[Federal Register Volume 75, Number 235 (Wednesday, December 8, 2010)]
[Proposed Rules]
[Pages 76526-76571]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-30386]
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Part II
Department of Health and Human Services
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Food and Drug Administration
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21 CFR Part 101
Food Labeling; Health Claim; Phytosterols and Risk of Coronary Heart
Disease; Proposed Rule
Federal Register / Vol. 75 , No. 235 / Wednesday, December 8, 2010 /
Proposed Rules
[[Page 76526]]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 101
[Docket Nos. FDA-2000-P-0102, FDA-2000-P-0133, and FDA-2006-P-0033;
Formerly Docket Nos. 2000P-1275, 2000P-1276, and 2006P-0316,
Respectively]
Food Labeling; Health Claim; Phytosterols and Risk of Coronary
Heart Disease
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the regulation authorizing a health claim on the relationship between
plant sterol esters and plant stanol esters and reduced risk of
coronary heart disease (CHD) for use on food labels and in food
labeling. The agency is taking this action based on evidence previously
considered by the agency, and FDA's own review of data on esterified
and nonesterified plant sterols and stanols (collectively,
phytosterols) \1\ published since the agency first authorized the
health claim by regulation. FDA is also taking these actions, in part,
in response to a health claim petition submitted by Unilever United
States, Inc. The proposal would amend the authorized use of the claim
by modifying the nature of the substances that may be the subject of
the claim for conventional foods to include nonesterified, or free,
phytosterols, by expanding the types of foods that may bear the claim
to include a broader range of foods, by modifying the daily dietary
intake of the substance specified in the claim as necessary for the
claimed benefit, by adjusting the minimum amount of the substance
required for a food to bear the claim, and by making other minor
changes.
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\1\ The term ``phytosterols'' is used as a collective term for
plant sterols and their hydrogenated stanol forms, whether used in
the free form or esterified with fatty acids. As discussed in more
detail elsewhere in this proposal, phytosterol is a term commonly
used by manufacturers and distributors of these substances.
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DATES: Submit written or electronic comments by February 22, 2011.
ADDRESSES: You may submit comments, identified by Docket Nos. FDA-2000-
P-0102, FDA-2000-P-0133, and FDA-2006-P-0033, by any of the following
methods:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: http://www.regulations.gov.
Follow the instructions for submitting comments.
Written Submissions
Submit written submissions in the following ways:
Fax: 301-827-6870.
Mail/Hand delivery/Courier (for paper, disk, or CD-ROM
submissions): Division of Dockets Management (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
Instructions: All submissions received must include the agency name
and docket numbers for this rulemaking. All comments received will be
posted without change to http://www.regulations.gov, including any
personal information provided. For detailed instructions on submitting
comments and additional information on the rulemaking process, see the
``Comments'' heading of the SUPPLEMENTARY INFORMATION section of this
document.
Docket: For access to the docket to read background documents or
comments received, go to http://www.regulations.gov and insert the
docket numbers, found in brackets in the heading of this document, into
the ``Search'' box and follow the prompts and/or go to the Division of
Dockets Management (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Blakeley Denkinger, Center for Food
Safety and Applied Nutrition (HFS-830), 5100 Paint Branch Pkwy.,
College Park, MD 20740, 301-436-1450.
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Background
II. Petition and Grounds for Amending the Health Claim on Plant
Sterols/Stanols and CHD
III. Eligibility for a Health Claim/Overview of Data
IV. Review of the Preliminary Requirements
V. Proposed Modifications to Current Sec. 101.83
A. Nature of the Substance
1. Esterification
2. Mixtures of Plant Sterols and Plant Stanols
3. Sources of Phytosterols
4. Designation of Substance as Phytosterols
5. Determining the Amount and Nature of the Substance
B. Nature of the Claim
1. Effective Cholesterol-Lowering Daily Dietary Intake
2. Servings per Day
3. Consuming Phytosterols With Meals
C. Nature of the Food Eligible to Bear the Claim
1. Qualifying Amount of Phytosterols per Serving
2. Nature of the Food
a. Conventional foods
b. Dietary supplements
3. Other Requirements
a. Disqualifying total fat level
b. Low saturated fat and low cholesterol criteria
c. Trans fat considerations
d. Minimum nutrient contribution requirement
D. Model Claims
E. Cautionary Statements
F. Status Under Section 301(ll) of Foods Containing
Nonesterified and Esterified Phytosterols
VI. Enforcement Discretion
VII. Environmental Impact
VIII. Analysis of Economic Impacts--Preliminary Regulatory Impact
Analysis
A. Need for the Rule
B. An Overview of the Changes in Behavior From the Regulatory
Options
C. Costs of Option 2 (the Proposed Rule)
D. Benefits of Option 2 (the Proposed Rule)
1. The importance of the health risk addressed by the claim
2. The benefits model
3. The increase in dietary intake of phytosterols
E. Costs and Benefits of Option 3
F. Costs and Benefits of Option 4
IX. Small Entity Analysis (or Initial Regulatory Flexibility
Analysis)
X. Paperwork Reduction Act of 1995
XI. Federalism
XII. Comments
XIII. References
I. Background
The Nutrition Labeling and Education Act of 1990 (NLEA) (Pub. L.
