="" against="" encouraging="" excessive="" consumption="" of="" a="" single="" food="" substance.="" if="" consumers="" were="" to="" interpret="" the="" claim="" erroneously="" as="" supporting="" consumption="" of="" soy="" as="" the="" sole="" source="" of="" dietary="" protein="" or="" supplementing="" a="" diet="" already="" adequate="" in="" protein="" from="" various="" sources="" with="" additional="" soy="" protein,="" then="" the="" two="" most="" important="" tenets="" of="" a="" healthful="" diet--variety="" and="" moderation--would="" be="" violated.="" (comment="" 62).="" one="" comment="" noted="" that,="" in="" the="" second="" model="" claim,="" the="" characterization="" of="" the="" total="" dietary="" intake="" of="" soy="" protein="" appeared="" to="" have="" omitted="" indication="" that="" the="" amount="" is="" ``per="" day.''="" fda="" agrees.="" this="" omission="" was="" inadvertent="" and="" the="" agency="" has="" corrected="" sec.="" 101.82="" (e)(1).="" although="" comments="" generally="" viewed="" as="" desirable="" providing="" information="" on="" both="" the="" total="" daily="" dietary="" intake="" of="" soy="" protein="" and="" the="" contribution="" of="" a="" single="" serving="" of="" a="" food="" to="" the="" total="" intake,="" some="" comments="" urged="" that="" it="" need="" not="" be="" provided="" in="" one="" place="" on="" the="" label="" with="" all="" of="" the="" other="" required="" information.="" many="" of="" these="" comments="" encouraged="" fda="" to="" make="" provisions="" for="" the="" use="" of="" abbreviated="" claims="" that="" would="" include="" a="" referral="" statement="" directing="" the="" consumer="" elsewhere="" on="" the="" package="" for="" the="" full="" claim.="" issues="" associated="" with="" abbreviated="" and="" split="" claims="" are="" addressed="" below.="" 3.="" abbreviated/split="" claims="" (comment="" 63).="" although="" there="" were="" not="" substantive="" objections="" regarding="" most="" of="" the="" required="" elements="" fda="" specified,="" a="" large="" number="" of="" comments="" objected="" to="" the="" model="" claims="" proposed="" in="" sec.="" 101.82="" (e),="" asserting="" that="" they="" are="" excessively="" long,="" complicated,="" and="" cumbersome,="" and="" requested="" that="" fda="" devise="" shorter="" claim="" statements.="" many="" of="" these="" comments="" expressed="" concerns="" that="" manufacturers="" would="" be="" reluctant="" to="" use="" and="" consumers="" unlikely="" to="" read="" [[page="" 57720]]="" such="" long,="" complex="" messages.="" they="" frequently="" suggested="" that="" fda="" provide="" for="" split="" claims="" in="" this="" rule.="" these="" would="" comprise="" a="" short="" or="" abbreviated="" claim="" (that="" need="" not="" contain="" all="" of="" the="" required="" elements="" identified="" in="" the="" rule)="" appearing="" on="" the="" principle="" display="" panel="" of="" the="" label="" together="" with="" a="" referral="" statement="" for="" the="" full="" claim="" elsewhere="" on="" the="" package.="" as="" support="" for="" these="" suggestions,="" many="" of="" the="" comments="" cited="" the="" keystone="" dialog's="" (ref.="" 159)="" endorsement="" of="" shorter="" claims="" and="" fda's="" own="" health="" claim="" consumer="" research="" (ref.="" 160),="" which="" the="" comments="" characterized="" as="" showing="" that="" short="" claims="" were="" more="" effective="" than="" long="" claims="" and="" that="" splitting="" claims="" between="" the="" front="" and="" back="" panels="" made="" little="" difference.="" fda="" notes,="" however,="" that="" the="" results="" of="" its="" consumer="" research="" were="" more="" complicated="" than="" indicated="" by="" that="" brief="" summary.="" the="" short="" and="" long="" claims="" studied="" differed="" in="" the="" inclusion="" of="" information="" about="" non-="" dietary="" risk="" factors="" and="" special="" populations="" at="" risk="" for="" the="" subject="" disease.="" the="" soy="" protein="" health="" claim="" already="" lacks="" these="" requirements.="" the="" study="" also="" found="" that,="" for="" some="" products="" with="" an="" abbreviated="" claim="" and="" a="" referral="" statement="" on="" the="" principal="" display="" panel,="" subjects="" were="" less="" likely="" to="" look="" at="" the="" back="" of="" the="" package="" for="" the="" full="" claim.="" concerns="" about="" health="" claims="" being="" too="" wordy="" and="" too="" lengthy="" have="" been="" raised="" to="" the="" agency="" in="" various="" ways,="" including="" by="" a="" petition="" submitted="" by="" the="" national="" food="" processors="" association="" (nfpa)="" (docket="" no.="" 94p-0390).="" in="" response="" to="" the="" nfpa="" petition,="" the="" agency="" proposed="" several="" changes="" to="" the="" requirements="" for="" health="" claims="" in="" the="" federal="" register="" of="" december="" 21,="" 1995="" (60="" fr="" at="" 66206)="" (the="" 1995="" proposal).="" at="" that="" time,="" fda="" stated="" that="" it="" had="" no="" desire="" for="" its="" regulations="" to="" stand="" in="" the="" way="" unnecessarily="" of="" the="" use="" of="" health="" claims="" and="" the="" presentation="" of="" the="" important="" information="" contained="" in="" them.="" the="" agency="" stated="" that,="" while="" health="" claims="" are="" being="" used="" on="" the="" label="" and="" in="" labeling,="" they="" could="" be="" used="" more="" extensively.="" the="" agency,="" therefore,="" proposed="" to="" provide="" for="" shorter="" health="" claims="" by="" making="" optional="" some="" of="" the="" elements="" that="" are="" presently="" required.="" fda="" also="" proposed="" to="" authorize="" the="" use="" of="" abbreviated="" claims.="" fda="" has="" reviewed="" the="" comments="" received="" in="" response="" to="" the="" 1995="" proposal="" on="" changing="" the="" requirements="" for="" health="" claims,="" including="" permitting="" the="" use="" of="" abbreviated="" claims,="" but="" it="" has="" not="" completed="" work="" on="" the="" final="" rule.="" given="" that="" this="" rule="" is="" pending,="" and="" given="" its="" relevance="" to="" the="" issue="" of="" abbreviated="" claims,="" fda="" has="" decided="" to="" defer="" a="" decision="" on="" allowing="" for="" abbreviated="" or="" split="" claims="" on="" soy="" protein="" and="" the="" risk="" of="" chd.="" the="" agency="" intends="" to="" resolve="" this="" matter="" in="" the="" context="" of="" the="" rulemaking="" based="" on="" the="" nfpa="" petition.="" thus,="" at="" this="" time,="" the="" agency="" is="" making="" provision="" only="" for="" a="" full="" claim.="" e.="" other="" issues="" 1.="" consideration="" of="" health="" claims="" for="" benefits="" of="" soy="" protein="" in="" addition="" to="" effects="" on="" cholesterol="" levels="" and="" risk="" of="" coronary="" heart="" disease="" (comment="" 64).="" a="" few="" comments="" urged="" that="" fda="" consider="" authorizing="" claims="" about="" other="" putative="" beneficial="" effects="" of="" soy="" protein="" or="" soy="" products="" on="" cardiovascular="" disease="" in="" addition="" to="" cholesterol="" lowering="" as="" well="" as="" putative="" beneficial="" effects="" on="" other="" diseases="" or="" health="" conditions="" such="" as="" cancer,="" osteoporosis,="" and="" menopausal="" symptoms.="" one="" comment="" suggested="" that="" statements="" derived="" from="" preliminary="" research="" on="" the="" putative="" beneficial="" effects="" of="" soy="" isoflavones="" be="" allowed="" on="" food="" labels="" and="" in="" labeling.="" these="" suggestions="" are="" beyond="" the="" scope="" of="" the="" present="" rulemaking.="" the="" present="" rulemaking="" is="" based="" on="" fda's="" review="" of="" information="" submitted="" in="" a="" petition="" about="" the="" relationship="" of="" soy="" protein="" and="" reduced="" risk="" of="" chd="" based="" exclusively="" on="" studies="" of="" the="" cholesterol="" lowering="" effects="" of="" soy="" protein.="" the="" agency="" has="" neither="" received="" nor="" reviewed="" relevant="" data="" for="" any="" other="" possible="" effects="" of="" soy="" protein="" relevant="" to="" risk="" of="" heart="" disease="" or="" of="" other="" diseases="" or="" health-="" related="" conditions.="" any="" interested="" person="" who="" has="" such="" data="" may="" submit="" a="" petition="" to="" the="" agency="" detailing="" the="" information="" for="" fda's="" review="" and="" evaluation="" of="" whether="" such="" information="" meets="" the="" requirements="" for="" authorization="" of="" a="" health="" claim.="" (comment="" 65).="" at="" the="" same="" time,="" one="" comment="" expressed="" concern="" that="" the="" authorization="" of="" a="" health="" claim="" on="" the="" relationship="" of="" soy="" protein="" and="" risk="" of="" chd="" might="" be="" read="" by="" some="" consumers="" as="" an="" implied="" claim="" for="" other="" putative="" benefits="" of="" soy="" foods.="" fda="" concludes,="" however,="" that="" the="" requirements="" it="" has="" set="" forth="" for="" the="" health="" claim="" already="" narrow="" the="" focus="" of="" the="" claim="" sufficiently="" to="" the="" relationship="" that="" fda="" evaluated.="" accordingly,="" consumers="" should="" not="" be="" so="" misled="" by="" the="" claim.="" 2.="" drug="" claims="" vs.="" health="" claims="" for="" foods="" (comment="" 66).="" one="" comment="" objected="" to="" fda's="" provision="" of="" a="" health="" claim="" for="" foods="" containing="" soy="" protein="" and="" reduced="" risk="" of="" chd="" when="" fda="" had="" not="" approved="" estrogen="" as="" a="" drug="" to="" have="" an="" indication="" for="" prevention="" of="" cardiovascular="" disease="" despite="" a="" large="" body="" of="" supportive="" evidence.="" the="" comment="" asserted="" that="" fda="" must="" evaluate="" all="" products="" with="" the="" same="" ground="" rules.="" this="" assertion="" is="" incorrect.="" as="" the="" agency="" explained="" in="" the="" 1993="" health="" claims="" final="" rule="" (58="" fr="" at="" 2506),="" the="" scientific="" standard="" for="" authorization="" of="" a="" health="" claims="" is="" less="" stringent="" than="" the="" requirements="" for="" approval="" of="" a="" new="" drug="" under="" section="" 505="" of="" the="" act="" (21="" u.s.c.="" 355).="" 3.="" claims="" for="" other="" vegetable="" proteins="" (comment="" 67).="" one="" comment="" reviewed="" data="" on="" the="" possible="" mechanisms="" for="" soy="" protein's="" hypocholesterolemic="" effects="" and="" concluded="" that="" they="" may="" be="" due="" in="" part="" to="" its="" amino="" acid="" composition,="" specifically="" its="" high="" arginine="" and="" low="" methionine="" content.="" the="" comment="" noted="" that="" other="" vegetable="" proteins,="" such="" as="" pea="" proteins,="" have="" a="" similar="" amino="" acid="" profile="" and="" would="" likely="" have="" the="" same="" effect="" on="" risk="" of="" chd="" as="" soy="" protein.="" the="" comment="" proposed="" that="" qualifying="" levels="" of="" both="" arginine="" and="" isoflavones="" be="" required="" for="" the="" health="" claim="" and="" that="" the="" claim="" not="" be="" limited="" to="" soy="" protein.="" fda="" finds="" that="" this="" suggestion="" is="" outside="" the="" scope="" of="" the="" current="" rulemaking.="" fda="" has="" not="" reviewed="" any="" data="" on="" the="" hypocholesterolemic="" effects="" of="" specific="" vegetable="" proteins="" other="" than="" soy.="" (comment="" 68).="" another="" comment="" that="" also="" discussed="" the="" possible="" importance="" of="" the="" amino="" acid="" composition="" of="" soy="" protein="" to="" its="" cholesterol-lowering="" ability="" suggested="" that="" the="" title="" of="" the="" new="" claim="" should="" be="" ``protein="" from="" certain="" foods="" and="" reduced="" risk="" of="" chd''="" in="" anticipation="" that="" data="" will="" be="" generated="" showing="" hypocholesterolemic="" effects="" of="" other="" vegetable="" proteins="" with="" amino="" acid="" compositions="" similar="" to="" soy="" protein.="" having="" reviewed="" data="" only="" on="" soy="" protein="" and="" being="" aware="" of="" no="" similar="" body="" of="" evidence="" about="" any="" other="" vegetable="" protein,="" fda="" finds="" this="" suggestion="" premature.="" 4.="" regulatory="" issues="" regarding="" soy="" protein="" claims="" in="" other="" countries="" (comment="" 69).="" one="" comment="" provided="" extensive="" information="" about="" a="" complaint="" brought="" against="" a="" company="" regarding="" a="" particular="" television="" advertising="" campaign="" for="" a="" non-dairy="" soy="" beverage="" product="" in="" new="" zealand="" that="" was="" alleged="" to="" be="" deceptive.="" this="" information="" included="" an="" unpublished="" report="" of="" a="" study="" comparing="" the="" effects="" of="" the="" non-dairy="" soy="" beverage="" to="" milk="" that="" was="" inadequate="" for="" assessing="" a="" [[page="" 57721]]="" hypocholesterolemic="" effect="" for="" soy="" protein="" or="" the="" soy="" product="" itself="" because="" dietary="" saturated="" fat="" and="" cholesterol="" varied="" substantially="" in="" the="" two="" dietary="" treatments.="" another="" comment="" raised="" concerns="" about="" the="" importation="" of="" foods="" from="" the="" united="" states="" that="" may="" bear="" health="" claims="" in="" violation="" of="" mexican="" law.="" the="" fda="" advises="" that="" violations="" of="" laws="" or="" regulations="" of="" other="" countries="" with="" respect="" to="" claims="" made="" on="" food="" labels="" or="" labeling="" or="" claims="" made="" in="" advertising="" are="" outside="" the="" scope="" of="" the="" present="" rulemaking.="" companies="" doing="" business="" in="" other="" countries="" are="" responsible="" for="" complying="" with="" the="" relevant="" statutory="" and="" regulatory="" requirements="" of="" those="" countries.="" 5.="" genetically="" modified="" soybeans="" (comment="" 70).="" two="" comments="" noted="" that="" much="" of="" the="" current="" soybean="" crop="" in="" the="" united="" states="" consists="" of="" genetically="" modified="" varieties="" of="" soybeans.="" one="" comment="" requested="" that="" products="" bearing="" the="" health="" claim="" be="" required="" to="" indicate="" on="" the="" label="" whether="" genetically="" modified="" soybeans="" were="" used.="" the="" other="" comment="" noted="" that="" genetic="" modification="" may="" alter="" the="" content="" of="" isoflavones="" and="" other="" biologically="" active="" components="" of="" soy="" and="" suggested="" that="" research="" was="" needed="" to="" determine="" if="" such="" genetic="" modifications="" raise="" additional="" safety="" concerns.="" the="" comments="" provided="" no="" data="" or="" other="" information="" to="" justify="" labeling="" or="" substantiate="" any="" safety="" concerns.="" fda="" has="" considered="" these="" comments="" and="" disagrees="" with="" both,="" for="" the="" following="" reasons.="" fda="" has="" stated="" its="" expectation="" that="" companies="" consult="" with="" the="" agency="" early="" in="" the="" process="" of="" developing="" a="" bioengineered="" food="" and="" that="" they="" provide="" the="" agency="" with="" a="" summary="" of="" safety="" data="" and="" a="" nutritional="" assessment="" for="" its="" review="" (ref.="" 161).="" to="" date,="" three="" companies="" have="" consulted="" with="" the="" agency="" about="" bioengineered="" soybeans.="" two="" companies="" developed="" soybeans="" that="" are="" resistant="" to="" the="" herbicides="" glyphosate="" and="" glufosinate,="" respectively.="" a="" third="" company="" modified="" the="" oil="" composition="" of="" the="" soybean="" to="" increase="" its="" levels="" of="" oleic="" acid,="" and="" it="" must="" be="" labeled="" as="" high="" oleic="" acid="" soybean.="" one="" company="" stopped="" further="" development="" of="" a="" genetically="" modified="" soybean="" that="" involved="" the="" addition="" of="" a="" brazil="" nut="" protein="" when="" it="" discovered="" that="" the="" protein="" would="" cause="" allergic="" reactions.="" the="" safety="" and="" nutritional="" assessments="" of="" the="" three="" bioengineered="" soybeans="" show="" that="" there="" are="" no="" unintended="" effects="" of="" the="" genetic="" modification="" (refs.="" 162="" through="" 167).