101-535) amended the Federal Food, Drug, and Cosmetic Act (the act) in
a number of important ways. The NLEA clarified FDA's authority to
regulate health claims on food labels and in food labeling by amending
the act to add section 403(r) to the act (21 U.S.C. 343(r)). Section
403(r) of the act specifies, in part, that a food is misbranded if it
bears a claim that expressly or by implication characterizes the
relationship of a nutrient to a disease or health-related condition
unless the claim is made in accordance with section 403(r)(3) (for
conventional foods) or 403(r)(5)(D) (for dietary supplements).
The NLEA directed FDA to issue regulations authorizing health
claims (i.e., labeling claims that characterize the relationship of a
nutrient to a disease or health-related condition) for conventional
foods only if the agency determines, based upon the totality of
publicly available scientific evidence (including evidence from well-
designed studies conducted in a manner that is consistent with
generally recognized scientific procedures and principles) that there
is significant scientific
[[Page 76527]]
agreement (SSA), among experts qualified by scientific training and
experience to evaluate such claims, that the claim is supported by such
evidence (21 U.S.C. 343(r)(3)(B)(i)). Congress delegated to FDA the
authority to establish the procedure and standard for health claims for
dietary supplements (21 U.S.C. 343(r)(5)(D)).
FDA issued regulations establishing general requirements for health
claims in labeling for conventional foods on January 6, 1993 (58 FR
2478). Among the regulations issued under that final rule were: (1)
Section 101.14 (21 CFR 101.14), which sets out the rules for the
authorization of health claims by regulation based on significant
scientific agreement, and prescribes general requirements for the use
of health claims; and (2) section 101.70 (21 CFR 101.70), which
provides a process for petitioning the agency to authorize health
claims about the substance-disease relationship and sets out the types
of information that any such petition must include. Each of these
regulations became effective on May 8, 1993. On January 4, 1994 (59 FR
395), FDA issued a final rule applying the requirements of Sec. Sec.
101.14 and 101.70 to health claims for dietary supplements.
On February 1, 2000, Lipton, a subsidiary of Unilever United States
Inc. (Unilever), submitted to FDA a health claim petition (Docket No.
FDA-2000-P-0102 (formerly Docket No. 2000P-1275)) seeking authorization
of a claim characterizing a relationship between consumption of plant
sterol esters and the risk of CHD. The petition limited its request to
health claims in the labeling of spreads and dressings for salad \2\
containing at least 1.6 gram (g) of plant sterol esters per reference
amount customarily consumed (RACC) and the risk of CHD. On February 15,
2000, McNeil Consumer Healthcare (McNeil) submitted to FDA a health
claim petition (Docket No. FDA-2000-P-0133 (formerly Docket No. 2000P-
1276)) requesting that the agency authorize a health claim
characterizing the relationship between plant stanol esters and the
risk of CHD. Both petitioners requested that FDA exercise its authority
under section 403(r)(7) of the act to make any authorizing regulation
effective on publication, pending consideration of public comment and
publication of a final rule.
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\2\ The agency is using the term ``dressings for salad''
throughout this document in lieu of the term ``salad dressing'' used
by the petitioners because the standard of identity for ``salad
dressing'' in Sec. 169.150 (21 CFR 169.150) refers to a limited
class of dressings for salad, i.e., those that contain egg yolk and
meet certain other specifications and resemble mayonnaise type
products. ``Salad dressing'' as defined in Sec. 169.150 does not
include a number of common types of dressings for salad, such as
Italian dressing.
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On September 8, 2000 (65 FR 54686),\3\ the agency issued an interim
final rule (IFR) in response to these two health claim petitions to
provide for health claims on the relationship between plant sterol/
stanol esters and the reduced risk of CHD (codified in Sec. 101.83 (21
CFR 101.83)). FDA concluded that, based on the totality of the publicly
available scientific evidence, there was significant scientific
agreement among qualified experts that a health claim for plant sterol/
stanol esters and a reduced risk of CHD was supported by such evidence
(65 FR 54686 at 54700).
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\3\ A correction notice published in the Federal Register on
November 24, 2000 (65 FR 70466).
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Specifically, the agency determined that there is significant
scientific agreement that diets that include plant sterol esters and
plant stanol esters may reduce the risk of CHD. FDA found that high
blood (serum or plasma) total and low density lipoprotein (LDL)
cholesterol are major modifiable risk factors in the development of
CHD. The agency determined that the scientific evidence established
that including plant sterol and plant stanol esters in the diet helps
to lower blood total and LDL cholesterol levels.
Current Sec. 101.83 now provides for a health claim on the label
or labeling of a food meeting certain criteria provided the claim among
other things: (1) States that plant sterol and plant stanol esters
should be consumed as part of a diet low in saturated fat and
cholesterol, (2) uses the term plant (or vegetable oil) sterol esters
or plant (or vegetable oil) stanol esters, (3) specifies that the daily
dietary intake necessary to reduce the risk of CHD is 1.3 g or more for
plant sterol esters or 3.4 g or more for plant stanol esters, (4)
specifies the contribution a serving of the product makes to the daily
dietary intake level, and (5) specifies that the daily dietary intake
of plant sterol or stanol esters should be consumed in two servings
eaten at different times of the day with other foods.
The IFR was effective upon publication on September 8, 2000, with a
75-day comment period that closed on November 22, 2000. On June 6,
2001, the agency issued a notice of an extension of the period for
issuance of a final rule (66 FR 30311). In this notice, the agency
stated that, due to the complexities of the issues involved and the
lack of agency resources, the agency would be unable to issue a final
rule within the prescribed 270 days from date of publication of the
IFR.
After the comment period had closed, the agency received two
requests to extend the comment period. Because several additional
substantial issues had been raised in these comments, FDA reopened the
comment period on October 5, 2001 (66 FR 50824). The agency
specifically requested comment on the following: (1) The eligibility of
nonesterified (free) plant sterols and plant stanols to bear a health
claim, (2) daily intake levels necessary to reduce the risk of CHD, (3)
the eligibility of mixtures of plant sterols and plant stanols to bear
a health claim, (4) the significance of serum apolipotrotein B
concentration as a surrogate marker for CHD risk, and (5) issues
regarding safe use of plant sterol and stanols in foods and the
necessity of an advisory label statement.
On February 14, 2003, FDA issued a letter announcing its intentions
to consider the exercise of enforcement discretion, pending publication
of the final rule, with respect to certain requirements of the health
claim (Ref. 1). Under the conditions of the letter, FDA said it would
consider enforcement discretion if: (1) The food contains at least 400
milligrams (mg) of phytosterols per RACC; (2) mixtures of phytosterol
substances (i.e., mixtures of sterols and stanols) contain at least 80
percent beta-sitosterol, campesterol, stigmasterol, sitostanol, and
campestanol (combined weight); (3) the food meets the requirements of
Sec. 101.83(c)(2)(iii)(B), (c)(2)(iii)(C), and (c)(2)(iii)(D); \4\ (4)
products containing phytosterols, including mixtures of sterols and
stanols in esterified or nonesterified forms, use a collective term in
lieu of the terms required by Sec. 101.83(c)(2)(i)(D) \5\ in the
health claim to describe the substance (e.g., ``plant sterols'' or
``phytosterols''); (5) the claim
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specifies that the daily dietary intake of phytosterols that may reduce
the risk of CHD is 800 mg or more per day, expressed as the weight of
nonesterified phytosterol; (6) vegetable oils for home use that exceed
the total fat disqualifying level bear the health claim along with a
disclosure statement that complies with Sec. 101.13(h) (21 CFR
101.13(h)); \6\ and (7) use of the claim otherwise complies with Sec.
101.83.
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\4\ Section 101.83(c)(2)(iii)(B)--The food must be ``low in
saturated fat'' and ``low in cholesterol'' as defined in Sec.
101.62 (21 CFR 101.62); Sec. 101.83(c)(2)(iii)(C)--the food must
meet the limits for total fat in Sec. 101.14(a)(4) (e.g., for
individual foods, 13.0 g fat per RACC, per labeled serving and if
the RACC is 30 g or less or 2 tablespoons or less, per 50 g) except
that spreads and dressings for salad are not required to meet the
limit per 50 g if the label of the food bears a disclosure statement
per Sec. 101.13(h) (e.g., ``See nutrition information for fat
content''); and Sec. 101.83(c)(2)(iii)(D)--the food must meet the
minimum nutrient contribution requirement in Sec. 101.14(e)(6)
(e.g., except for dietary supplements, the food contains 10 percent
or more of the Daily Value of vitamin A, vitamin C, iron, calcium,
protein, or fiber per RACC prior to any nutrient addition) unless it
is a dressing for salad.
\5\ The IFR required that the substance for the claim be
specified as ``plant sterol esters'' or ``plant stanol esters''
except that if the sole source of the substance was vegetable oil,
the terms ``vegetable oil sterol esters'' or ``vegetable oil stanol
esters'' may be used.
\6\ E.g., ``See nutrition information for fat content.''
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II. Petition and Grounds for Amending the Health Claim on Plant
Sterols/Stanols and CHD
In response to the IFR, and the October 5, 2001 (66 FR 50824),
reopening of the comment period, the agency received approximately 37
comments from a variety of sources. These comments came from
professional organizations, industry, consumer groups, health care
professionals, academia, and research scientists. The majority of the
comments supported authorization of the health claim for phytosterol
esters and CHD but requested modification of one or more provisions.
The agency has conducted an extensive re-evaluation of the
scientific evidence regarding the relationship between consumption of
phytosterols and the risk of CHD. This re-evaluation focused primarily
on evidence from intervention studies that address the specific
amendments that are being considered in this proposed rule. (These
studies are summarized in Tables 1 and 2 at the end of this document
and are discussed below.) FDA's process for this re-evaluation took
into consideration all available scientific evidence of which FDA was
aware and was consistent with FDA evidence-based review approach to
health claims (Ref. 2).
The more recent scientific evidence affirms the agency's conclusion
regarding the validity of the relationship between consumption of
phytosterol esters and a risk of CHD under the SSA standard. FDA has no
reason at this time, based on either public comment or on currently
available scientific evidence, to reconsider that basic conclusion. The
re-evaluation, however, did cause the agency to reconsider the scope of
the substances eligible for the health claim and the requirements for
use of the health claim in the labeling of food.
Based on evidence from those intervention studies, and in light of
the comments received in response to the IFR, the agency has determined
that current Sec. 101.83 should be amended to reflect the current
state of the science under the SSA standard. Because the agency has not
provided a formal opportunity for public comment on the modifications
proposed to current Sec. 101.83, and because of the time that has
elapsed since publishing the IFR, the agency has decided to issue a
proposed rule to amend current Sec. 101.83 rather than finalizing,
with modification, the IFR. This approach provides an opportunity for
public comment prior to issuance of the final rule.
On May 5, 2006, Unilever submitted a health claim petition under
section 403(r)(4) of the act (Docket No. FDA-2006-P-0033 (formerly
Docket No. 2006P-0316)). The petition requested that FDA amend Sec.