="" in="" particular,="" these="" soybeans="" possess="" the="" same="" nutritional="" profile="" as="" their="" parent="" or="" other="" commercially="" available="" soybeans,="" except="" that="" the="" high="" oleic="" acid="" soybean="" has="" a="" modified="" fat="" profile,="" as="" intended.="" in="" addition,="" levels="" of="" isoflavones,="" trypsin="" inhibitors,="" and="" endogenous="" allergens="" are="" unchanged.="" the="" agency="" therefore="" concludes="" that="" there="" is="" no="" basis="" to="" the="" comment's="" assertion="" that="" currently="" available="" bioengineered="" soybeans="" may="" raise="" additional="" safety="" concerns.="" nor="" is="" there="" any="" basis="" to="" require="" that="" bioengineered="" soybeans="" be="" identified="" in="" food="" labeling="" as="" such.="" iii.="" environmental="" impact="" the="" agency="" has="" previously="" considered="" the="" environmental="" effects="" of="" this="" rule="" as="" announced="" in="" the="" soy="" protein="" proposed="" rule="" (63="" fr="" 62977="" at="" 62993)="" and="" the="" soy="" protein="" reproposal="" (64="" fr="" 45932="" at="" 45935).="" the="" agency="" determined="" that="" this="" action="" is="" of="" a="" type="" that="" does="" not="" individually="" or="" cumulatively="" have="" a="" significant="" effect="" on="" the="" human="" environment,="" and="" that="" neither="" an="" environmental="" assessment="" nor="" an="" environmental="" impact="" statement="" is="" required,="" but="" provided="" incorrect="" citations="" for="" categorical="" exclusion="" in="" the="" proposed="" rules.="" the="" correct="" citation="" is="" 21="" cfr="" 25.32(p).="" no="" new="" information="" or="" comments="" have="" been="" received="" that="" would="" affect="" the="" agency's="" previous="" determination.="" iv.="" analysis="" of="" economic="" impacts="" a.="" cost-benefit="" analysis="" fda="" has="" examined="" the="" impacts="" of="" this="" final="" rule="" under="" executive="" order="" 12866.="" executive="" order="" 12866="" directs="" federal="" agencies="" to="" assess="" the="" 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="" effects;="" 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="" final="" rule="" is="" neither="" an="" economically="" significant="" nor="" a="" significant="" regulatory="" action="" as="" defined="" by="" executive="" order="" 12866.="" in="" addition,="" fda="" has="" determined="" that="" this="" rule="" does="" not="" constitute="" a="" significant="" rule="" under="" the="" unfunded="" mandates="" reform="" act="" of="" 1995="" requiring="" cost="" benefit="" and="" other="" analyses.="" a="" significant="" rule="" is="" defined="" in="" 2="" u.s.c.="" 1532="" (a)="" as="" ``a="" federal="" mandate="" that="" may="" result="" in="" the="" expenditure="" by="" state,="" local="" and="" tribal="" governments="" in="" the="" aggregate,="" or="" by="" the="" private="" sector,="" of="" $100,000,000="" (adjusted="" annually="" for="" inflation)="" in="" any="" 1="" year.''="" finally,="" 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="" has="" determined="" that="" this="" final="" 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="" as="" one="" that="" the="" administrator="" has="" determined="" has="" resulted="" or="" is="" likely="" to="" result="" in:="" (a)="" an="" annual="" effect="" on="" the="" economy="" of="" $100,000,000="" or="" more;="" or="" (b)="" a="" major="" increase="" in="" costs="" or="" prices="" for="" consumers,="" individual="" industries,="" federal,="" state,="" or="" local="" government="" agencies,="" or="" geographic="" regions;="" or="" (c)="" significant="" adverse="" effects="" on="" competition,="" employment,="" investment,="" productivity,="" innovation,="" or="" on="" the="" ability="" of="" united="" states-based="" enterprises="" to="" compete="" with="" foreign-based="" enterprises="" in="" domestic="" or="" export="" markets.="" b.="" regulatory="" options="" fda="" did="" not="" discuss="" regulatory="" options="" in="" the="" analysis="" of="" the="" proposed="" rule,="" because="" no="" costs="" were="" identified="" in="" that="" analysis.="" public="" comments="" on="" the="" proposed="" rule="" raised="" a="" number="" of="" potential="" costs="" and="" a="" number="" of="" issues="" that="" may="" affect="" the="" benefits="" of="" this="" rule.="" the="" comments="" also="" suggested="" a="" large="" number="" of="" regulatory="" options.="" the="" primary="" options="" suggested="" in="" the="" comments="" were="" as="" follows:="" (1)="" take="" no="" new="" regulatory="" action.="" (2)="" take="" no="" action,="" but="" generate="" or="" wait="" for="" additional="" information="" on="" which="" to="" base="" a="" future="" action.="" (3)="" take="" proposed="" action.="" (4)="" take="" proposed="" action,="" but="" specify="" a="" different="" minimum="" level="" of="" soy="" protein="" for="" products="" bearing="" the="" claim.="" (5)="" take="" proposed="" action,="" but="" specify="" a="" minimum="" level="" of="" soy="" isoflavones="" in="" addition="" to="" a="" minimum="" level="" of="" soy="" protein="" for="" products="" bearing="" the="" claim.="" (6)="" take="" proposed="" action,="" but="" revise="" the="" wording="" of="" the="" claim="" or="" require="" that="" warnings="" or="" other="" statements="" accompany="" the="" claim.="" (7)="" take="" proposed="" action,="" but="" specify="" a="" different="" maximum="" total="" fat="" content="" or="" grant="" an="" exemption="" from="" the="" maximum="" total="" fat="" requirement="" for="" foods="" made="" with="" natural="" soy="" beans="" that="" have="" no="" added="" fat.="" [[page="" 57722]]="" (8)="" take="" proposed="" action,="" but="" use="" a="" different="" procedure="" for="" determining="" level="" of="" soy="" protein="" in="" particular="" products.="" 1.="" option="" one:="" take="" no="" new="" regulatory="" action="" by="" convention,="" the="" option="" of="" taking="" no="" new="" regulatory="" action="" is="" the="" baseline="" in="" comparison="" with="" which="" the="" costs="" and="" benefits="" of="" the="" other="" options="" are="" determined.="" therefore,="" neither="" costs="" nor="" benefits="" are="" associated="" with="" taking="" no="" new="" regulatory="" action.="" 2.="" option="" two:="" take="" no="" action,="" but="" generate="" or="" wait="" for="" additional="" information="" on="" which="" to="" base="" a="" future="" action="" a="" number="" of="" comments="" suggested="" delaying="" action="" until="" further="" research="" is="" carried="" out="" on:="" (1)="" the="" mechanism="" by="" which="" soy="" protein="" reduces="" the="" risk="" of="" coronary="" heart="" disease="" (chd),="" including="" the="" role="" of="" soy="" isoflavones;="" (2)="" the="" effect="" of="" particular="" methods="" of="" manufacturing="" soy="" protein="" isolates="" and="" products="" containing="" soy="" protein;="" (3)="" the="" effect="" of="" other="" characteristics="" of="" the="" diet="" such="" as="" fiber="" or="" mineral="" content;="" (4)="" potential="" health="" risks="" associated="" with="" increased="" intake="" of="" soy="" protein,="" soy="" isoflavones,="" other="" components="" of="" soybeans,="" and="" artifacts="" of="" particular="" methods="" of="" manufacturing="" soy="" protein="" isolates="" and="" products="" containing="" soy="" protein;="" (5)="" consumption="" patterns="" of="" foods="" containing="" soy="" protein="" and="" the="" percentage="" of="" such="" foods="" that="" meet="" the="" proposed="" requirements="" for="" the="" health="" claim;="" and="" (6)="" methods="" of="" measuring="" the="" level="" of="" soy="" protein="" in="" foods.="" the="" cost="" of="" delay="" is="" the="" elimination="" of="" the="" benefits="" that="" would="" have="" been="" realized="" between="" the="" effective="" date="" of="" the="" non-delayed="" rule="" and="" the="" effective="" date="" of="" the="" delayed="" rule.="" the="" potential="" benefits="" of="" delay="" are:="" (1)="" the="" reduction="" of="" potential="" health="" risks,="" if="" any,="" associated="" with="" increased="" intake="" of="" soy="" protein="" and="" other="" relevant="" substances;="" (2)="" the="" reduced="" likelihood="" of="" the="" potential="" reduction="" in="" the="" perceived="" reliability="" of="" fda-approved="" claims="" that="" might="" occur="" if="" future="" research="" were="" to="" require="" the="" soy="" protein="" health="" claim="" be="" revised;="" (3)="" the="" increase="" in="" the="" health="" benefits="" generated="" by="" a="" delayed="" health="" claim="" that,="" potentially,="" would="" be="" more="" accurate="" or="" complete.="" as="" discussed="" below,="" the="" comments="" did="" not="" provide="" information="" establishing="" that="" the="" benefits="" of="" delaying="" the="" rule="" outweigh="" the="" costs.="" 3.="" option="" three:="" take="" proposed="" action="" costs="" a="" number="" of="" comments="" suggested="" that="" this="" rule="" might="" lead="" to="" adverse="" health="" effects.="" according="" to="" these="" comments,="" potential="" health="" risks="" are="" associated="" with="" an="" increased="" intake="" of:="" (1)="" soy="" protein;="" (2)="" other="" components="" of="" soybeans="" including="" soybean="" trypsin="" inhibitors="" and="" isoflavones="" such="" as="" genistein;="" (3)="" artifacts="" of="" particular="" methods="" of="" manufacturing="" soy="" protein="" isolates="" or="" products="" containing="" soy="" protein,="" such="" as="" nitrates,="" nitrosamines,="" and="" lysinolanine;="" and="" (4)="" artifacts="" of="" genetically="" engineered="" soy="" protein.="" among="" the="" potential="" health="" concerns="" related="" to="" these="" substances="" mentioned="" in="" the="" comments="" were="" the="" following:="" (1)="" allergenicity;="" (2)="" reduced="" bioavailability="" of="" vitamins="" and="" minerals="" including="" zinc="" and="" iron;="" (3)="" hormonal="" alterations,="" including="" changes="" in="" fertility="" and="" functioning="" of="" sex="" glands;="" (4)="" toxicity="" in="" estrogen="" sensitive="" tissues="" and="" an="" increase="" in="" estrogen-="" related="" diseases;="" (5)="" vascular="" dementia;="" (6)="" adverse="" effects="" on="" the="" central="" nervous="" system="" and="" behavioral="" changes;="" (7)="" thyroid="" abnormalities,="" including="" goiter;="" (8)="" cancer;="" (9)="" diabetes;="" (10)="" liver="" disease;="" (11)="" adverse="" effects="" on="" the="" immune="" and="" endocrine="" systems;="" and="" (12)="" adverse="" effects="" on="" metabolism.="" other="" comments="" argued="" that="" no="" health="" concerns="" would="" be="" associated="" with="" the="" intake="" levels="" of="" soy="" protein="" and="" the="" other="" substances="" that="" can="" be="" associated="" with="" soy="" protein,="" such="" as="" soy="" isoflavones="" or="" various="" by-products="" of="" manufacturing="" soy="" protein="" isolates,="" that="" are="" likely="" to="" result="" from="" the="" proposed="" health="" claim.="" as="" discussed="" previously="" in="" the="" preamble="" to="" this="" rule,="" fda="" finds="" that="" there="" is="" no="" evidence="" that="" any="" increase="" in="" the="" intake="" of="" soy="" protein="" or="" the="" other="" substances="" discussed="" in="" the="" comments="" presents="" a="" risk="" of="" adverse="" health="" effects.="" the="" availability="" of="" the="" health="" claim="" may="" increase="" the="" number="" of="" products="" containing="" soy="" protein.="" increased="" availability="" of="" products="" containing="" soy="" protein="" may="" increase="" the="" likelihood="" that="" those="" who="" are="" allergic="" to="" soy="" protein="" may="" consume="" such="" products.="" the="" net="" effect="" of="" this="" rule="" on="" the="" incidence="" of="" allergic="" reactions="" to="" soy="" protein="" is="" unclear.="" as="" discussed="" earlier="" in="" the="" preamble,="" the="" presence="" of="" the="" health="" claim="" will="" serve="" to="" notify="" consumers="" of="" the="" presence="" of="" soy="" protein="" in="" products="" that="" bear="" the="" claim.="" however,="" some="" consumers="" who="" are="" allergic="" to="" soy="" protein="" may="" not="" already="" know="" they="" are="" allergic="" to="" soy="" protein="" and="" some="" consumers="" who="" do="" know="" they="" are="" allergic="" may="" inadvertently="" consume="" such="" products="" despite="" the="" presence="" of="" the="" health="" claim.="" fda="" has="" insufficient="" information="" to="" estimate="" the="" net="" effect="" on="" the="" incidence="" of="" allergic="" reactions="" to="" soy="" protein.="" in="" addition,="" the="" addition="" of="" soy="" protein="" to="" products="" that="" do="" not="" currently="" contain="" soy="" protein="" may="" reduce,="" to="" some="" degree,="" the="" number="" of="" soy-free="" products="" that="" are="" available="" to="" those="" who="" are="" allergic="" to="" soy="" protein.="" this="" reduction="" in="" product="" choice="" may="" lead="" to="" utility="" losses="" for="" those="" consumers.="" however,="" a="" large="" number="" of="" products="" will="" continue="" to="" not="" contain="" soy="" protein,="" so="" this="" utility="" loss="" will="" probably="" be="" modest.="" this="" rule="" may="" also="" increase="" the="" incidence="" of="" the="" adverse="" health="" effects="" associated="" with="" zinc="" deficiency,="" which="" is="" typically="" related="" to="" largely="" plant-based="" diets,="" to="" some="" degree.="" however,="" fda="" has="" insufficient="" information="" to="" estimate="" this="" effect.="" some="" comments="" suggested="" that="" this="" rule="" might="" indirectly="" increase="" the="" incidence="" of="" chd.="" according="" to="" these="" comments,="" the="" proposed="" health="" claim="" could="" lead="" some="" consumers="" to="" overestimate="" the="" role="" of="" soy="" protein="" in="" preventing="" chd="" and="" to="" neglect="" other="" actions="" that="" have="" an="" equal="" or="" greater="" effect="" on="" the="" risk="" of="" chd.="" other="" comments="" argued="" that="" this="" rule="" might="" lead="" to="" the="" adverse="" health="" effects="" caused="" by="" poor="" nutrition="" because="" the="" proposed="" health="" claim="" might="" lead="" some="" consumers="" to="" concentrate="" unduly="" on="" foods="" containing="" soy="" protein="" and="" to="" neglect="" the="" other="" components="" of="" a="" balanced="" diet.="" another="" comment="" argued="" the="" proposed="" health="" claim="" could="" lead="" to="" miscellaneous="" adverse="" health="" effects="" because="" it="" might="" be="" interpreted="" by="" some="" consumers="" as="" an="" endorsement="" of="" the="" miscellaneous="" benefits="" that="" are="" sometimes="" claimed="" for="" soy="" products,="" such="" as="" the="" prevention="" of="" cancer="" or="" osteoporosis.="" this="" comment="" argued="" that="" this="" interpretation="" would="" lead="" some="" consumers="" to="" neglect="" the="" actions="" that="" reduce="" the="" risk="" of="" these="" other="" conditions.="" some="" consumers="" may="" misinterpret="" the="" proposed="" health="" claim="" (or="" any="" other="" health="" claim).="" however,="" the="" fact="" that="" the="" proposed="" health="" claim="" states="" that="" the="" risk="" of="" chd="" may="" be="" reduced="" by="" an="" unspecified="" degree="" by="" consuming="" a="" specified="" level="" of="" soy="" protein="" per="" day,="" as="" part="" of="" a="" low="" saturated="" fat="" and="" low="" cholesterol="" diet,="" makes="" it="" unlikely="" that="" many="" consumers="" will="" neglect="" other="" activities="" that="" reduce="" the="" risk="" of="" chd="" or="" neglect="" other="" types="" of="" foods.="" similarly,="" the="" fact="" that="" the="" health="" claim="" specifies="" chd="" makes="" it="" unlikely="" that="" many="" consumers="" will="" interpret="" the="" claim="" as="" an="" endorsement="" of="" other="" benefits="" that="" are="" sometimes="" claimed="" for="" soy="" products.="" the="" comments="" did="" not="" provide="" sufficient="" information="" to="" allow="" fda="" to="" estimate="" the="" likelihood="" of="" these="" effects.="" furthermore,="" these="" potential="" effects="" are="" no="" more="" likely="" to="" be="" associated="" with="" the="" proposed="" claim="" than="" with="" any="" other="" claim.="" [[page="" 57723]]="" some="" comments="" suggested="" that="" this="" rule="" might="" indirectly="" increase="" the="" incidence="" of="" miscellaneous="" adverse="" health="" effects="" by="" decreasing="" the="" perceived="" reliability="" of="" fda-approved="" health="" claims="" in="" general.