101.83 to permit use of the health claim for phytosterols in a food
that provides the full daily intake in a single serving. On August 18,
2006, FDA notified the petitioner that it had completed its initial
review of the petition and that the petition had been filed for further
action in accordance with section 403(r)(4) of the act. The agency is
issuing this proposed rule, in part, in response to Unilever's
petition.
III. Eligibility for a Health Claim/Overview of Data
FDA concluded in the IFR that there was significant scientific
agreement that the consumption of phytosterol esters may reduce the
risk of CHD. FDA's prior evaluation of the scientific evidence to
substantiate a relationship between phytosterols and CHD risk focused
on results from intervention studies designed to investigate the effect
of phytosterol ester consumption on blood total and LDL cholesterol
levels. FDA's evaluation of the scientific evidence to substantiate a
relationship between phytosterol ester consumption and CHD risk
included the review of 20 phytosterol-ester intervention studies that
measured blood (serum or plasma) total or LDL cholesterol levels.
Since issuance of the IFR, there have been a substantial number of
studies conducted and published on the relationship between esterified
and nonesterified phytosterols and risk of CHD. As part of the re-
evaluation of the scientific evidence, FDA requested the Agency for
Healthcare, Research and Quality (AHRQ) to identify intervention
studies that had been conducted since 2000 on the relationship between
phytosterols and CHD risk. FDA identified additional relevant
intervention studies based on comments submitted in response to the
IFR, the 2001 reopening of the comment period and by conducting its own
literature review. In total, FDA identified 66 intervention studies in
which the cholesterol-reducing effect of conventional foods containing
phytosterols was evaluated. FDA identified seven intervention studies
in which the cholesterol-reducing effect of dietary supplements
containing phytosterols was evaluated. Consistent with FDA's prior
evaluation and its evidence-based review approach to the evaluation of
health claims, the agency recognizes elevated blood (serum or plasma)
total cholesterol and LDL cholesterol levels to be valid surrogate
endpoints for CHD risk (Ref. 3). Although other types of study
endpoints, such as measurement of intestinal absorption of cholesterol,
are useful for examining issues such as mechanism of action, they do
not provide direct evidence of an effect on disease risk.\7\ Thus, FDA
evaluated only intervention studies that used the valid surrogate
endpoints of CHD (i.e., blood total and LDL cholesterol), to evaluate
the potential effects of phytosterol intake on CHD risk. Consistent
with the agency's prior evaluation of phytosterol esters, FDA also
reviewed intervention studies that evaluated the effect of phytosterol
intake in individuals who were generally healthy and not yet diagnosed
with CHD.
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\7\ Although FDA sought comment on whether use of serum
apolipoprotein B is an appropriate surrogate endpoint for CHD (66 FR
50824 at 50825 and 50826), the agency has concluded that it is not
because it has not been adequately validated.
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Following FDA's evidence-based review approach to the scientific
evaluation of health claims, the agency excluded intervention studies
that included patients diagnosed with CHD. Of the 66 intervention
studies on conventional foods containing phytosterols identified by
FDA, scientific conclusions could not be drawn from 15 intervention
studies for the following reasons. Five intervention studies did not
include an appropriate control group (Refs. 4, 5, 6, 7, and 8). Without
an appropriate control group, it cannot be determined whether changes
in the endpoint of interest were due to phytosterol consumption or to
unrelated and uncontrolled extraneous factors. Four intervention
studies did not conduct statistical analysis between the control and
treatment group (Refs. 9, 10, 11, and 12). Statistical analysis of the
substance/disease relationship is a critical factor because it provides
the comparison between subjects consuming phytosterols and those not
consuming phytosterols to determine whether there is a reduction of CHD
risk. When statistics are not performed on the specific substance/
disease relationship, it cannot be determined
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whether there is a difference between the two groups. Five intervention
studies provided a combination of phytosterols and other food
components (e.g., polyunsaturated oils, soy protein, beta-glucan and
other viscous fibers) that may be beneficial in reducing total and/or
LDL cholesterol levels (Refs. 13, 14, 15, 16, and 17). Therefore, it is
not possible to evaluate the independent relationship between
phytosterols and CHD risk. One study did not provide baseline and post-
study blood total and LDL cholesterol levels, including statistical
data (Ref. 18). Without knowing if baseline and/or post-intervention
total and/or LDL levels were significantly different, it is difficult
to interpret the findings of the intervention. Thus, FDA identified 51
intervention studies from which scientific conclusions could be drawn
about the relationship between phystosterols in conventional foods and
risk of CHD. (These studies are summarized in table 1 at the end of
this document and are discussed below).
The intervention studies included in this review are studies that
tested phytosterols, derived from either vegetable oils or from tall
oil; \8\ as sterols, their stanol derivatives, or sterol/stanol
mixtures; and used in the form of fatty acid esterified phytosterols or
nonesterified phytosterols. A number of techniques were used to
solublize and disperse nonesterified phytosterols in food (e.g.,
lecithin emulsion, microcrystalline forms, dissolving in heated oil).
The majority of intervention studies used phytosterol-enriched
conventional foods, most frequently margarine-like spreads. A very
limited number of intervention studies provided phytosterols as
ingredients in dietary supplements. With few exceptions, the subjects
were instructed to consume the enriched foods with meals, and either
once a day or up to three times a day. Intake levels in these
intervention studies ranged from 0.45 to 9 g per day, though most
intervention studies added phytosterols to the diet in the range of
about 1 to 3 g per day.\9\ With a few exceptions, the participants in
these intervention studies were moderately hypercholesterolemic. The
results of these intervention studies are consistent with the results
of the intervention studies that had been considered in the IFR in that
consumption of 1 to 3 g of phytosterols per day in phytosterol-enriched
foods resulted in statistically significant reductions (5 to 15
percent) in blood LDL cholesterol levels relative to a placebo control
(see table 1 at the end of this document).