="" some="" comments="" noted="" the="" presence="" of="" a="" certain="" degree="" of="" uncertainty="" concerning="" the="" mechanism="" by="" which="" soy="" protein="" reduces="" the="" risk="" of="" chd.="" one="" comment="" argued="" that="" if="" further="" research="" on="" this="" mechanism="" were="" to="" find="" that="" isoflavones="" or="" other="" components="" of="" soybeans="" are="" involved,="" and="" the="" health="" claim="" were="" subsequently="" revised="" to="" reflect="" those="" findings,="" then="" fda's="" scientific="" reputation="" and="" the="" perceived="" value="" of="" fda-="" approved="" health="" claims="" could="" be="" adversely="" affected.="" other="" comments="" implied="" that="" uncertainty="" over="" the="" mechanism="" means="" that="" future="" research="" might="" show="" that="" soy="" protein="" does="" not="" affect="" the="" risk="" of="" chd.="" other="" comments="" argued="" that="" the="" proposed="" claim="" would="" reduce="" fda's="" scientific="" credibility="" because="" it="" would="" mean="" that="" fda="" is="" treating="" soy="" protein="" in="" a="" manner="" that="" is="" inconsistent="" with="" how="" fda="" treats="" certain="" other="" substances="" that="" may="" reduce="" the="" risk="" of="" chd,="" including="" estrogens="" and="" linseed="" oil.="" future="" research="" could="" lead="" to="" results="" that="" would="" lead="" fda="" to="" revise="" the="" soy="" health="" claim.="" however,="" the="" comments="" did="" not="" provide="" sufficient="" information="" to="" allow="" fda="" to="" estimate="" the="" likelihood="" of="" revisions="" or="" to="" assess="" the="" impact="" of="" these="" revisions="" on="" the="" perceived="" reliability="" of="" fda-approved="" health="" claims="" in="" general.="" the="" latter="" relationship="" is="" highly="" speculative,="" because="" it="" depends="" on="" consumers="" not="" knowing="" that="" scientific="" knowledge="" is="" in="" a="" constant="" state="" of="" development.="" in="" addition,="" although="" some="" revisions="" may="" be="" necessary,="" it="" is="" unlikely="" that="" future="" research="" will="" indicate="" that="" soy="" protein="" has="" no="" effect="" on="" chd.="" as="" stated="" earlier="" in="" the="" preamble,="" fda="" has="" concluded="" that="" the="" scientific="" evidence="" establishes="" that="" increased="" intake="" of="" soy="" protein="" reduces="" the="" risk="" of="" chd="" and="" that="" this="" effect="" is="" not="" simply="" an="" artifact="" of="" the="" substitution="" of="" lower="" fat="" and="" cholesterol="" products="" for="" higher="" fat="" and="" cholesterol="" products.="" the="" comment="" that="" suggested="" otherwise="" ignores="" the="" many="" studies="" in="" which="" fat,="" saturated="" fat,="" and="" cholesterol="" were="" the="" same="" in="" treatment="" and="" control="" groups="" and="" soy="" protein="" still="" exerted="" an="" effect="" on="" the="" risk="" of="" chd.="" also,="" fda="" disagrees="" that="" the="" only="" mechanism="" discussed="" in="" the="" petition="" was="" the="" soy="" isoflavone="" mechanism.="" finally,="" the="" comments="" did="" not="" provide="" sufficient="" information="" to="" estimate="" the="" effect="" of="" the="" purported="" inconsistencies="" on="" the="" perceived="" value="" of="" fda-="" approved="" health="" claims.="" however,="" in="" general,="" it="" is="" unclear="" that="" the="" failure="" to="" authorize="" a="" health="" claim="" for="" one="" substance="" would="" reduce="" the="" effectiveness="" of="" a="" health="" claim="" for="" another="" substance.="" a="" number="" of="" comments="" addressed="" the="" method="" fda="" proposed="" to="" use="" to="" determine="" the="" level="" of="" soy="" protein.="" many="" of="" the="" comments="" recommended="" revising="" the="" proposed="" rule.="" these="" comments="" are="" discussed="" under="" option="" 8="" below.="" c.="" benefits="" the="" analysis="" of="" the="" proposed="" rule="" discussed="" the="" benefit="" of="" this="" rule="" in="" terms="" of="" the="" value="" to="" consumers="" of="" the="" information="" communicated="" in="" the="" proposed="" health="" claim.="" the="" comments="" did="" not="" provide="" information="" directly="" relevant="" to="" estimating="" this="" value.="" however,="" a="" number="" of="" comments="" addressed="" the="" health="" and="" other="" benefits="" that="" might="" be="" generated="" by="" changes="" in="" consumer="" behavior="" that="" might="" follow="" from="" this="" rule.="" as="" discussed="" in="" the="" analysis="" of="" the="" proposed="" rule,="" the="" value="" of="" these="" other="" benefits="" may="" be="" considered="" a="" lower="" bound="" on="" the="" value="" to="" consumers="" of="" the="" information="" communicated="" in="" the="" health="" claim.="" this="" value="" is="" a="" lower="" bound="" because="" some="" consumers="" might="" want="" that="" information,="" but="" nevertheless="" choose="" not="" to="" modify="" their="" behavior.="" in="" addition,="" the="" value="" of="" these="" other="" benefits="" may="" be="" considered="" an="" appropriate="" independent="" metric="" for="" valuing="" the="" benefits="" of="" this="" rule="" because="" consumers="" may="" value="" the="" information="" in="" the="" claim="" based="" on="" the="" usefulness="" of="" that="" information="" for="" reducing="" the="" risk="" of="" chd="" but="" may="" underestimate="" or="" overestimate="" the="" usefulness="" of="" that="" information.="" many="" comments="" argued="" that="" this="" rule="" would="" lead="" to="" a="" reduction="" in="" the="" incidence="" of="" chd="" and="" provided="" information="" relevant="" to="" estimating="" that="" reduction.="" a="" few="" comments="" argued="" that="" this="" rule="" would="" not="" lead="" to="" a="" reduction="" in="" the="" incidence="" of="" chd="" because="" soy="" protein="" does="" not="" affect="" the="" risk="" of="" chd.="" one="" comment="" argued="" that="" this="" rule="" would="" generate="" benefits="" by="" obviating,="" in="" some="" cases,="" the="" need="" for="" riskier="" and="" more="" expensive="" pharmacological="" treatments="" for="" reducing="" the="" risk="" of="" chd.="" thus,="" according="" to="" this="" comment,="" this="" rule="" might="" generate="" benefits="" even="" if="" no="" reduction="" in="" the="" incidence="" of="" chd="" were="" to="" take="" place.="" quantifying="" the="" effect="" of="" the="" proposed="" health="" claim="" on="" the="" incidence="" of="" chd="" would="" involve="" a="" number="" of="" uncertainties="" and="" any="" ensuing="" estimate="" would="" be="" imprecise.="" in="" addition,="" there="" would="" be="" little="" value="" to="" generating="" such="" an="" estimate="" because,="" as="" discussed="" above,="" the="" comments="" did="" not="" provide="" sufficient="" information="" to="" estimate="" the="" purported="" costs="" of="" this="" rule.="" therefore,="" although="" fda="" believes="" this="" final="" rule="" will="" generate="" benefits,="" this="" analysis="" will="" not="" attempt="" to="" quantify="" the="" effect="" of="" this="" rule="" on="" the="" incidence="" of="" chd.="" some="" comments="" argued="" that="" increasing="" soy="" intake="" would="" generate="" benefits="" other="" than="" a="" reduction="" in="" the="" risk="" of="" chd,="" including="" reduction="" in="" the="" incidence="" of="" cancer,="" osteoporosis,="" and="" menopausal="" symptoms.="" these="" types="" of="" effects="" would="" be="" relevant="" to="" the="" estimation="" of="" the="" benefits="" of="" this="" rule.="" however,="" fda="" has="" reviewed="" no="" scientific="" evidence="" to="" assess="" whether="" such="" benefits="" exist="" or="" to="" estimate="" the="" size="" of="" such="" benefits.="" 4.="" option="" four:="" take="" proposed="" action,="" but="" specify="" a="" different="" minimum="" level="" of="" soy="" protein="" for="" products="" bearing="" the="" claim="" many="" comments="" suggested="" revising="" the="" minimum="" level="" of="" soy="" protein="" that="" is="" required="" for="" a="" product="" to="" be="" able="" to="" bear="" the="" proposed="" health="" claim.="" some="" comments="" addressed="" the="" significance="" of="" the="" 25="" g="" per="" day="" of="" soy="" protein="" on="" which="" the="" proposed="" 6.25="" g="" per="" racc="" requirement="" was="" based.="" one="" comment="" noted="" that="" studies="" have="" found="" that="" soy="" protein="" affects="" the="" risk="" of="" chd="" at="" intake="" levels="" of="" between="" 17="" g="" and="" 31="" g="" per="" day.="" another="" comment="" argued="" that="" between="" 30="" g="" to="" 50="" g="" of="" soy="" protein="" per="" day="" is="" necessary="" to="" produce="" clinically="" significant="" results="" on="" the="" incidence="" of="" chd.="" specifying="" the="" particular="" daily="" intake="" of="" soy="" protein="" that="" will="" have="" a="" significant="" effect="" on="" the="" risk="" of="" chd="" involves="" some="" uncertainty.="" however,="" fda="" does="" not="" have="" sufficient="" information="" to="" estimate="" the="" effect="" of="" specifying="" different="" levels="" and="" the="" comments="" did="" not="" provide="" sufficient="" information="" to="" allow="" fda="" to="" do="" so.="" as="" discussed="" earlier="" in="" the="" preamble,="" fda="" believes="" the="" 25="" g="" soy="" protein="" per="" day="" level="" is="" supported="" by="" the="" scientific="" literature="" and="" disagrees="" that="" intake="" levels="" of="" 30="" g="" to="" 50="" g="" per="" day="" is="" necessary="" to="" produce="" clinically="" significant="" results="" on="" the="" incidence="" of="" chd.="" other="" comments="" did="" not="" address="" the="" 25="" g="" soy="" protein="" per="" day="" target="" level="" but="" did="" address="" the="" 6.25="" g="" per="" racc="" requirement="" derived="" from="" the="" daily="" target="" level.="" some="" comments="" argued="" that="" the="" per="" racc="" requirement="" was="" overly="" restrictive="" and="" that="" few="" products="" would="" qualify="" for="" the="" health="" claim="" under="" this="" requirement.="" one="" comment="" analyzed="" the="" list="" of="" products="" that="" was="" presented="" in="" the="" petition="" as="" qualifying="" for="" the="" health="" claim="" and="" found="" that="" only="" 61="" products="" would="" qualify="" if="" multiple="" flavors="" of="" the="" same="" product="" were="" omitted,="" and="" that="" 88="" products="" would="" [[page="" 57724]]="" qualify="" if="" multiple="" flavors="" were="" not="" omitted.="" this="" comment="" also="" noted="" that="" many="" of="" the="" products="" on="" the="" list="" that="" would="" qualify="" are="" products="" that="" are="" meant="" to="" be="" added="" to="" other="" products="" rather="" than="" consumed="" on="" their="" own,="" that="" it="" was="" unclear="" whether="" the="" final="" products="" would="" themselves="" meet="" the="" requirements="" for="" the="" proposed="" claim.="" another="" comment="" noted="" that="" many="" of="" the="" qualifying="" products="" listed="" in="" the="" petition="" were="" varieties="" of="" non-dairy="" soy="" beverages="" or="" tofu,="" which="" this="" comment="" argued="" have="" not="" been="" well="" accepted="" by="" american="" consumers.="" other="" comments="" noted="" that="" most="" of="" the="" soy="" products="" that="" are="" available="" on="" the="" market="" that="" would="" meet="" the="" proposed="" per="" racc="" requirement="" are="" entree-="" type="" products="" that="" consumers="" would="" probably="" not="" consume="" four="" times="" per="" day.="" some="" comments="" suggested="" that="" only="" vegetarian="" or="" soy="" burgers,="" shakes,="" tofu,="" and="" non-dairy="" soy="" beverages="" would="" meet="" the="" proposed="" per="" racc="" requirement.="" one="" comment="" noted="" that="" many="" of="" the="" products="" that="" meet="" the="" racc="" requirements="" are="" specialty="" items="" that="" are="" only="" available="" at="" health="" food="" stores.="" in="" contrast,="" other="" comments="" argued="" that="" many="" existing="" soy="" products="" meet="" the="" proposed="" per="" racc="" requirement="" or="" could="" easily="" be="" reformulated="" to="" meet="" that="" requirement.="" one="" comment="" suggested="" that="" the="" vast="" majority="" of="" products="" containing="" soy="" protein="" that="" are="" currently="" available="" on="" the="" market="" meet="" the="" proposed="" racc="" level.="" these="" comments="" argued="" that="" the="" assumption="" of="" four="" eating="" occasions="" per="" day="" that="" was="" used="" to="" derive="" the="" 6.25="" g="" per="" racc="" requirement="" from="" the="" 25="" g="" per="" day="" level="" was="" reasonable.="" among="" the="" products="" listed="" in="" these="" comments="" were="" the="" following:="" tofu,="" soy-based="" beverages,="" soy="" burgers="" and="" other="" meat="" alternatives,="" frozen="" deserts,="" protein="" bars,="" cheese="" and="" yogurt="" alternatives,="" soybeans,="" soynut="" butter,="" soynuts,="" tempeh,="" miso,="" and="" soy="" flour="" or="" soy="" protein="" powder.="" another="" comment="" implied="" that="" any="" product="" in="" which="" protein="" is="" normally="" consumed="" could="" easily="" be="" modified="" to="" meet="" the="" per="" racc="" requirements,="" including="" snack="" foods,="" breakfast="" cereals,="" burger="" patties,="" and="" more="" formal="" entrees.="" some="" comments="" argued="" that="" the="" 6.25="" g="" per="" racc="" restrictions="" would="" effectively="" prevent="" baked="" products="" from="" bearing="" the="" claim.="" one="" comment="" noted="" that="" achieving="" a="" level="" of="" 6.25="" g="" per="" racc="" in="" these="" products="" would="" require="" incorporating="" soy="" flour="" at="" 15="" percent="" inclusion="" or="" greater="" and="" that="" would="" yield="" a="" product="" that="" would="" be="" unacceptable="" to="" consumers="" and="" would="" also="" be="" too="" costly="" to="" compete="" effectively="" with="" other="" products.="" many="" comments="" argued="" that="" the="" benefits="" of="" this="" rule="" would="" be="" greater="" if="" commonly="" consumed="" products="" such="" as="" baked="" products="" were="" able="" to="" bear="" the="" proposed="" health="" claim.="" one="" comment="" argued="" that="" a="" per="" racc="" requirement="" that="" allowed="" baked="" goods="" containing="" soy="" protein="" to="" bear="" the="" health="" claim="" might="" lead="" to="" additional="" benefits="" in="" terms="" of="" encouraging="" the="" consumption="" of="" products="" from="" grain="" group="" of="" the="" usda/dhhs="" food="" guide="" pyramid,="" which="" this="" comment="" claims="" are="" currently="" underconsumed.="" other="" comments="" argued="" that="" the="" proposed="" per="" racc="" requirement="" would="" effectively="" prevent="" other="" types="" of="" products="" from="" bearing="" the="" health="" claim.="" one="" comment="" argued="" that="" it="" is="" difficult="" to="" incorporate="" 6.25="" g="" soy="" protein="" into="" a="" single="" racc="" of="" most="" such="" foods="" in="" a="" way="" that="" it="" would="" be="" palatable="" to="" most="" american="" consumers,="" given="" current="" and="" reasonably="" anticipated="" technology.="" some="" of="" the="" comments="" that="" argued="" that="" few="" products="" would="" be="" able="" to="" meet="" the="" 6.25="" g="" per="" racc="" requirement="" recommended="" lowering="" the="" minimum="" per="" racc="" level="" to="" allow="" a="" wider="" variety="" of="" foods="" to="" qualify="" for="" the="" health="" claim="" and="" to="" make="" it="" easier="" for="" consumers="" to="" achieve="" an="" intake="" of="" 25="" g="" soy="" protein="" per="" day.="" some="" comments="" argued="" that="" a="" level="" of="" 4="" g="" per="" racc="" would="" allow="" baked="" goods,="" allow="" soy="" pasta,="" low-fat="" extended="" meat="" products,="" and="" vegetarian="" burgers="" made="" with="" soy="" flour="" and="" textured="" soy="" protein="" to="" bear="" the="" claim.="" these="" comments="" noted="" that="" assuming="" intake="" levels="" of="" 5="" to="" 6="" servings="" per="" day="" of="" these="" types="" of="" products="" would="" be="" reasonable="" and="" that="" 4="" g="" per="" racc="" would,="" therefore,="" be="" consistent="" with="" a="" daily="" intake="" of="" 25="" g="" per="" day.="" another="" comment="" suggested="" that="" fda="" has="" legal="" precedent="" for="" setting="" the="" per="" racc="" requirement="" as="" low="" as="" 2.5="" g="" per="" racc.="" in="" contrast,="" some="" of="" the="" comments="" that="" argued="" that="" few="" products="" would="" meet="" the="" 6.25="" g="" per="" racc="" requirement="" recommended="" raising="" the="" per="" racc="" level="" to="" reduce="" the="" number="" of="" servings="" that="" would="" be="" necessary="" to="" obtain="" 25="" g="" soy="" protein="" per="" day.="" some="" comments="" argued="" that="" if="" the="" primary="" source="" of="" soy="" protein="" were="" from="" meals="" in="" which="" high="" protein="" meat="" dishes="" are="" currently="" eaten,="" then="" the="" per="" racc="" requirement="" should="" be="" based="" on="" two="" or="" three="" servings="" per="" day,="" rather="" than="" the="" proposed="" assumption="" of="" four="" servings="" per="" day.="" thus,="" these="" comments="" suggested="" that="" fda="" revise="" the="" per="" racc="" requirement="" from="" 6.25="" g="" to="" either="" 8.3="" g="" or="" 12.5="" g.="" fda="" has="" insufficient="" information="" on="" the="" characteristics="" of="" the="" soy="" products="" that="" are="" currently="" on="" the="" market="" to="" determine="" the="" proportion="" of="" such="" products="" that="" would="" qualify="" for="" the="" health="" claim,="" the="" ease="" with="" which="" existing="" products="" can="" be="" reformulated="" to="" meet="" the="" requirements="" for="" making="" the="" health="" claims,="" or="" the="" ease="" with="" which="" new="" products="" can="" be="" developed="" that="" would="" meet="" the="" requirements="" for="" making="" the="" health="" claim.="" in="" addition,="" fda="" has="" insufficient="" information="" on="" the="" consumption="" patterns="" of="" the="" relevant="" products="" to="" determine="" whether="" lowering="" the="" per="" racc="" level="" would="" lead="" more="" or="" fewer="" consumers="" to="" consume="" 25="" g="" soy="" protein="" per="" day.="" some="" comments="" noted="" that="" the="" proposed="" health="" claim="" contains="" information="" on="" (1)="" the="" daily="" intake="" level="" of="" soy="" protein="" that="" is="" associated="" with="" reduced="" risk="" of="" chd="" and="" (2)="" the="" level="" of="" soy="" protein="" in="" a="" serving="" of="" the="" product="" bearing="" the="" claim.="" according="" to="" these="" comments,="" the="" provision="" of="" this="" information="" obviates="" the="" need="" to="" restrict="" the="" claim="" to="" products="" having="" 6.25="" g="" or="" more="" soy="" protein="" per="" racc,="" because="" consumers="" can="" easily="" determine="" the="" relative="" significance="" of="" particular="" products="" as="" a="" source="" of="" soy="" protein.="" these="" comments="" implied="" that="" specifying="" a="" much="" lower="" minimum="" level="" of="" soy="" protein="" would="" increase="" benefits="" because="" a="" wider="" variety="" of="" products="" would="" then="" be="" able="" to="" bear="" the="" claim="" and="" consumers="" would="" more="" easily="" be="" able="" to="" achieve="" an="" intake="" of="" 25="" g="" soy="" protein="" per="" day.="" allowing="" the="" claim="" to="" appear="" on="" products="" containing="" very="" low="" levels="" of="" soy="" protein="" might="" increase="" the="" usefulness="" of="" the="" claim="" for="" consumers="" and="" might="" lead="" to="" a="" greater="" reduction="" in="" chd="" than="" would="" be="" produced="" by="" taking="" the="" proposed="" action.="" the="" agency="" is="" unable="" to="" determine="" the="" likelihood="" of="" this="" effect.="" other="" comments="" suggested="" revising="" the="" per="" racc="" requirement="" for="" other="" reasons.="" one="" comment="" argued="" that="" the="" per="" racc="" requirement="" should="" be="" changed="" to="" a="" requirement="" based="" on="" serving="" size.="" this="" comment="" argued,="" for="" example,="" that="" a="" single="" veggie="" burger="" that="" contains="" 6.25="" g="" of="" soy="" protein="" should="" qualify="" for="" the="" health="" claim,="" even="" if="" the="" product="" does="" not="" meet="" the="" per="" racc="" requirement="" because="" the="" burger="" pattie="" is="" larger="" than="" the="" applicable="" racc.="" changing="" the="" per="" racc="" requirement="" to="" a="" per="" serving="" requirement="" would="" probably="" increase="" the="" number="" of="" products="" that="" would="" be="" able="" to="" bear="" the="" proposed="" health="" claim="" and="" might,="" therefore,="" increase="" the="" health="" benefits="" generated="" by="" the="" claims.="" however,="" the="" comments="" did="" not="" provide="" sufficient="" information="" to="" estimate="" this="" effect.="" in="" addition,="" this="" revision="" would="" require="" revision="" of="" the="" regulations="" at="" 21="" cfr="" 101.12(g),="" and="" is,="" therefore,="" beyond="" the="" scope="" of="" this="" rulemaking.="" [[page="" 57725]]="" one="" comment="" noted="" that="" the="" correct="" declaration="" of="" 6.25="" g="" soy="" protein="" is="" 6="" g="" because="" current="" law="" mandates="" that="" the="" amount="" of="" protein="" be="" rounded="" to="" the="" nearest="" whole="" number.="" according="" to="" this="" comment,="" this="" rounding="" might="" confuse="" consumers.="" if="" consumers="" were="" confused="" about="" the="" level="" of="" soy="" protein="" in="" the="" racc="" of="" a="" particular="" product="" and="" the="" significance="" of="" that="" product="" for="" meeting="" the="" specified="" daily="" intake="" level,="" then="" the="" benefits="" of="" the="" health="" claim="" might="" be="" lower="" than="" they="" would="" be="" otherwise.="" this="" comment="" suggested="" that="" the="" per="" racc="" requirement="" be="" revised="" from="" 6.25="" g="" to="" either="" 6="" g="" or="" 7="" g.="" as="" discussed="" previously,="" the="" rounding="" requirement="" applies="" only="" to="" the="" nutrition="" facts="" panel="" and="" soy="" protein="" content="" is="" not="" allowed="" to="" appear="" on="" the="" nutrition="" facts="" panel.="" 5.="" option="" five:="" take="" proposed="" action,="" but="" specify="" a="" minimum="" level="" of="" soy="" isoflavones="" in="" addition="" to="" the="" proposed="" minimum="" level="" of="" soy="" protein="" for="" products="" bearing="" the="" claim="" some="" comments="" argued="" that="" the="" effect="" of="" soy="" protein="" on="" the="" risk="" of="" chd="" may="" depend="" on="" the="" presence="" of="" soy="" isoflavones.="" these="" comments="" recommended="" that="" the="" health="" claim="" be="" restricted="" to="" products="" that="" contain="" a="" minimum="" level="" of="" total="" soy="" isoflavones,="" of="" particular="" isoflavones,="" of="" both="" total="" isoflavones="" and="" particular="" isoflavones,="" or="" of="" amino="" acids="" such="" as="" arginine="" and="" methionine.="" some="" of="" the="" comments="" that="" argued="" that="" the="" beneficial="" effects="" of="" soy="" protein="" may="" depend="" on="" the="" presence="" of="" soy="" isoflavones="" also="" noted="" that="" particular="" manufacturing="" or="" processing="" methods="" can="" affect="" the="" level="" of="" soy="" isoflavones.="" these="" comments="" recommended="" that="" the="" health="" claim="" be="" restricted="" to="" products="" that="" have="" been="" manufactured="" or="" processed="" in="" particular="" ways.="" for="" example,="" many="" comments="" noted="" that="" alcohol="" washing="" reduces="" isoflavone="" content="" and="" suggested="" that="" products="" containing="" alcohol="" washed="" or="" extracted="" soy="" protein="" isolate="" should="" not="" be="" authorized="" to="" bear="" the="" health="" claim.="" some="" comments="" added="" that="" there="" is="" no="" evidence="" that="" adding="" purified="" soy="" isoflavone="" extract="" back="" into="" such="" products="" is="" effective="" and="" argued="" that="" any="" isoflavone="" requirement="" should="" be="" based="" on="" naturally="" occurring="" isoflavones.="" as="" discussed="" earlier="" in="" this="" preamble,="" fda="" finds="" that="" the="" scientific="" evidence="" does="" not="" indicate="" that="" the="" effect="" of="" soy="" protein="" on="" the="" risk="" of="" chd="" varies="" with="" the="" presence="" of="" soy="" isoflavones="" or="" amino="" acids.="" therefore,="" no="" additional="" benefit="" would="" result="" from="" restricting="" the="" claim="" to="" products="" having="" particular="" levels="" of="" isoflavones,="" or="" produced="" using="" particular="" methods="" of="" manufacture.="" 6.="" option="" six:="" take="" proposed="" action,="" but="" revise="" wording="" of="" the="" claim="" or="" require="" that="" warnings="" or="" other="" statements="" accompany="" the="" claim="" some="" comments="" suggested="" that="" fda="" require="" additional="" information="" be="" put="" on="" the="" labels="" of="" product="" bearing="" the="" proposed="" claim="" that="" explains="" the="" conditions="" under="" which="" soy="" protein="" reduces="" the="" risk="" of="" chd.="" for="" example,="" some="" comments="" suggested="" that="" product="" labels="" should="" make="" it="" clear="" that="" no="" benefits="" should="" be="" expected="" for="" daily="" soy="" protein="" intake="" levels="" of="" less="" than="" 25="" g.="" some="" comments="" argued="" that="" the="" beneficial="" effects="" of="" soy="" protein="" accrue="" only="" to="" consumers="" who="" have="" high="" cholesterol="" levels="" and="" suggested="" that="" the="" proposed="" health="" claim="" be="" revised="" to="" communicate="" this="" fact.="" although="" requiring="" a="" label="" statement="" clarifying="" that="" benefits="" should="" not="" be="" expected="" for="" daily="" soy="" protein="" intake="" levels="" of="" less="" than="" 25="" g="" might="" generate="" benefits,="" the="" marginal="" benefits="" of="" such="" a="" statement="" are="" unclear="" given="" that="" the="" proposed="" health="" claim="" relates="" health="" effects="" to="" an="" intake="" of="" 25="" g="" per="" day="" and="" not="" to="" the="" intake="" of="" any="" particular="" product.="" the="" comment="" did="" not="" provide="" sufficient="" information="" to="" estimate="" the="" marginal="" benefit="" of="" an="" additional="" statement="" concerning="" the="" significance="" of="" the="" 25="" g="" per="" day="" intake="" level.="" finally,="" as="" discussed="" previously="" in="" this="" preamble,="" fda="" has="" determined="" that="" the="" effect="" of="" soy="" protein="" on="" the="" risk="" of="" chd="" may="" depend,="" in="" part,="" on="" initial="" cholesterol="" levels,="" but="" does="" not="" accrue="" only="" to="" those="" with="" high="" initial="" cholesterol="" levels.="" therefore,="" restricting="" the="" health="" claim="" to="" apply="" to="" only="" those="" with="" high="" initial="" cholesterol="" levels="" would="" not="" generate="" marginal="" benefits.="" some="" of="" the="" comments="" that="" argued="" that="" the="" increased="" consumption="" of="" products="" containing="" soy="" protein="" could="" lead="" to="" health="" risks="" suggested="" that="" fda="" require="" warning="" labels="" on="" those="" products="" to="" alert="" consumers="" of="" the="" risks.="" other="" comments="" suggested="" that="" various="" types="" of="" information="" relevant="" to="" the="" purported="" health="" risks="" be="" reported="" on="" product="" labels.="" for="" example,="" one="" comment="" that="" argued="" that="" increased="" intake="" of="" soy="" protein="" could="" lead="" to="" zinc="" deficiency="" suggested="" that="" the="" labels="" of="" products="" bearing="" the="" health="" claim="" indicate="" the="" phytate="" and="" zinc="" content="" per="" serving="" for="" those="" products.="" one="" comment="" suggested="" that="" labels="" indicate="" a="" recommended="" maximum="" daily="" intake="" of="" soy="" protein="" to="" prevent="" the="" health="" risks="" associated="" with="" overconsumption="" of="" products="" containing="" soy="" protein.="" this="" comment="" argued="" that="" daily="" consumption="" of="" between="" 25="" g="" and="" 100="" g="" of="" isolated="" soy="" protein="" could="" result="" in="" nitrosamine="" exposures="" that="" exceeds="" established="" no="" significant="" risk="" levels.="" one="" comment="" argued="" that="" manufacturers="" should="" voluntary="" provide="" information="" on="" product="" labels="" on="" various="" issues="" such="" as="" manufacturing="" methods="" and="" the="" use="" of="" pesticides,="" because="" consumers="" have="" a="" right="" to="" such="" information.="" fda="" has="" determined="" that="" there="" is="" no="" evidence="" that="" health="" risks="" are="" associated="" with="" increased="" intake="" of="" soy="" protein="" or="" the="" other="" substances="" discussed="" in="" the="" comments.="" label="" statements="" warning="" of="" possible="" allergic="" reactions="" to="" soy="" protein="" would="" provide="" some="" potentially="" valuable="" information="" to="" consumers="" who="" do="" not="" realize="" they="" are="" allergic="" to="" soy="" protein="" or="" that="" such="" allergies="" are="" possible.="" however,="" such="" labeling="" would="" not="" provide="" useful="" information="" to="" those="" consumers="" who="" are="" already="" aware="" of="" the="" fact="" that="" allergies="" to="" common="" foods="" are="" possible,="" and="" might="" discourage="" the="" consumption="" of="" soy="" protein="" by="" those="" who="" are="" not="" allergic="" to="" soy="" protein.="" fda="" has="" insufficient="" information="" to="" estimate="" the="" costs="" or="" benefits="" of="" such="" a="" warning="" statement="" or="" to="" determine="" if="" such="" a="" warning="" statement="" would="" provide="" a="" net="" benefit="" to="" consumers.="" associating="" warning="" statements="" with="" the="" proposed="" health="" claim="" would="" generate="" no="" marginal="" benefits="" for="" consumers="" who="" know="" they="" are="" allergic="" to="" soy="" protein="" because="" the="" health="" claim="" would="" already="" indicate="" the="" presence="" of="" soy="" protein.="" label="" statements="" addressed="" to="" the="" potential="" effect="" of="" increased="" consumption="" of="" products="" containing="" soy="" protein="" on="" zinc="" deficiency,="" such="" as="" a="" warning="" statement,="" indications="" of="" the="" zinc="" and="" phytate="" content="" of="" products="" containing="" soy="" protein,="" or="" recommended="" maximum="" daily="" intakes,="" might="" reduce="" the="" likelihood="" that="" increased="" consumption="" of="" these="" products="" will="" lead="" to="" zinc="" deficiency.="" earlier="" in="" the="" preamble="" to="" this="" rule,="" fda="" determined="" that="" consumers="" would="" not="" find="" information="" relating="" to="" the="" zinc="" and="" phytate="" content="" of="" products="" containing="" soy="" protein="" useful.="" the="" other="" suggested="" labeling="" approaches="" for="" addressing="" the="" effect="" of="" increased="" consumption="" of="" these="" products="" on="" zinc="" deficiency="" may="" be="" useful="" for="" some="" consumers.="" however,="" again,="" the="" benefit="" of="" such="" labeling="" must="" be="" compared="" to="" the="" possible="" costs="" in="" terms="" of="" discouraging="" the="" use="" of="" such="" products="" among="" those="" who="" are="" not="" at="" risk="" of="" zinc="" deficiency.="" fda="" has="" insufficient="" information="" to="" estimate="" the="" costs="" or="" benefits="" of="" the="" other="" suggested="" labeling="" approaches="" or="" determining="" whether="" such="" approaches="" would="" generate="" net="" benefits.="" one="" comment="" suggested="" eliminating="" the="" language="" relating="" the="" effect="" of="" soy="" protein="" to="" diets="" low="" in="" saturated="" fat="" and="" [[page="" 57726]]="" cholesterol="" because="" the="" effect="" of="" soy="" protein="" on="" the="" risk="" of="" chd="" is="" independent="" of="" these="" other="" factors.="" the="" benefit="" of="" eliminating="" this="" language="" is="" that="" consumers="" who="" are="" not="" currently="" eating="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol="" may="" be="" more="" likely="" to="" react="" to="" the="" health="" claim="" if="" the="" effect="" of="" soy="" protein="" is="" not="" presented="" as="" applying="" only="" to="" those="" eating="" diets="" low="" in="" saturated="" fat="" and="" cholesterol.