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\8\ As explained in more detail in section V.A.3 in this
proposed rule, tall oil is the term FDA is using in this proposed
rule to describe the byproducts of the kraft process of wood pulp
manufacture.
\9\ Weight of phytosterols is represented as nonesterified
sterols and/or stanols. One g of nonesterified stanols is equivalent
to 1.7 g stanol esters. One g of nonesterified sterols is equivalent
to 1.6 g sterol esters.
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As discussed elsewhere in this proposal, FDA tentatively concludes
that the results of the intervention studies involving the consumption
of dietary supplements containing phytosterols are limited and
inconsistent in demonstrating that such dietary supplements reduce
blood cholesterol levels. The available scientific evidence indicates
that dietary supplements containing phytosterol esters reduce
cholesterol as effectively as conventional foods containing
phytosterols. Although one intervention study showed cholesterol-
lowering efficacy for one formulation of dietary supplement containing
nonesterified phytosterols, there also is evidence that other types of
nonesterified phytosterol formulations were not effective in reducing
cholesterol. We tentatively conclude that the available evidence is
insufficient to establish what factors are key in predicting which
nonesterified phytosterol formulations will be effective and which will
not be when consumed as ingredients in dietary supplements.
IV. Review of the Preliminary Requirements
A health claim characterizes the relationship between a substance
and a disease or health-related condition (Sec. 101.14(a)(1)). A
substance means a specific food or component of food, regardless of
whether the food is in conventional food form or a dietary supplement.
(Sec. 101.14(a)(2)). To be eligible for a health claim, if to be
consumed at other than decreased dietary levels, the food or food
component must contribute taste, aroma, nutritive value, or some other
technical effect to the food and be safe and lawful under the
applicable safety provisions of the act at levels necessary to justify
the claim (Sec. 101.14(b)(3)).
As noted in the IFR, CHD is a disease for which the U.S. population
is at risk and it therefore qualifies as a disease for which a health
claim may be made under Sec. 101.14(b)(1) (65 FR 54686 at 54687).
Current Sec. 101.83 authorizes a health claim regarding CHD for two
substances: (1) Plant sterol esters prepared by esterifying a mixture
of plant sterols from edible oils with food-grade fatty acids; the
mixture consisting of at least 80 percent beta-sitosterol, campesterol,
and stigmasterol (combined weight) and (2) plant stanol esters prepared
by esterifying a mixture of plant stanols derived from edible oils, or
from byproducts of the kraft paper pulping process, with food-grade
fatty acids; the mixture consisting of at least 80 percent sitostanol
and campestanol (combined weight) (Sec. 101.83(c)(2)(ii)). The
regulation does not currently authorize health claims for mixtures of
the two substances. Moreover, the regulation requires a health claim
regarding one of the two substances to specify which one is the subject
of the claim (Sec. 101.83(c)(2)(i)(C)).
For reasons discussed elsewhere in this preamble, FDA is proposing
to amend Sec. 101.83 to expand the substances eligible for the
authorized health claim regarding CHD. Under the proposed amendments,
phytosterols would be the subject of the regulation. As the agency
noted in the IFR, plant sterols occur throughout the plant kingdom and
are present in many edible fruits, vegetables, nuts, seeds, cereals,
and legumes in both nonesterified and esterified forms (65 FR 54686 at
54687 and 54688). As the hydrogenated form of plant sterols, plant
stanols are also present in foods such as wheat, rye, corn, and certain
vegetable oils (65 FR 54686 at 54688). Therefore, phytosterols qualify
as substances for which a health claim may be made under Sec.
101.14(a)(2).
As was true of phytosterol esters, the scientific evidence suggests
that phytosterols achieve their intended effect by functioning to
assist the digestive process. Upon the same reasoning provided for
phytosterol esters in the IFR, therefore, phytosterols provide
nutritive value through assisting in the efficient functioning of a
classical nutritional process and of other metabolic processes
necessary for the normal maintenance of human existence (see 65 FR
54686 at 54688). Accordingly, the agency concludes that the preliminary
requirement of Sec. 101.14(b)(3)(i) is satisfied.
Finally, under Sec. 101.14(b)(3)(ii), phytosterols, at levels
necessary to justify the claim, must be safe and lawful under the
applicable food safety provisions of the act. For conventional foods,
this evaluation involves considering whether the substance is generally
recognized as safe (GRAS), listed as a food additive, or authorized by
a prior sanction issued by FDA. (See Sec. 101.70(f).) Dietary
ingredients in dietary supplements are not subject to the food additive
provisions of the act (see section 201(s)(6) of the act (21 U.S.C.
321(s)(6))). Rather, they are subject to the adulteration provisions in
section 402 of the act (21 U.S.C. 342) and, if applicable, the new
dietary
[[Page 76530]]
ingredient provisions in section 413 of the act (21 U.S.C. 350b).
Through the agency's GRAS notification program, FDA has received
numerous submissions from food manufacturers regarding the GRAS status
of phytosterols when used in certain conventional foods at levels
necessary to justify the claim under the proposed amendments to Sec.