="" an="" increase="" in="" the="" number="" of="" consumers="" likely="" to="" react="" to="" the="" health="" claim="" may="" increase="" the="" benefits="" of="" the="" health="" claim.="" however,="" the="" size="" of="" this="" marginal="" benefit="" is="" unclear="" because,="" as="" discussed="" earlier,="" the="" available="" data="" on="" the="" effects="" of="" soy="" protein="" show="" that="" soy="" protein="" has="" a="" more="" consistent="" effect="" on="" chd="" for="" those="" consuming="" a="" low="" fat="" and="" cholesterol="" diet="" than="" for="" others.="" the="" cost="" of="" eliminating="" this="" language="" is="" that="" some="" consumers="" might="" believe="" that="" achieving="" a="" certain="" intake="" of="" soy="" protein="" can="" substitute="" for="" eating="" a="" diet="" low="" in="" saturated="" fat="" and="" cholesterol="" and="" might,="" therefore,="" indirectly="" increase="" the="" intake="" of="" saturated="" fat="" and="" cholesterol.="" fda="" has="" insufficient="" information="" to="" determine="" if="" eliminating="" the="" language="" relating="" the="" effect="" of="" soy="" protein="" to="" diets="" low="" in="" saturated="" fat="" and="" cholesterol="" would="" generate="" net="" benefits="" or="" costs.="" some="" comments="" suggested="" that="" the="" proposed="" health="" claim="" was="" either="" too="" long="" or="" too="" complicated="" to="" be="" effective.="" many="" comments="" argued="" that="" the="" health="" claim="" would="" be="" more="" effective="" if="" it="" were="" shortened="" or="" replaced="" by="" a="" ``split="" claim.''="" many="" comments="" suggested="" wording="" for="" a="" shorter="" health="" claim.="" increasing="" the="" effectiveness="" of="" the="" health="" claim="" would="" increase="" the="" benefits="" associated="" with="" the="" health="" claim="" and="" would="" not="" affect="" costs.="" however,="" fda="" has="" insufficient="" information="" to="" analyze="" the="" effect="" of="" different="" labeling="" formats="" or="" wording.="" although="" fda="" has="" studied="" the="" effectiveness="" of="" split="" claims="" for="" other="" types="" of="" claims,="" the="" relevance="" of="" that="" information="" for="" a="" health="" claim="" on="" soy="" protein="" is="" unclear.="" 7.="" option="" seven:="" take="" proposed="" action,="" but="" specify="" a="" different="" maximum="" total="" fat="" content="" or="" grant="" an="" exemption="" from="" the="" maximum="" total="" fat="" requirement="" for="" foods="" made="" with="" natural="" soybeans="" that="" have="" no="" added="" fat="" many="" comments="" noted="" that="" the="" low="" fat="" requirement="" for="" products="" bearing="" the="" proposed="" health="" claim="" would="" prevent="" soybeans="" and="" traditional="" soybean="" products="" from="" bearing="" the="" health="" claim.="" this="" rule="" has="" been="" revised="" so="" that="" foods="" made="" from="" whole="" soybeans="" with="" no="" added="" fat="" are="" exempted="" from="" the="" low="" fat="" requirement.="" the="" benefit="" of="" this="" revision="" is="" that="" more="" products="" will="" be="" able="" to="" bear="" the="" proposed="" health="" claim="" and="" the="" benefits="" generated="" by="" the="" health="" claim="" may="" be="" increased.="" the="" cost="" of="" this="" revision="" is="" that="" the="" total="" fat="" content="" of="" some="" products="" bearing="" the="" claim="" may="" be="" slightly="" higher="" than="" under="" the="" proposed="" rule.="" as="" explained="" earlier="" in="" the="" preamble,="" a="" reduction="" of="" total="" fat="" facilitates="" maintenance="" of="" normal="" body="" weight="" and,="" therefore,="" reduces="" the="" risk="" of="" obesity.="" the="" reduction="" of="" this="" effect="" would="" cause="" an="" increase="" in="" the="" risk="" of="" obesity="" and,="" therefore,="" produce="" a="" countervailing="" increase="" in="" the="" risk="" of="" chd.="" in="" this="" case,="" the="" benefit="" of="" increasing="" the="" number="" of="" products="" probably="" outweighs="" the="" slight="" increase="" in="" the="" total="" fat="" content="" of="" qualifying="" products.="" 8.="" option="" eight:="" take="" proposed="" action,="" but="" use="" a="" different="" procedure="" for="" determining="" level="" of="" soy="" protein="" in="" particular="" products.="" many="" comments="" on="" the="" proposal="" addressed="" the="" analytical="" method="" that="" fda="" proposed="" to="" use="" to="" confirm="" the="" level="" of="" soy="" protein="" in="" products="" bearing="" the="" proposed="" health="" claim.="" these="" comments="" were="" discussed="" in="" the="" reproposal.="" the="" reproposal="" specified="" various="" types="" of="" records="" that="" might="" allow="" fda="" to="" calculate="" the="" level="" of="" soy="" protein="" in="" particular="" products.="" fda="" received="" a="" number="" of="" comments="" on="" the="" reproposal.="" most="" of="" these="" comments="" addressed="" the="" issue="" of="" which="" records="" fda="" will="" use="" to="" determine="" the="" soy="" protein="" content="" of="" foods.="" many="" comments="" argued="" that="" the="" reproposal="" appeared="" to="" allow="" fda="" wide="" discretion="" in="" determining="" which="" records="" to="" inspect="" and="" duplicate.="" these="" comments="" also="" expressed="" the="" concern="" that="" fda="" might="" inspect="" and="" duplicate="" records="" of="" each="" of="" the="" various="" types="" that="" were="" specified="" as="" potentially="" relevant="" in="" the="" reproposal,="" and="" might="" also="" inspect="" and="" duplicate="" as="" yet="" unspecified="" records="" that="" fda="" later="" determines="" are="" relevant.="" according="" to="" these="" comments,="" some="" of="" the="" resulting="" record="" inspection="" and="" duplication="" might="" be="" unwarranted.="" many="" comments="" suggested="" that="" the="" rule="" be="" revised="" to="" require="" manufacturers="" to="" provide="" fda="" with="" records="" that="" provide="" a="" reasonable="" basis="" for="" concluding="" that="" a="" particular="" product="" has="" sufficient="" soy="" protein="" content="" to="" bear="" the="" health="" claim.="" according="" to="" these="" comments,="" this="" revision="" would="" eliminate="" the="" possibility="" that="" fda="" will="" use="" the="" records="" inspections="" clause="" to="" inspect="" and="" duplicate="" records="" in="" situations="" in="" which="" such="" actions="" are="" not="" strictly="" necessary.="" one="" comment="" argued="" that="" the="" records="" inspection="" provision="" would="" give="" an="" unfair="" market="" advantage="" to="" firms="" that="" manufacture="" products="" whose="" sole="" source="" of="" protein="" is="" soy="" and="" which,="" therefore,="" need="" not="" provide="" fda="" access="" to="" records="" to="" establish="" the="" level="" of="" soy="" protein="" in="" their="" products.="" if="" fda="" were="" to="" require="" the="" inspection="" and="" duplication="" of="" records="" that="" firms="" attempting="" to="" use="" the="" soy="" protein="" health="" claim="" considered="" unnecessary="" to="" establish="" compliance="" with="" the="" requirements="" for="" making="" that="" claim,="" then="" those="" firms="" would="" have="" less="" incentive="" to="" use="" the="" claim="" and="" the="" benefits="" associated="" with="" allowing="" that="" claim="" would="" be="" reduced.="" however,="" fda="" has="" modified="" its="" proposal="" to="" inspect="" records="" to="" provide,="" instead,="" that="" manufacturers="" must="" identify="" and="" supply="" to="" fda,="" on="" written="" request,="" records="" that="" substantiate="" the="" amount="" of="" soy="" protein="" in="" a="" food="" that="" bears="" the="" soy="" protein="" health="" claim="" if="" soy="" is="" not="" the="" sole="" source="" of="" protein="" in="" the="" food.="" therefore,="" this="" rule="" will="" not="" require="" record="" inspection="" or="" unnecessary="" duplication="" of="" records.="" this="" rule="" may="" generate="" some="" distributive="" effects="" because="" it="" may="" put="" firms="" that="" are="" required="" to="" provide="" such="" records="" at="" a="" competitive="" disadvantage="" relative="" to="" firms="" that="" produce="" products="" in="" which="" soy="" is="" the="" only="" source="" of="" protein.="" however,="" these="" effects="" will="" probably="" be="" small="" because="" manufacturers="" probably="" already="" maintain="" the="" necessary="" records.="" d.="" small="" entity="" analysis="" fda="" has="" examined="" the="" impacts="" of="" this="" proposed="" rule="" under="" the="" regulatory="" flexibility="" act.="" the="" regulatory="" flexibility="" act="" (5="" u.s.c.="" 601-612)="" requires="" federal="" agencies="" to="" consider="" alternatives="" that="" would="" minimize="" the="" economic="" impact="" of="" their="" regulations="" on="" small="" businesses="" and="" other="" small="" entities.="" no="" compliance="" costs="" are="" generated="" by="" this="" rule="" because="" this="" rule="" does="" 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="" to="" those="" small="" businesses="" outweigh="" the="" costs.="" fda="" did="" not="" receive="" any="" comments="" that="" challenged="" this="" conclusion.="" accordingly,="" pursuant="" to="" the="" regulatory="" flexibility="" act,="" 5="" u.s.c.="" 605(b),="" fda="" certifies="" that="" this="" rule="" will="" not="" have="" a="" significant="" economic="" impact="" on="" a="" substantial="" number="" of="" small="" entities.="" v.="" paperwork="" reduction="" act="" of="" 1995="" this="" final="" rule="" contains="" information="" collection="" provisions="" that="" are="" subject="" to="" review="" by="" the="" office="" of="" management="" and="" budget="" (omb)="" under="" the="" paperwork="" reduction="" act="" of="" 1995="" (the="" pra)="" (44="" u.s.c.="" 3501-3520).="" the="" title,="" description,="" and="" respondent="" description="" [[page="" 57727]]="" are="" shown="" below="" with="" an="" estimate="" of="" the="" annual="" recordkeeping="" and="" reporting="" burden.="" included="" in="" the="" estimate="" is="" the="" time="" for="" reviewing="" instructions,="" searching="" existing="" data="" sources,="" gathering="" and="" maintaining="" the="" data="" needed,="" and="" completing="" and="" reviewing="" each="" collection="" of="" information.="" title:="" record="" retention="" requirements="" for="" the="" soy="" protein/chd="" health="" claim="" description:="" the="" regulation="" set="" forth="" in="" this="" rule="" authorizes="" the="" use="" in="" food="" labeling="" of="" a="" health="" claim="" about="" the="" relationship="" between="" soy="" protein="" and="" chd.="" section="" 403(r)="" of="" the="" act="" requires="" that="" food="" bearing="" a="" health="" claim="" authorized="" by="" regulation="" on="" a="" petition="" to="" the="" agency="" be="" labeled="" in="" compliance="" with="" the="" regulation="" issued="" by="" fda.="" in="" response="" to="" comments="" received="" on="" the="" soy="" protein="" proposed="" rule="" (63="" fr="" 62977),="" the="" agency="" proposed="" an="" alternative="" procedure="" for="" assessing="" compliance="" with="" the="" requirement="" that="" a="" food="" contain="" a="" qualifying="" amount="" of="" soy="" protein="" in="" the="" soy="" protein="" reproposal="" (64="" fr="" 45932).="" this="" procedure="" would="" have="" required="" that="" a="" manufacturer="" of="" a="" product="" bearing="" the="" proposed="" soy="" protein="" health="" claim="" whose="" product="" contains="" a="" source="" or="" sources="" of="" protein="" in="" addition="" to="" soy="" retain="" the="" records="" that="" permit="" the="" calculation="" of="" the="" ratio="" of="" soy="" protein="" to="" other="" sources="" of="" protein="" in="" the="" food.="" the="" manufacturer="" of="" such="" a="" food="" product="" would="" have="" been="" required="" to="" make="" those="" records="" available="" for="" review="" and="" copying="" by="" appropriate="" regulatory="" officials="" upon="" request="" and="" during="" site="" visits.="" comments="" received="" on="" the="" soy="" protein="" reproposal="" have="" been="" addressed="" by="" the="" agency="" in="" section="" ii.c.2="" of="" this="" document,="" and="" this="" rule="" reflects="" modifications="" made="" in="" response="" to="" those="" comments.="" this="" final="" rule="" requires="" a="" manufacturer="" of="" a="" product="" bearing="" the="" soy="" protein="" health="" claim="" whose="" product="" contains="" a="" source="" or="" sources="" of="" protein="" in="" addition="" to="" soy="" to="" identify="" and="" retain="" records="" that="" reasonably="" substantiate="" the="" ratio="" of="" soy="" protein="" to="" total="" protein.="" the="" rule="" also="" requires="" the="" manufacturer="" of="" such="" a="" food="" product="" to="" provide="" those="" records="" upon="" written="" request="" to="" appropriate="" regulatory="" officials.="" fda="" had="" submitted="" the="" information="" collection="" requirements="" to="" omb="" for="" review="" under="" the="" pra="" at="" the="" time="" the="" august="" 1999="" soy="" protein="" reproposal="" was="" published.="" in="" response,="" omb="" requested="" that="" fda="" respond="" to="" the="" need="" for="" the="" collection="" and="" the="" burden="" hours="" that="" will="" be="" imposed="" as="" a="" result="" of="" this="" collection.="" to="" bear="" the="" soy="" protein="" and="" chd="" health="" claim,="" foods="" must="" contain="" 6.25="" g="" soy="" protein="" per="" racc.="" for="" foods="" that="" contain="" soy="" as="" the="" sole="" source="" of="" protein,="" analytical="" methods="" for="" total="" protein="" can="" be="" used="" to="" quantify="" the="" amount="" of="" soy="" protein.="" at="" the="" present="" time,="" there="" is="" no="" validated="" analytical="" methodology="" available="" to="" quantify="" the="" amount="" of="" soy="" protein="" in="" foods="" that="" contain="" other="" proteins.="" for="" these="" latter="" foods,="" fda="" must="" rely="" on="" information="" known="" only="" to="" the="" manufacturer="" to="" assess="" compliance="" with="" the="" qualifying="" amount="" of="" soy="" protein.="" thus,="" fda="" is="" requiring="" manufacturers="" to="" have="" and="" keep="" records="" to="" substantiate="" the="" amount="" of="" soy="" protein="" in="" a="" food="" that="" bears="" the="" health="" claim="" and="" contains="" sources="" of="" protein="" other="" than="" soy,="" and="" to="" make="" such="" records="" available="" to="" appropriate="" regulatory="" officials="" upon="" written="" request.="" although="" no="" comments="" on="" the="" soy="" protein="" reproposal="" specifically="" addressed="" the="" estimated="" burden="" of="" the="" information="" collection="" requirements,="" several="" indicated="" that="" recordkeeping="" and="" record="" inspection="" would="" be="" burdensome.="" these="" comments="" expressed="" concern="" about="" fda's="" record="" inspection="" authority.="" in="" response="" to="" this="" concern,="" fda="" has="" determined="" that,="" in="" this="" case,="" it="" need="" not="" assert="" record="" inspection="" authority="" in="" order="" to="" obtain="" the="" information="" needed="" for="" compliance="" assessment.="" the="" comments="" also="" expressed="" concern="" about="" the="" potentially="" broad="" array="" of="" records="" that="" fda="" might="" demand.="" in="" response="" to="" this="" concern,="" fda="" clarified="" that="" it="" did="" not="" intend="" to="" specify="" the="" records="" to="" be="" supplied.="" rather,="" the="" final="" rule="" indicates="" that="" records="" will="" be="" requested="" in="" writing="" and="" that="" manufacturers="" will="" be="" responsible="" for="" identifying="" the="" records="" that="" they="" have="" used="" to="" substantiate="" the="" proportion="" of="" soy="" protein="" in="" their="" products.="" fda="" estimates="" the="" burden="" of="" this="" collection="" of="" information="" as="" follows:="" description="" of="" respondents:="" businesses="" or="" others="" for-profit.="" table="" 2.--estimated="" annual="" recordkeeping="" burden="">1
----------------------------------------------------------------------------------------------------------------
Annual Total
21 CFR No. of frequency per annual Hours per Total Hours
respondents response responses response
----------------------------------------------------------------------------------------------------------------
101.82(c)(2)(ii)(B)................. 25 1 25 1 25
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection.