101.83. These submissions have included data to support the
manufacturer's self-determinations that phytosterols under the intended
conditions of use identified in the submissions are GRAS.\10\ FDA did
not object to the conclusions in those submissions. The GRAS
submissions include conditions of use for a variety of conventional
foods, but not all conventional foods. The agency has not made its own
determination that phytosterols are GRAS. However, FDA is not aware of
any scientific evidence that phytosterols, whether free or esterified,
would be harmful. For those conventional foods that have been the
subject of a GRAS notification reviewed by FDA with conditions of use
that meet the eligibility criteria for the use of the health claim, and
for which FDA had no further questions, FDA concludes that the
preliminary requirement under Sec. 101.14(b) that phytosterols be safe
and lawful has been met for use in such conventional foods. We note, in
section C.1 of this document, the minimum level of phytosterols
necessary for a food to contain in order to be eligible to bear a claim
is 0.5 g per RACC. Not all conventional foods for which a GRAS
notification for phytosterols was submitted, to which the agency had no
further questions, are under conditions of use in food that would be
consistent with the eligibility requirements for the health claim,
e.g., certain foods may contain phytosterols at a level that is less
than the minimum of 0.5 g per RACC. Such foods would not be eligible to
bear the health claim if the rule is finalized as proposed. The agency
notes that authorization of a health claim for a substance should not
be interpreted as an affirmation that the substance is GRAS.
---------------------------------------------------------------------------
\10\ See, e.g., GRAS Notification Numbers (GRN) 000039, GRN
000048, GRN 000176, GRN 000177, GRN 000112, GRN 000181, GRN 000053,
and GRN 000206).
---------------------------------------------------------------------------
FDA has also received new dietary ingredient (NDI) notifications,
under section 413(a)(2) of the act, for the use of plant stanol esters
(Ref. 19) and for all plant sterols derived from tall oil (Ref. 20) as
dietary ingredients.\11\ In FDA's judgment, the data submitted with
these NDIs, considered in combination with the GRAS notifications it
has also received for phytosterols in conventional foods, provide an
adequate basis to conclude that a dietary supplement containing
phytosterol esters would reasonably be expected to be safe. Therefore,
FDA concludes that the preliminary requirement under Sec. 101.14 that
the use of phytosterols in dietary supplements be safe and lawful is
satisfied. However, the agency notes that the authorization of a health
claim for phytosterol esters in dietary supplements does not relieve
manufacturers and distributors of such products from ensuring that
their products are not adulterated under section 402 or 413 of the act.
---------------------------------------------------------------------------
\11\ Section 413(a) of the act requires that manufacturers and
distributors of dietary supplement ingredients that had not been
used for food or as a dietary supplement ingredient prior to October
15, 1994, or that are in a form that has been chemically modified
from the form in which it was used in food, submit to FDA at least
75 days before the ingredient is introduced into interstate
commerce, information that is the basis on which the manufacturer or
distributor determined that the dietary supplement containing the
ingredient will reasonably be expected to be safe.
---------------------------------------------------------------------------
V. Proposed Modifications to Current Sec. 101.83
A. Nature of the Substance
1. Esterification
Current Sec. 101.83 limits the substances eligible for the health
claim to those specified in the two original health claim petitions as
follows: (1) Plant sterols derived from vegetable oils and prepared by
esterifying, with food-grade fatty acids, a mixture of plant sterols,
consisting of at least 80 percent beta-sitosterol, campesterol, and
stigmasterol (combined weight); and (2) plant stanol esters derived
from vegetable oils or from byproducts of the kraft paper pulping
process derived from vegetable oils or from byproducts of the kraft
paper pulping process and prepared by esterifying, with food-grade
fatty acids, a mixture of plant stanols, consisting of at least 80
percent sitostanol and campestanol (combined weight) (Sec.
101.83(c)(2)(ii)). The regulation does not authorize a health claim for
nonesterified phytosterols. Several comments received in response to
the IFR requested that the agency permit foods containing nonesterified
phytosterols to bear the health claim.
In finding that the phytosterol esters specified in the current
regulation reduce the risk of CHD under the SSA standard, FDA expressed
agreement in the IFR with the petitioners that the fatty acid portion
of plant sterol/stanol esters is likely to be readily hydrolyzed by
digestive lipases upon ingestion and that the resultant free
phytosterol is left to be incorporated into intestinal micelles in a
manner that prohibits the absorption of cholesterol. The phytosterol is
therefore the active portion of the ester (65 FR 54686 at 54690, 54691,
54694, and 54705). Although the scientific evidence on which FDA relied
in issuing the IFR included studies of both esterified and
nonesterified phytosterols FDA had not considered, in the IFR,
cholesterol-lowering efficacy of nonesterified phytosterols.
In response to the IFR, FDA received a number of comments asserting
that the IFR should be modified to allow use of the health claim for
nonesterified phytosterols, as well as phytosterol esters. Other
comments argued that nonesterified phytosterols should not be eligible
for the health claim because the available evidence on the efficacy of
nonesterified plant sterols and stanols is too limited and the
characterization of the substance is too scant to support their
inclusion in the final rule. In FDA's notice to reopen the comment
period (66 FR 50824, October 5, 2001), the agency asked for any
additional data on the effectiveness of nonesterified phytosterols in
reducing the risk of CHD.
Esterification with fatty acids was one of the initial techniques
used to increase lipid solubility of phytosterols and facilitate
incorporation of phytosterols into foods. However, other techniques
have also been demonstrated effective in enhancing the solubility of
nonesterified phytosterols in conventional foods. Techniques for
solubilization of phytosterols include the following: (1) Dissolving
them into heated fats (Refs. 21 and 22), (2) re-crystallization by
cooling after dissolution in heated oil (Refs. 23 and 24), (3)
mechanically pulverizing crystalline phytosterols to a fine particle
size (Refs. 25 and 26), and (4) emulsifying them with lecithin (Ref.
27).
Nonesterified phytosterols dissolved in oils are as effective in
lowering cholesterol as are equivalent amounts of phytosterol esters.
However, due to the limited lipid solubility of nonesterified
phytosterols, the amount of fat needed to dissolve an effective amount
of phytosterols is substantially greater for nonesterified phytosterols
than for phytosterol esters. The solubility of sitosterol/sitostanol in
rape seed oil mayonnaise increased about tenfold when esterified with
fatty acids (Ref. 28).
Although current Sec. 101.83 provides only for a claim about
phytosterol esters, the evidence that was considered in the IFR
included five intervention
[[Page 76531]]
studies that investigated the effects of nonesterified phytosterols on
serum total and/or LDL cholesterol levels (Refs. 21, 28, 29, 30, and
31). In addition, 12 intervention studies published since the IFR have
involved nonesterified phytosterols added to conventional foods (Refs.
22, 24, 25, 26, 27, 32, 33, 34, 35, 36, 37, and 38) (see table 1 at the
end of this document). In these 17 intervention studies, subjects
consumed conventional foods providing from 0.7 to 5 g per day of
nonesterified plant sterols, plant stanols, or plant sterol/stanol
mixtures during intervention periods of 3 weeks to 6 months. Thirteen
of the seventeen intervention studies reported finding statistically
significant reductions in blood total and/or LDL cholesterol from the
consumption of foods containing nonesterified phytosterols.
Two intervention studies directly compared the cholesterol lowering
efficacy of similar amounts of nonesterified and esterified
phytosterols in conventional foods (Refs. 35 and 38) (see table 1 at
the end of this document). Nestel et al., 2001 (Ref. 35) reported that
consumption of 2.4 g per day of soy phytosterols, as either plant
sterol esters or as nonesterified plant stanols, suspended in
conventional foods and consumed with meals over a 4-week period,
significantly lowered serum LDL cholesterol levels and that there was
no statistically significant difference in the cholesterol-lowering
effect between the two forms of phytosterols. Abumweiss et al., 2006
(Ref. 38) reported that 1.7 g per day of phytosterols, provided as
either nonesterified plant sterols or fatty acid esterified plant
sterols dissolved in margarine did not significantly lower total or LDL
cholesterol compared to the placebo.
In the majority of these 17 intervention studies, nonesterified
phytosterols were suspended in fat-free or low-fat foods (e.g., orange
juice, low-fat dairy foods or other fat-free beverage, bread, cereal,
and jam); in other studies nonesterified phytosterols were suspended in
high-fat foods (e.g., margarine, butter, chocolates and meats) (see
table 1 at the end of this document). In most of these intervention
studies, the study design specified that the food enriched with
phytosterols be consumed with meals. In the few nonesterified
phytosterol intervention studies that did not specify the phytosterol-
enriched foods be consumed with meals (Refs. 24 and 25), the types of
food used (meats, bread, jam, and margarine) make it likely that they
would have been consumed concurrently with other foods.
Based on the totality of available scientific evidence, FDA agrees
with the comments asserting that the blood cholesterol-lowering
efficacy of conventional foods containing nonesterified forms of
phytosterols is comparable to that of fatty acid esterified
phytosterols. Although esterification with fatty acids is one technique
that facilitates dispersion of phytosterols in foods with a high fat
content, FDA tentatively concludes that there is significant scientific
agreement that fatty acid esterification is not necessary for
phytosterols to be incorporated into food matrices or for phytosterols
to be effective in lowering blood cholesterol when added to
conventional foods. FDA also tentatively concludes that, for
conventional foods, it is reasonable to expand the substance that is
the subject of the claim to include both nonesterified and esterified
phytosterols.
Therefore, the agency is proposing to amend current Sec.
101.83(c)(2)(ii) to define the substances eligible for the health claim
to include both phytosterols esterified with certain food-grade fatty
acids and, for the conventional foods for which the claim is
authorized, nonesterified phytosterols as substances for which the
health claim may be made. As discussed elsewhere in this document,
however, FDA is not proposing that dietary supplements containing only
nonesterified phytosterols be eligible for the health claim.
2. Mixtures of Plant Sterols and Plant Stanols
Current Sec. 101.83 distinguishes between plant sterol esters and
plant stanol esters. The plant sterol component of the plant sterol
ester that is the subject of current Sec. 101.83 must be comprised of
at least 80 percent (combined weight) of beta-sitosterol, campesterol,
and stigmasterol (Sec. 101.83(c)(2)(ii)(A)(1)). Similarly, the plant
stanol component of the plant stanol ester that is the subject of the
health claim must be comprised of at least 80 percent (combined weight)
sitostanol and campestanol (Sec. 101.83(c)(2)(ii)(B)(1)). The
effective cholesterol-lowering daily intake specified in the current
regulation for plant sterol esters is 1.3 g per day (equivalent to 0.8
g per day of nonesterified sterol) and that for plant stanol esters is
3.4 g per day (equivalent to 2 g per day of nonesterified stanol)
(Sec. 101.83(c)(2)(i)(G)).