Table 3.--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
No. of Total
21 CFR Section No. of responses per annual Hours per Total hours
respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
101.82(c)(2)(ii)(B)................. 5 1 5 1 5
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection.
Manufacturers must determine that their products are qualified to
bear any claim used on foods labels or in labeling, including meeting
the requirement for a qualifying amount of soy protein to bear the
health claim authorized for use by this regulation. In the absence of a
validated analytical methodology for soy protein in foods that contain
other proteins, manufacturers will need to use records, e.g., the
food's formulation or recipe, to determine if such a food contains 6.25
g per RACC. In this rule, FDA is requiring that firms maintain the
records they use to determine that a food is qualified to bear the
claim, and that those records be submitted to FDA upon written request.
Based upon its experience with the use of health claims, FDA estimated
that 25 firms would market products bearing a soy protein and CHD
health claim and that one of each firm's products would contain a
source or sources of protein in addition to soy. FDA received no
comments that challenged this estimate. FDA estimates that, annually,
it would request records to assess compliance from 20 percent of firms
subject to the
[[Page 57728]]
recordkeeping requirement. The records that would be required to be
retained by Sec. 101.82(c)(ii)(B)(2) are records that, as described
above, FDA believes a prudent and responsible manufacturer uses and
retains as a normal part of doing business. Thus, the burden to the
food manufacturer would be that involved in assembling and providing
the records to appropriate regulatory officials upon written request.
The requirements contained in this rule would require only a minimal
burden, no more than one hour per response, from respondents.
The information collection provisions of this final rule have been
submitted to OMB for review. FDA will publish a notice in the Federal
Register announcing OMB's decision to approve, modify, or disapprove
the information collection provisions in this final rule. An agency may
not conduct or sponsor, and a person is not required to respond to, a
collection of information unless it displays a currently valid OMB
control number.
VI. 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.
1. Protein Technologies International, Inc., ``Health Claim
Petition,'' May 4, 1998 [CP1, vol. 1-3].
2. Protein Technologies International, Inc., ``Addendum to
Health Claim Petition,'' August 10, 1998 [CP1, vol. 4].
3. American Soybean Association, ``Health Claim Petition for Soy
Protein,'' October 29, 1998 [C1, vol. 8-12].
4. DHHS, Public Health Service (PHS), ``The Surgeon General's
Report on Nutrition and Health,'' U.S. Government Printing Office,
Washington, DC, pp. 83-137, 1988.
5. Food and Nutrition Board, National Academy of Sciences,
``Diet and Health: Implications for Reducing Chronic Disease Risk,''
National Academy Press, Washington, DC, pp. 291-309 and 529-547,
1989.
6. DHHS, Public Health Service (PHS) and National Institutes of
Health, ``National Cholesterol Education Program: Population Panel
Report,'' Bethesda, MD, pp. 1-40, 1990.
7. Sempos, C. T., J. I. Cleeman, M. D. Carroll, C. L. Johnson,
P.S. Bachorik, D. J. Gordon, V. L. Burt, R. R. Briefel, C. D. Brown,
K. Lippel, and B. M. Rifkind, ``Prevalence of High Blood Cholesterol
Among U.S. Adults. An Update Based on Guidelines From the Second
Report of the National Cholesterol Education Program Adult Treatment
Panel,'' Journal of the American Medical Association, 269:3009-3014,
1993.
8. Ross, R., ``Atherosclerosis,'' in Cecil--Textbook of
Medicine, J. B. Wyndaarden, L. H. Smith, and J. C. Bennett, editors.
Harcourt Brace Johanevich, Inc. Philadelphia, P. 293-298, 1992.
9. Van Sickle, G. J., G. K. Powell, P. J. McDonald, and R. M.
Goldblum, ``Milk- and Soy Protein-induced Enterocolitis: Evidence
for Lymphocyte Sensitization to Specific Food Proteins,''
Gastroenterology, 88:1915-1921, 1985.
10. Sampson, H. A. and S. M. Scanlon, ``Natural History of Food
Hypersensitivity in Children with Atopic Dermatitis,'' Journal of
Pediatrics, 115:23-27, 1989.
11. Roebuck, B. D., ``Trypsin Inhibitors: Potential Concern for
Humans?'' Journal of Nutrition, 117:398-400, 1987.
12. Anderson, R. L. and W. J. Wolf, ``Compositional Changes in
Trypsin Inhibitors, Phytic acid, Saponins and Isoflavones Related to
Soybean Processing,'' Journal of Nutrition, 125:581S-588S, 1995.
13. Erdman, J. W., Jr. and R. M. Forbes, ``Effects of Soya
Protein on Mineral Availability,'' Journal of the American Oil
Chemists' Society, 58:489-493, 1981.
14. Liener, I. ``Significance for Humans of Biologically Active
Factors in Soybeans and Other Food Legumes,'' Journal of the
American Oil Chemists' Society, 56:121-129, 1979.
15. Kennedy, A. R., ``The Evidence for Soy Products as Cancer
Preventive Agents.'' Journal of Nutrition, 125:733S-743S, 1995.
16. Adlercreutz H. and W. Mazur, ``Phyto-oestrogens and Western
Diseases,'' Annals of Medicine, 29:95-120, 1997.
17. Liener, I. E., ``Factors Affecting the Nutritional Quality
of Soya Products,'' Journal of the American Oil Chemists' Society,
58:406-415, 1981.
18. Erdman, J. W., Jr. and E. J. Fordyce, ``Soy Products and the
Human Diet,'' American Journal of Clinical Nutrition, 49:725-737,
1989.
19. Breslau, N. A., L. Brinkley, K. D. Hill, and C. Y. C. Pak,
``Relationship of Animal Protein-rich Diet to Kidney Stone Formation
and Calcium Metabolism,'' Journal of Clinical Endocrinology and
Metabolism, 66:140-146, 1988.
20. Portale, A. A., B. P. Halloran, M. M. Murphy, and R. C.
Morris, Jr., ``Oral Intake of Phosphorus Can Determine the Serum
Concentration of 1,25-dihydroxy-vitamin D by Determining its
Production Rate in Humans.'' Journal of Clinical Investigation,
77:46-55, 1986.
21. Moule, G. R., ``Clinical Aspects of Nutritional Infertility
of Ewes,'' Australian Veterinary Journal, 46:428-435, 1970.
22. Anthony, M. S., T. B. Clarkson, C. L. Hughes, Jr., T. M.
Morgan, and G. L. Burke, ``Soybean Isoflavones Improve
Cardiovascular Risk Factors Without Affecting the Reproductive
System of Peripubertal Rheusus Monkeys,'' Journal of Nutrition,
126:43-50, 1996.
23. Honore, E. K., J. K. Williams, M. S. Anthony, and T. B.
Clarkson, ``Soy Isoflavones Enhance Coronary Vascular Reactivity in
Atherosclerotic Female Macaques,'' Fertility and Sterility, 67:148-
154, 1997.
24. Cline, J. M., J. C. Paschold, M. S. Anthony, I. O. Obasanjo,
and M. R. Adams, ``Effects of Hormonal Therapies and Dietary Soy
Phytoestrogens on Vaginal Cytology in Surgically Postmenopausal
Macaques,'' Fertility and Sterility, 65:1031-1035, 1996.
25. Lee, H. P., L. Gourley, S. W. Duffy, J. Esteve, J. Lee, and
N. E. Day, ``Dietary Effects on Breast-cancer Risk in Singapore,''
Lancet, 337:1197-1200, 1991.
26. Cassidy, A., S. Bingham, and K. D. R. Setchell, ``Biological
Effects of a Diet of Soy Protein Rich in Isoflavones on the
Menstrual Cycle of Premenopausal Women,'' American Journal of
Clinical Nutrition, 60:333-340, 1994.
27. Bakhit, R. M., B. P. Klein, D. Essex-Sorlie, J. O. Ham, J.
W. Erdman, Jr., and S. M. Potter, ``Intake of 25 g of Soybean
Protein With or Without Soybean Fiber Alters Plasma Lipids in Men
With Elevated Cholesterol Concentrations,'' Journal of Nutrition,
124:213-222, 1994.
28. Baum, J. A., H. Teng, J. W. Erdman, Jr., R. M. Weigel, B. P.
Klein, V. W. Persky, S. Freels, P. Surya, R. M. Bakhit, E. Ramos, N.
F. Shay, and S. M. Potter, ``Long-term Intake of Soy Protein
Improves Blood Lipid Profiles and Increases Mononuclear Cell Low-
density-lipoprotein Receptor Messenger RNA in Hypercholesterolemic,
Postmenopausal Women,'' American Journal of Clinical Nutrition,
68:545-551, 1998.
29. Bosello, O., L. Cominacini, I. Zocca, U. Garbin, R. Compri,
A. Davoli, and L. Brunetti, ``Short-and Long-term Effects of
Hypocaloric Diets Containing Proteins of Different Sources on Plasma
Lipids and Apoproteins of Obese Subjects,'' Annals of Nutrition
Metabolism, 32:206-214, 1988.
30. Carroll, K. K., P. M. Giovannetti, M. W. Huff, O. Moase, D.
C. K. Roberts, and B. M. Wolfe, ``Hypocholesterolemic Effect of
Substituting Soybean Protein for Animal Protein in the Diet of
Healthy Young Women,'' American Journal of Clinical Nutrition,
31:1312-1321, 1978.
31. Crouse, J. R., III, T. Morgan, J. G. Terry, J. Ellis, M.
Vitolins, and G. L. Burke, ``A Randomized Trial Comparing the Effect
of Casein with That of Soy Protein Containing Varying Amounts of
Isoflavones on Plasma Concentrations of Lipids and Lipoproteins,''
Archives of Internal Medicine, 159:2070-2076, 1999.
32. Cruz, M. L. A., W. W. Wong, F. Mimouni, D. L. Hachey, K. D.
R. Setchell, P. D. Klein, and R. C. Tsang, ``Effects of Infant
Nutrition on Cholesterol Synthesis Rates,'' Pediatric Research,
35:135-140, 1994.
33. Descovich, G. C., C. Ceredi, A. Gaddi, M. S. Benassi, G.
Mannino, L. Colombo, L. Cattin, G. Fontana, U. Senin, E. Mannarino,
C. Caruzzo, E. Bertelli, C. Fragiacomo, G. Noseda, M. Sirtori, and
C. R. Sirtori, ``Multicentre Study of Soybean Protein Diet for
Outpatient Hypercholesterolaemic Patients,'' Lancet, 2:709-712,
1980.
34. A. Gaddi, G. C. Descovich, G. Noseda, C. Fragiacomo, A.
Nicolini, G. Montanari, G. Vanetti, M. Sirtori, E. Gatti, and C. R.
Sirtori, ``Hypercholesterolaemia Treated by Soybean Protein Diet,''
Archives of Disease in Childhood, 62:274-278, 1987.
35. Gaddi, A., A. Ciarrocchi, A. Matteucci, S. Rimondi, G.
Ravaglia, G. C. Descovich, and C. R. Sirtori, ``Dietary Treatment
for Familial Hypercholesterolemia--Differential Effects of Dietary
Soy Protein According to the Apolipoprotein E Phenotypes,'' American
Journal of Clinical Nutrition, 53:1191-1196, 1991.
[[Page 57729]]
36. Giovannetti, P. M., K. K. Carroll, and B. M. Wolfe,
``Constancy of Fasting Serum Cholesterol of Healthy Young Women Upon
Substitution of Soy Protein Isolate for Meat and Dairy Protein in
Medium and Low Fat Diets,'' Nutrition Research, 6:609-618, 1986.
37. Goldberg, A. P., A. Lim, J. B. Kolar, J. J. Grundhauser, F.
H. Steinke, and G. Schonfeld, ``Soybean Protein Independently Lowers
Plasma Cholesterol Levels in Primary Hypercholesterolemia,''
Atherosclerosis, 43:355-368, 1982.
38. Gooderham, M. J., H. Adlercreutz, S. T. Ojala, K. Wahala,
and B. J. Holub, ``A Soy Protein Isolate Rich in Genistein and
Daidzein and its Effects on Plasma Isoflavone Concentrations,
Platelet Aggregation, Blood Lipids and Fatty Acid Composition of
Plasma Phospholipid in Normal Men,'' Journal of Nutrition, 126:2000-
2006, 1996.
39. Grundy, S. M. and J. J. Abrams, ``Comparison of Actions of
Soy Protein and Casein on Metabolism of Plasma Lipoproteins and
Cholesterol in Humans,'' American Journal of Clinical Nutrition,
38:245-252, 1983.
40. Holmes, W. L., G. B. Rubel, and S. S. Hood, ``Comparison of
the Effect of Dietary Meat Versus Dietary Soybean Protein on Plasma
Lipids of Hyperlipidemic Individuals,'' Atherosclerosis, 36:379-387,
1980.
41. Huff, M. W., P. M. Giovannetti, and B. M. Wolfe, ``Turnover
of Very Low-density Lipoprotein-Apoprotein B is Increased by
Substitution of Soybean Protein for Meat and Dairy Protein in the
Diets of Hypercholsterolemic Men,'' American Journal of Clinical
Nutrition, 39:888-897, 1984.
42. Jacques, H., D. Laurin, S. Moorjani, F. H. Steinke, C.
Gagne, D. Brun, and P. J. Lupien, ``Influence of Diets Containing
Cow's Milk or Soy Protein Beverage on Plasma Lipids in Children with
Familial Hypercholesterolemia,'' Journal of the American College of
Nutrition, 11 (suppl): 69S-73S, 1992.
43. Jenkins, D. J. A., T. M. S. Wolever, G. Spiller, G. Buckley,
Y. Lam, A. L. Jenkins, and R. G. Josse, ``Hypocholesterolemic Effect
of Vegetable Protein in a Hypocaloric Diet,'' Atherosclerosis,
78:99-107, 1989.
44. Kurowska, E. M., J. Jordan, J. D. Spence, S. Wetmore, L. A.
Piche, M. Radzikowski, P. Dandona, and K. K. Carroll, ``Effects of
Substituting Dietary Soybean Protein and Oil for Milk Protein and
Fat in Subjects with Hypercholesterolemia, ``Clinical Investigative
Medicine, 20:162-170, 1997.
45. Laurin, D., H. Jacques, S. Moorjani, F. H. Steinke, C.
Gagne, D. Brun, and P. J. Lupien, ``Effects of a Soy-protein
Beverage on Plasma Lipoproteins in Children with Familial
Hypercholesterolemia,'' American Journal of Clinical Nutrition,
54:98-103, 1991.
46. Lovati, M. R., C. Manzoni, A. Canavesi, M. Sirtori, V.
Vaccarino, M. Marchi, G. Gaddi, and C. R. Sirtori, ``Soybean Protein
Diet Increases Low Density Lipoprotein Receptor Activity in
Mononuclear Cells from Hypercholesterolemic Patients,'' Journal of
Clinical Investigation, 80:1498-1502, 1987.
47. Meinertz, H., O. Faergeman, K. Nilausen, M. J. Chapman, S.
Goldstein, and P. M. Laplaud, ``Effects of Soy Protein and Casein in
Low Cholesterol Diets on Plasma Lipoproteins in Normolipidemic
Subjects,'' Atherosclerosis, 72:63-70, 1988.
48. Meinertz, H., K. Nilausen, and O. Faergeman, ``Soy Protein
and Casein in Cholesterol-enriched Diets: Effects on Plasma
Lipoproteins in Normolipidemic Subjects,'' American Journal of
Clinical Nutrition, 50:786-793, 1989.
49. Mercer, N. J. H., K. K. Carroll, P. M. Giovannetti, F. H.
Steinke, and B. M. Wolfe, ``Effects on Human Plasma Lipids of
Substituting Soybean Protein Isolate for Milk Protein in the Diet,''
Nutrition Reports International, 35:279-287, 1987.
50. Meredith, L., M. Liebman, and K. Graves, ``Alterations in
Plasma Lipid Levels Resulting from Tofu and Cheese Consumption in
Adult Women,'' Journal of the American College of Nutrition, 8:573-
579, 1989.
51. Potter, S. M., R. M. Bakhit, D. L. Essex-Sorlie, K. E.
Weingartner, K. M. Chapman, R. A. Nelson, M. Prabhudesai, W. D.
Savage, A. I. Nelson, L. W. Winter, and J. W. Erdman, Jr.,
``Depression of Plasma Cholesterol in Men by Consumption of Baked
Products Containing Soy Protein,'' American Journal of Clinical
Nutrition, 58:501-506, 1993.
52. Potter, J. M. and P. J. Nestel, ``Greater Bile Acid
Excretion with Soy Bean Than with Cow Milk in Infants,'' American
Journal of Clinical Nutrition, 29:546-551, 1976.
53. Sacks, F. M., J. L. Breslow, P. G. Wood, and E. H. Kass,
``Lack of an Effect of Dairy Protein (Casein) and Soy Protein on
Plasma Cholesterol of Strict Vegetarians. An Experiment and a
Critical Review,'' Journal of Lipid Research, 24:1012-1020, 1983.
54. Shorey, R. L., B. Bazan, G. S. Lo, and F. H. Steinke,
``Determinants of Hypercholesterolemic Response to Soy and Animal
Protein-based Diets,'' American Journal of Clinical Nutrition,
34:1769-1778, 1981.
55. Sirtori, C. R., E. Agradi, F. Conti, O. Mantero, and E.
Gatti, ``Soybean-protein Diet in the Treatment of Type-II
Hyperlipoproteinaemia,'' Lancet, 1:275-277, 1977.
56. Sirtori, C. R., C. Zucchi-Dentone, M. Sirtori, E. Gatti, G.
C. Descovich, A. Gaddi, L. Cattin, P. G. Da Col, U. Senin, E.
Mannarino, G. Avellone, L. Colombo, C. Fragiacomo, G. Noseda, and S.
Lenzi, ``Cholesterol-lowering and HDL-raising Properties of
Lecithinated Soy Proteins in Type II Hyperlipidemic Patients,''
Annals of Nutrition Metabolism, 29:348-357, 1985.
57. Steele, M. G., ``The Effect on Serum Cholesterol Levels of
Substituting Milk with a Soya Beverage,'' Australian Journal of
Nutrition and Dietetics, 49:24-28, 1992.
58. van Raaij, J. M. A., M. B. Katan, J. G. A. J. Hautvast, and
R. J. J. Hermus, ``Effects of Casein Versus Soy Protein Diets on
Serum Cholesterol and Lipoproteins in Young Healthy Volunteers,''
American Journal of Clinical Nutrition, 34:1261-1271, 1981.
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 Volunteers,'' American Journal of Clinical Nutrition, 35:925-
934, 1982.
60. Verrillo, 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 Effect of Undigested Fraction of Soybean
Protein in Young Female Volunteers,'' Journal of Nutritional Science
and Vitaminology, 41:187-195, 1995.
63. Widhalm, K., G. Brazda, B. Schneider, and S. Kohl, ``Effect
of Soy Protein Diet Versus Standard Low Fat, Low Cholesterol Diet on
Lipid and Lipoprotein Levels in Children with Familial or Polygenic
Hypercholesterolemia,'' Journal of Pediatrics, 123:30-34, 1993.
64. Wolfe, B. M., P. M. Giovannetti, D. C. H. Cheng, D. C. K.
Roberts, and K. K. Carroll, ``Hypolipidemic Effect of Substituting
Soybean Protein Isolate for All Meat and Dairy Protein in the Diets
of Hypercholesterolemic Men,'' Nutrition Reports International,
24:1187-1198, 1981.
65. Nagata, C., N. Takatsuka, Y. Kurisu, and H. Shimizu,
``Decreased Serum Total Cholesterol Concentration is Associated with
High Intake of Soy Products in Japanese Men and Women,'' Journal of
Nutrition, 128:209-213, 1998.
66. Anderson, J. W., B. M. Johnstone, and M. E. Cook-Newell,
``Meta-analysis of the Effects of Soy Protein Intake on Serum
Lipids,'' New England Journal of Medicine, 333:276-282, 1995.
67. DHHS, National Heart, Lung, and Blood Institute, National
Cholesterol Education Program, ``Report of the Expert Panel on
Population Strategies for Blood Cholesterol Reduction (Population
Panel Report),'' Chapter II. Background and Introduction, NIH
Publication No. 93-3046, Bethesda, MD, 1993.
68. Food and Nutrition Board, National Academy of Sciences,
``Diet and Health: Implications for Reducing Chronic Disease Risk,''
National Academy Press, Washington, DC, pp. 23-40, 1989.
69. Department of Health and Human Services, ``Guide to Clinical
Preventive Services: Report of the U.S Preventive Services Task
Force,'' 2d edition, Washington, DC: Office of Public Health and
Science, U.S. Department of Health and Human Services, April 1989.
70. Anthony, M. S., T. B. Clarkson, B. C. Bullock, and J. D.
Wagner, ``Soy Protein Versus Soy Phytoestrogens in the Prevention of
Diet-induced Coronary Artery Atherosclerosis of Male Cynomolgus
Monkeys,'' Arteriosclerosis, Thrombosis, and Vascular Biology,
17:2524-2531, 1997.
71. Nestle, P. J., T. Yamashita, T. Sashara, S. Pomeroy, A.
Dart, P. Komesaroff, A. Owen, and M. Abbey, ``Soy Isoflavones
Improve
[[Page 57730]]
Systemic Arterial Compliance but Not Plasma Lipids in Menopausal and
Perimenopausal Women,'' Arteriosclerosis, Thrombosis, and Vascular
Biology, 17:3392-3398, 1997.
72. Sitori, C. R., E. Gianazza, C. Manzoni, M. R. Lovati, and P.
A. Murphy, ``Role of Isoflavones in the Cholesterol Reduction of Soy
Proteins in the Clinic,'' letter to the editor, American Journal of
Clinical Nutrition, 65:166-167, 1997.
73. American Academy of Pediatrics, Committee on Nutrition,
``Policy Statement--Soy Protein-based Formulas: Recommendations for
Use in Infant Feeding,'' Pediatrics, 101:148-153, 1998.
74. Ministry of Health, ``Soy-based Infant Formula,''
Wellington, New Zealand.
75. Kahl, L., Office of Premarket Approval, Center for Food
Safety and Applied Nutrition, FDA, Letter to M. W. Empie, Archer
Daniels Midland Company, November 25, 1998.
76. Select Committee on GRAS Substances, Life Sciences Research
Office, ``Evaluation of the Health Aspects of Soy Protein Isolates
as Food Ingredients,'' Prepared for the Bureau of Foods, Food and
Drug Administration, Contract No. 223-75-2004, Federation of
American Societies for Experimental Biology, Bethesda, MD, 1979.
77. Hymowitz, T. and J.R. Harlan, ``Introduction of the Soybean
to North America by Samuel Bowen in 1765, Georgia, Gazette,
September 17, 1766,'' article from http/www.nsrl.uiuc.edu/
beanhistory/intrnall.html.
78. Sheehan, D.M., ``Herbal Medicines, Phytoestrogens, and
Toxicity: Risk:Benefit Considerations,'' Proceedings of the Society
for Experimental Biology and Medicine, 217:379-385, 1998.
79. Liener, I.E., ``Trypsin Inhibitors: Concern for Human
Nutrition or Not?'' Journal of Nutrition, 116:920-923, 1986.
80. Liener, I.E., R.L. Goodale, A. Deshmukh, T.L. Satterberg, G.
Ward, C.M. DiPietro, P.E. Bankey, and J.W. Borner, ``Effect of a
Trypsin Inhibitor from Soybeans (Bowman-Birk) on the Secretory
Activity of the Human Pancreas,'' Gastroenterology, 94:419-427,
1988.
81. Liener, I.E., ``Possible Adverse Effects of Soybean
Anticarcinogens,'' Journal of Nutrition, 125:744S-750S, 1995.
82. Liener, I.E., ``Soybean Protease Inhibitors and Pancreatic
Carcinogenesis,'' letter to the editor, Journal of Nutrition,
126:582-583, 1996.
83. Kennedy, A.R., ``The Bowman-Birk Inhibitor from Soybeans as
an Anticarcinogenic Agent,'' American Journal of Clinical Nutrition,
68(suppl):1406S-1412S, 1998.
84. Mills, P.K., W.L. Beeson, D.E. Abbey, G.E. Fraser, and R.L.
Phillips, ``Dietary Habits and Past Medical History as Related to
Fatal Pancreas Cancer Risk Among Adventists,'' Cancer, 61:2578-2585,
1988.
85. Fitch, C.D., W.F. Harville, J.S. Dinning, and F.S. Porter,
``Iron Deficiency in Monkeys Fed Diets Containing Soybean Protein,''
Proceedings of the Society for Experimental Biology and Medicine,
116:130-133, 1964.
86. Cook, J.D., T.A. Morck, and S.R. Lynch, ``The Inhibitory
Effect of Soy Products on Nonheme Iron Absorption in Man,'' American
Journal of Clinical Nutrition, 34:2622-2629, 1981.
87. Hurrell, R.F., M.A. Juillerat, M.B. Reddy, S.R. Lynch, S.A.
Dassenko, and J.D. Cook, ``Soy Protein, Phytate, and Iron Absorption
in Humans,'' American Journal of Clinical Nutrition, 56:573-578,
1992.
88. Lynch, S.R., S.A. Dassenko, T.A. Morck, J.L. Beard, and J.D.
Cook, ``Soy Protein Products and Heme Iron Absorption in Humans,''
American Journal of Clinical Nutrition, 41:13-20, 1985.
89. Bodwell, C.E., C.W. Miles, E. Morris, E.S. Prather, W.
Mertz, and J.J. Canary, ``Long-term Consumption of Beef Extended
with Soy Protein by Men, Women, and Children: II. Effects on Iron
Status,'' Plant Foods in Human Nutrition, 37:361-376, 1987.
90. Lonnerdal, B., ``Nutritional Aspects of Soy Formula,'' Acta
Pediatrica Supplement, 402:105-108, 1994.
91. Prasad, A.S., S. Mefta, J. Abadallah, J. Kaplan, G.J.
Brewer, J.F. Bach, and M. Dardenne, ``Serum Thymulin in Human Zinc
Deficiency,'' Journal of Clinical Investigation, 82:1202-1210, 1988.
92. Sandstrom, B. and A. Cederblad, ``Zinc Absorption from
Composite Meals. II. Influence of the Main Protein Source,''
American Journal of Clinical Nutrition, 33:1778-1783, 1980.
93. Solomons, N.W., M. Janghorbani, B.T. Ting, F.H. Steinke, M.
Christensen, R. Bijlani, N. Istfan, and V.R. Young,
``Bioavailability of Zinc from a Diet Based on Isolated Soy Protein:
Application in Young Men of the Stable Isotope Tracer,
70Zn,'' Journal of Nutrition, 112:1809-1821, 1982.
94. Oberleas, D., ``Mechanism of Zinc Homeostasis,'' Journal of
Inorganic Biochemistry, 64:231-241, 1996.
95. Lo, G.S., S.L. Settle, F.H. Steinke, and D.T. Hopkins,
``Effect of Phytate:Zinc Molar Ratio and Isolated Soybean Protein on
Zinc Bioavailability,'' Journal of Nutrition, 111:2223-2235, 1981.
96. Dees, C., J.S. Foster, S. Ahamed, and J. Wimalasena,
``Dietary Estrogens Stimulate Human Breast Cells to Enter the Cell
Cycle,'' Environmental Health Perspectives, 105(suppl 3):633-636,
1997.
97. Adlercreutz, C.H.T., B.R. Goldin, S.L. Gorbach, K.A.V.
Hockerstedt, S. Watanabe, E.K. Hamalainen, M.H. Markanen, T.H.
Makela, K.W. Wahala, T.A. Hase, and T. Fotsis, ``Soybean
Phytoestrogen Intake and Cancer Risk,'' Journal of Nutrition,
125(suppl):757S-770S, 1995.
98. Barnes, S., ``Effect of Genistein on In Vitro and In Vivo
Models of Cancer,'' Journal of Nutrition, 125(suppl):777S-783S,
1995.
99. Petrakis N.L., S. Barnes, E.B. King; J. Lowenstein, J.
Wiencke, M.M. Lee, R. Miike, M. Kirk, and L. Coward, ``Stimulatory
Influence of Soy Protein Isolate on Breast Secretion in Pre- and
Postmenopausal Women.'' Cancer Epidemiology, Biomarkers, and
Prevention, 5:785-794, 1996.
100. McMichael-Phillips, D.F., C. Harding, M. Morton, S.A.
Roberts, A. Howell, C.S. Potten, and N.J. Bundred, ``Effects of Soy-
protein Supplementation on Epithelial Proliferation in
Histologically Normal Human Breast,'' American Journal of Clinical
Nutrition, 68(suppl):1431S-1436S, 1998.
101. Wu, A.H., R.G. Ziegler, A.M.Y. Nomura, D.W. West, L.N.
Kolonel, P.L. Horn-Ross, R.N. Hoover, and M.C. Pike, ``Soy Intake
and Risk of Breast Cancer in Asians and Asian Americans,'' American
Journal of Nutrition, 69(suppl):1437S-1443S, 1998.
102. Setchell, K.D.R., S.J. Gossellin, M.B. Welsh, J.O.
Johnston, W.F. Balistreri, L.W. Kramer, B.L. Dresser, and M.J. Tarr,
``Dietary Estrogens--A Probable Cause of Infertility and Liver
Disease in Captive Cheetahs,'' Gastroenterology, 93:225-233, 1987.
103. Leopold, A.S., M. Erwin, J. Oh, and B. Browning,
``Phytoestrogens: Adverse Effects on Reproduction in California
Quail,'' Science 191:98-99, 1976.
104. Drane, H.M., D.S. Patterson, B.A. Roberts, and N. Saba,
``Oestrogenic Activity of Soya-bean Products,'' Food and Cosmetic
Toxicolology, 18:425-427, 1980
105. Cassidy, A., S. Bingham, and K.D.R. Setchell, ``Biological
Effects of a Diet of Soy Protein Rich in Isoflavones on the
Menstrual Cycle of Premenopausal Women,'' American Journal of
Clinical Nutrition, 60:333-340, 1994.
106. Duncan, A.M., B.E. Merz, X. Xu, T.C. Nagel, W.R. Phillips,
and M.S. Kurzer, ``Soy Isoflavones Exert Modest Hormonal Effects in
Premenopausal Women,'' Journal of Clinical Endocrinology and
Metabolism, 84:192-197, 1999.
107. Faber, K.A. and C.L. Hughes, Jr., ``Dose-response
Characteristics of Neonatal Exposure to Genistein on Pituitary
Responsiveness to Gonadotropin Releasing Hormone and Volume of the
Sexually Dimorphic Nucleus of the Preoptic Area (SDN-POA) in
Postpubertal Castrated Female Rats.'' Reproductive Toxicology, 7:35-
39, 1993.
108. Faber, K.A. and C.L. Hughes, Jr., ``The Effect of Neonatal
Exposure to Diethylstibestrol, Genistein, and Zearalenone on
Pituitary Responsivesness and Sexually Dimorphic Nucleus Volume in
the Castrated Adult Rat,'' Biology of Reproduction, 45:649-653,
1991.
109. Medlock, K.L., W.S. Branham, and D.M. Sheehan, ``Effects of
Coumestrol and Equol on the Developing Reproductive Tract of the
Rat.'' Proceedings of the Society for Experimental Biology and
Medicine, 208:67-71, 1995.
110. Medlock, K.L., W.S. Branham, and D.M. Sheehan, ``The
Effects of Phytoestrogens on Neonatal Rat Uterine Growth and
Development.'' Proceedings of the Society for Experimental Biology
and Medicine, 208:307-313, 1995.
111. Harrison, R. M., P. P. Phillippi, and M. C. Henson,
``Effects of Genistein on Estradiol Production in Pregnant Rhesus
Monkeys (Macaca mulatta),'' abstract, American Journal of
Primatology, 45:183, 1998.
112. Fritz, W. A., L. Coward, J. Wang, and C. A. Lamartiniere,
``Dietary Genistein: Perinatal Mammary Cancer Prevention,
Bioavailability and Toxicity Testing in the Rat.'' Carcinogenesis,
19:2151-2158, 1998.
113. Freni-Titulaer, L. W., J. F. Cordero, L. Haddock, G.
Lebron, R. Martinez, and J. L. Mills, ``Premature Thelarche in
Puerto Rico. A Search for Environmental Factors.'' American Journal
of Diseases of Children, 140:1263-1267, 1986.
[[Page 57731]]
114. White, L., H. Petrovitch, G. W. Ross, and K. Masaki,
``Association of Mid-life Consumption of Tofu with Late Life
Cognitive Impairment and Dementia: The Honolulu:Asia Aging Study,''
abstract, The Neurobiology of Aging, 17 (suppl 4), S121, 1996.
115. White, L., H. Petrovitch, G. W. Ross, K. H. Masaki, R. D.
Abbott, E. L. Teng, B. L. Rodriguez, P. L. Blanchette, R. J. Havlik,
G. Wergowske, D. Chiu, D. J. Foley, C. Murdaugh, and J. D. Curb,
``Prevalence of Dementia in Older Japanese-American Men in Hawaii:
The Honolulu-Asia Aging Study,'' Journal of the American Medical
Association, 276:955-960, 1996.
116. Sheehan, D. M., E. Willingham, D. Gaylor, J. M. Bergeron,
and D. Crewes, ``No Threshold Dose for Estradiol-induced Sex
Reversal of Turtle Embryos: How Little is Too Much?'' Environmental
Health Perspectives, 107:155-159, 1999.
117. Sheehan, D. M., ``Literature Analysis of No-threshold Dose-
response Curves for Endocrine Disruptors,'' abstract, Teratology,
57:219, 1998.
117A. Setchell, K. D. R., ``Phytoestrogens: the Biochemistry,
Physiology, and Implications for Human Health of Soy Isoflavones,''
American Journal of Clinical Nutrition, 68 (suppl):1333S-1346S,
1998.
118-119. Lu, L. J. and K. E. Anderson, ``Sex and Long-term Soy
Diets Affect the Metabolism and Excretion of Soy Isoflavones in
Humans,'' American Journal of Clinical Nutrition, 68 (suppl):1500S-
1504S, 1998.
120. Kimura, S., J. Suwa, M. Ito, and H. Sato, ``Development of
Malignant Goiter by Defatted Soybean with Iodine-free Diet in
Rats,'' Gann, 67:763-765, 1976.
121. Van Wyk, J. J., M. B. Arnold, J. Wynn, and F. Pepper, ``The
Effects of a Soybean Product on Thyroid Function in Humans,''
Pediatrics, 24:752-760, 1959.
122. Hydovitz, J. D., ``Occurrence of Goiter in an Infant on a
Soy Diet,'' New England Journal of Medicine, 262:351-353, 1960.
123. Shepard, T. H., G. E. Pyne, J. E. Kirschvink, and M.
McLean, ``Soybean Goiter: Report of Three Cases,'' New England
Journal of Medicine, 262:1099-1103, 1960.
124. Pinchera, A., M. H. MacGillivray, J. D. Crawford, and A. G.
Freeman, ``Thyroid Refractoriness in an Athyreotic Cretin Fed
Soybean Formula,'' New England Journal of Medicine, 273:83-87, 1965.
125. Chorazy, P. A., S. Himelhoch, N. J. Hopwood, N. G. Greger,
and D. C. Postellon, ``Persistent Hypothyroidism in an Infant
Receiving a Soy Formula: Case Report and Review of the Literature,''
Pediatrics, 96:148-150, 1995.
126. Ishizuki, Y., Y. Hirooka, Y. Murata, and K. Togashi, ``The
Effects on the Thyroid Gland of Soybeans Administered Experimentally
in Healthy Subjects,'' Nippon Naibunpi Gakkai Zasshi, 67:622-629,
1991.
127. Divi, R.L., H. C. Chang, and D. R. Doerge, ``Anti-thyroid
Isoflavones from Soybean: Isolation, Characterization, and
Mechanisms of Action,'' Biochemical Pharmacology, 54:1087-1096,
1997.
128. Divi, R. L. and D. R. Doerge, Inhibition of Thyroid
Peroxidase by Dietary Flavonoids.'' Chemical Research and
Toxicology, 9:16-23, 1996.
129. Fort, P., R. Lanes, S. Dahlem, B. Recker, M. Wyman-Daum, M.
Pugliese, and F. Lifshitz, ``Breast Feeding and Insulin-dependent
Diabetes Mellitus in Children,'' Journal of the American College of
Nutrition, 5:439-441, 1986.
130. Fort, P., N. Moses, M. Fasano, T. Goldberg, and F.
Lifschitz, ``Breast and Soy-formula Feedings in Early Infancy and
the Prevalence of Autoimmune Thyroid Disease in Children,'' Journal
of the American College of Nutrition, 9:164-167, 1990.
131. Monoz, L. A. and W. H. Yang, ``Kunitz Soybean Inhibitor: A
Specific Allergen in Food,'' New England Journal of Medicine,
302:1126-1128, 1980.
132. Livsmedels Verket, National Food Administration, Allergic
Reactions to Food, April 10, 1997, report based on Foucard, T., U.
Edberg, and I. Malmheden Yman, ``Fatal and Severe Food
Hypersensitivity. Peanut and Soya Underestimated Allergens,''
Lakartidningen, 94:2635-2638, 1997.
133. Malmheden Yman, I, Livsmedels Verket, National Food
Administration, Letter to Jane McLennan, Ministry of Health, New
Zealand, May 30, 1997.
134. Eigenman, P.A., A.W. Burks, G.A. Bannon, and H.A. Sampson,
``Identification of Unique Antigenic Fractions of Soy and Peanut,''
abstract, Journal of Allergey and Clinical Immunology, 97:328, 1996.
135. Gunn, R.A., P.R. Taylor, and E.J. Gangarosa,
``Gastrointestinal Illness Associated with Consumption of a Soy
Protein Extender,'' Journal of Food Protection, 43:525-527, 1980.
136. Teixeira, S., S.M. Potter, R. Weigel, S. Hannum, C.M.
Hasler, and J.W. Erdman, Jr., ``Effects of Feeding 4 Levels of Soy
Protein for 3 and 6 Weeks on Blood Lipids and Apolipoproteins in
Moderately Hypercholesterolemic Men,'' submitted.
137. Wong, W.W., E.O.B. Smith, J.E. Stuff, D.L. Hachey, W.C.
Heird, and H.J. Pownell, ``Cholesterol-lowering Effect of Soy
Protein in Normocholesterolemic and Hypercholesterolemic Men,''
American Journal of Clinical Nutrition, 68 (suppl):1385S-1389S,
1998.
138. Fumagalli, R., L. Soleri, R. Farina, R. Musanti, O.
Mantero, G. Noseda, E. Gatti, and C.R. Sirtori, ``Fecal Cholesterol
Excretion Studies in Type II Hypercholesterolemic Patients Treated
with the Soybean Protein Diet,'' Atherosclerosis, 43:341-353, 1982.
139. Jenkins, D. J. A., C. W. C. Kendall, C. C. Mehling, T.
Parker, A. V. Rao, S. Agarwal, R. Novokmet, P. J. H. Jones, M.
Raeini, J. A. Story, E. Furumoto, E. Vidgen, L. C. Griffin, S. C.
Cunnane, M. A. Ryan, and P. W. Connolly, ``Combined Effect of
Vegetable Protein (Soy) and Soluble Fiber Added to a Standard
Cholesterol-lowering Diet,'' Metabolism, 48:809-816, 1999.
140. Jenkins, D. J. A., C. W. C. Kendall, E. Vidgen, C. C.
Mehling, T. Parker, H. Seyler, D. Faulkner, M. Garsetti, L. C.
Griffin, S. Agarwal, A. V. Rao, S. C. Cunnane, M. A. Ryan, P. W.
Connolly, L. A. Leiter, V. Vuksan, and R. Josse, ``The Effect on
Serum Lipids and Oxidized LDL of Supplementing Self-selected Low-fat
Diets with Soluble Fiber, Soy, and Vegetable Protein Foods,''
submitted.
141. Washburn, S., G. L. Burke, T. Morgan, and M. Anthony,
``Effect of Soy Protein Supplementation on Serum Lipoproteins, Blood
Pressure, and Menopausal Symptoms in Perimenopausal Women,''
Menopause: The Journal of the American Menopause Society, 6:7-13,
1999.
142. Nilausen, K., and H. Meinertz, ``Variable Lipemic Response
to Dietary Soy Protein in Healthy, Normolipidemic Men,'' American
Journal of Clinical Nutrition, 68(suppl):1380S-1384S, 1998.
143. Duane, W.C., ``Effects of Soybean Protein and Very Low
Dietary Cholesterol on Serum Lipids, Biliary Lipids, and Fecal
Sterols in Humans,'' Metabolism, 48:489-494, 1999.
144. Yu-Poth, S., G. Zhao, T. Etherton, M. Naglak, S.
Jonnalagadda, and P. M. Kris-Etherton, ``Effects of the National
Cholesterol Education Program's Step I and Step II Dietary
Intervention Programs on Cardiovascular Disease Risk Factors: A
Meta-analysis,'' American Journal of Clinical Nutrition, 69:632-646,
1999.
145. Denke, M. A., ``Revisiting the Effectiveness of the
National Cholesterol Education Program's Step I and Step II Diets:
Cholesterol-lowering Diets in a Pharmaceutically Driven World,''
American Journal of Clinical Nutrition, 69:581-582, 1999.
146. Denke, M. A., ``Review of Human Studies Evaluating
Individual Dietary Responsiveness in Patients with
Hypercholesterolemia,'' American Journal of Clinical Nutrition,
62(suppl):471S-477S, 1995.
147. Balmir F., R. Staack, E. Jeffrey, M. D. Jimenez, L. Wang,
and S. M. Potter, ``An Extract of Soy Flour Influences Serum
Cholesterol and Thyroid Hormones in Rats and Hamsters,'' Journal of
Nutrition, 126:3046-3053, 1996.
148. Sugano, M., and K. Koba, ``Dietary Protein and Lipid
Metabolism: A Multifunctional Effect,'' Annals of the New York
Academy of Sciences, 676:215-222, 1993.
149. Kirk, E. A., P. Sutherland, S. A. Wang, A. Chait, and R. C.
Leboeuf, ``Dietary Isoflavones Reduce Plasma Cholesterol and
Atherosclerosis in C57BL/6 Mice But Not LDL Receptor-deficient
Mice,'' Journal of Nutrition, 128:954-959, 1998.
150. Tovar-Palacio, C., S. M. Potter, J. C. Hafermann, and N. F.
Shay, ``Intake of Soy Protein and Soy Protein Extracts Influences
Lipid Metabolism and Hepatic Gene Expression in Gerbils,'' Journal
of Nutrition, 128:839-842, 1998.
151. Anthony, M. S., G. L. Burk, C. L. Hughes Jr., and T. B.
Clarkson, ``Does Soy Supplementation Improve Coronary Heart Disease
(CHD) Risk?'' abstract, Circulation, 91:I-925, 1995.
152. Colquhoun, D. M., R. J. Hicks, and G. E. Kelly, ``Lack of
Effect of Isoflavones on Human Serum Lipids and Lipoproteins,''
abstract, Arteriosclerosis, 109:75, 1994.
153. Hodgson J. M., I. B. Puddey, L. J. Beilin, T. A. Mori, and
K. D. Croft, ``Supplementation with Isoflavonoid Phytoestrogens Does
Not Alter Serum Lipid Concentrations: A Randomized Controlled Trial
in Humans,'' Journal of Nutrition, 128:728-732, 1998.
154. Cassidy, A., S. Bingham, and K. Setchell, ``Biological
Effects of Isoflavones in
[[Page 57732]]
Young Women: Importance of the Chemical Composition of Soyabean
Products,'' British Journal of Nutrition, 74:587-601, 1995.
155. Sirtori, C. R., E. Gatti, O. Mantero, F. Conti, E. Agradi,
E. Tremoli, M. Sirtori, L. Fraterrigo, L. Tavazzi, and D.
Kritchevsky, ``Clinical Experience with the Soybean Protein Diet in
the Treatment of Hypercholesterolemia,'' American Journal of
Clinical Nutrition, 32:1645-1658, 1979.
156. Sirtori, C. R., M. R. Lovati, C. Manzoni, M. Monetti, F.
Pazzucconi, and E. Gatti, ``Soy and Cholesterol Reduction: Clinical
Experience,'' Journal of Nutrition, 125(suppl):589S-605S, 1995.
157. Sirtori, C. R., Universita Degli Studi di Milano, letter to
E. Gugger, Archer Daniels Midland Company, May 25, 1997.
158. USDA Food Composition Laboratory and Nutrition Data
Laboratory, Department of Food Science and Human Nutrition of the
Iowa State University, ``USDA-Iowa State University Database on the
Isoflavone Content of Foods--1999,'' US Department of Agriculture.
159. ``The Keystone National Policy Dialog on Food, Nutrition,
and Health: Final Report,'' Keystone, CO, 1996, pp. 57-70.
160. Levy, A., B. Derby, and B. Roe, ``Consumer Impacts of
Health Claims: An Experimental Study, FDA Center for Food Safety and
Applied Nutrition, Division of Market Studies,'' January 1997.
161. Office of Premarket Approval, Center for Food Safety and
Applied Nutrition and Office of Surveillance and Compliance, Center
for Veterinary Medicine, Food and Drug Administration, ``Guidance on
Consultation Procedures: Foods Derived from New Plant Varieties,''
October, 1997.
162. Rulis, A. M., Office of Premarket Approval, Center for Food
Safety and Applied Nutrition, FDA, ``Letter to Diane Re, The
Agricultural Group of Monsanto,'' January 27, 1995.
163. Food and Drug Administration, ``Memorandum of Conference,''
Participants: Monsanto and FDA, September 19, 1994.
164. Rulis, A. M., Office of Premarket Approval, Center for Food
Safety and Applied Nutrition, FDA, ``Letter to Sally L. Van Wert,
AgrEvo USA Company,'' May 12, 1998.
165. Food and Drug Administration, ``Note to the File: BNF0055--
Glufosinate-tolerant Soybean Lines,'' April 21, 1998.
166. Rulis, A. M., Office of Premarket Approval, Center for Food
Safety and Applied Nutrition, FDA, ``Letter to Edward W. Raliegh,
DuPont Agricultural Products,'' March 14, 1997.
167. Food and Drug Administration, ``Memorandum of Conference,''
Participants: DuPont and FDA, December 5, 1996.
List of Subjects in 21 CFR Part 101
Food labeling, Nutrition, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, 21 CFR part
101 is amended as follows:
PART 101--FOOD LABELING
The authority citation for 21 CFR part 101 continues to read as
follows:
1. Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331,
342, 343, 348, 371.
2. Add Sec. 101.82 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.
(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 assess qualifying levels of soy protein in the
following fashion: FDA will measure total protein content by the
appropriate method of analysis given in the ``Official Methods of
Analysis of the AOAC International,'' as
[[Page 57733]]
described at Sec. 101.9(c)(7). For products that contain no sources of
protein other than soy, FDA will consider the amount of soy protein as
equivalent to the total protein content. For products that contain a
source or sources of protein in addition to soy, FDA will, using the
measurement of total protein content, calculate the soy protein content
based on the ratio of soy protein ingredients to total protein
ingredients in the product. FDA will base its calculation on
information identified and supplied by manufacturers, such as nutrient
data bases or analyses, recipes or formulations, purchase orders for
ingredients, or any other information that reasonably substantiates the
ratio of soy protein to total protein. Manufacturers must maintain
records sufficient to substantiate the claim for as long as the
products are marketed and provide these records, on written request, to
appropriate regulatory officials.
(iii) Nature of the food eligible to bear the claim. (A) The food
product shall contain at least 6.25 g of soy protein per 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'' and ``low cholesterol'' food;
and
(C) The food shall meet the nutrient content requirement in
Sec. 101.62 for a ``low fat'' food, unless it consists of or is derived
from whole soybeans and contains no fat in addition to the fat
inherently present in the whole soybeans it contains or from which it
is derived.
(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 a day may reduce the risk of heart disease. One
serving of [name of food] provides ____ grams of soy protein.
Dated: October 19, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 99-27693 Filed 10-20-99; 10:35 a.m.]
BILLING CODE 4160-01-P