The agency requested comment on the variability of beta-sitosterol,
campesterol, and stigmasterol composition in the plant sterol ester
products reported to be effective in lowering cholesterol (65 FR 54686
at 54705) and requested similar information with respect to the
variability of stanol composition of plant stanol products (65 FR 54686
at 54706). FDA further requested comment on the requirements that
sterol composition of plant sterol esters be at least 80 percent
(combined weight) beta-sitosterol, campesterol, and stigmasterol (65 FR
54686 at 54705) and that the stanol composition of plant stanol esters
be at least 80 percent (combined weight) sitostanol and campestanol.
The 2001 reopening of the IFR comment period (66 FR 50824) specifically
sought submission of additional data on the effectiveness of plant
sterol and stanol mixtures in reducing serum cholesterol levels.
Some comments requested that the scope of the health claim be
broadened to include mixtures of plant sterols and stanols as eligible
substances. One comment stated that for purposes of the health claim
the effective cholesterol-lowering daily intake level for plant
sterols, plant stanols, or plant sterol/stanol mixtures must be
considered the same because available scientific evidence shows plant
sterols and plant stanols to be equivalent in their serum cholesterol-
lowering effect. Other comments asserted that the IFR should not be
broadened to include plant sterol/stanol mixtures because these
substances have not been the subject of a health claim petition. These
comments asserted that FDA should only consider health claims for other
phytosterol substances based on petitions submitted by proponents of
such claims.
The totality of scientific evidence includes reports from five
intervention studies of cross-over design that directly compared the
cholesterol-lowering effects of similar intake levels of plant sterols
and plant stanols within each study and at intake levels ranging from
1.8 and 3 g per day (Refs. 22, 35, 39, 40, and 41) (see table 1 at the
end of this document). Three of the five intervention studies reported
that equivalent intake levels of plant sterols and plant stanols were
equally effective in lowering of blood total and/or LDL cholesterol
levels (Refs. 22, 39, and 41). The other two intervention studies
reported that plant sterols resulted in a greater reduction in LDL
cholesterol compared to an equivalent intake level of plant stanols
(Refs. 35 and 40).
There are nine intervention studies that investigated the
cholesterol-lowering effects of mixtures of plant sterols and plant
stanols added to conventional foods (Refs. 21, 22, 24, 25,
[[Page 76532]]
32, 34, 37, 42, and 43) (see table 1 at the end of this document).
Eight of the nine studies, which provided 1.7 to 5 g per day of such
mixtures foods consumed with meals, reported finding significant LDL
cholesterol reductions of 5 to 15 percent relative to a placebo
control. The magnitude of the effect on lowering LDL cholesterol did
not vary meaningfully between the intervention studies involving
mixtures of plant sterols and plant stanols and interventions studies
involving plant sterols or plant stanols alone. Only one of the plant
sterol/stanol mixture intervention studies reported finding no
statistically significant lowering of LDL cholesterol (Ref. 34). The
phytosterol composition of the mixtures used in most of these
intervention studies was approximately 75 to 85 percent sterols and 10
to 15 percent stanols; two intervention studies used phytosterol
mixtures that contained 50 percent sterol and 50 percent stanol (Refs.
42 and 22).
Based on the intervention studies demonstrating no meaningful
difference between the effectiveness of plant sterols and plant stanols
in lowering cholesterol and the intervention studies demonstrating that
mixtures of plant sterols and plant stanols effectively lower
cholesterol, FDA tentatively concludes that there is significant
scientific agreement among qualified experts to support the
relationship between foods containing mixtures of plant sterols and
plant stanols and CHD.
FDA is therefore proposing to combine current Sec.
101.83(c)(2)(ii)(A)(1) and (c)(2)(ii)(B)(1), and to adopt the term
``phytosterol'' as inclusive of both plant sterols and plant stanols.
Proposed Sec. 101.83(c)(2)(ii) would specify the eligible substance as
``phytosterols.'' The proposal would also add a new paragraph (Sec.
101.83(a)(3)) in the background section of amended Sec. 101.83 to
define the term ``phytosterols'' and to clarify the regulation's use of
that collective term. As discussed in section V.4 of this document, the
proposal would further establish the permissible terminology that could
be used to describe the substances subject to the health claim (Sec.
101.83(c)(2)(i)(D)).
3. Sources of Phytosterols
Current Sec. 101.83(c)(2)(ii) specifies that eligible plant sterol
esters must be derived from edible oils and that eligible plant stanols
must be derived from either edible oils or from byproducts of the kraft
paper pulping process. Some comments to the IFR urged FDA to broaden
the nature of the substance to include both sterols and stanols derived
from either vegetable oils or from wood oils.
The restriction on the source of plant sterol esters to edible oils
in current Sec. 101.83(c)(2)(ii)(A)(1) reflects the original health
claim petition's specifications. The petition for a health claim
characterizing a relationship between plant sterol esters and CHD
limited itself to plant sterols derived from edible oils (i.e., those
edible oils that are vegetable oils). The origin of FDA's use of the
``byproducts of the kraft paper pulping process'' in current Sec.
101.83(c)(2)(ii)(B)(1) was the terminology used by the original health
claim petition for plant stanol esters. The petitioner submitted
documentation to support its self-determination that plant stanol
esters, whether obtained from vegetable oils or byproducts of the kraft
paper pulping process, were GRAS (65 FR 54686 at 54706). FDA notes,
however, that some of the intervention studies that were considered for
purposes of re-evaluating the scientific basis for the authorized
health claim identified the source of the phytosterols as ``tall oil.''
Tall oil is a byproduct of the wood pulp industry, usually recovered
from pine wood ``black liquor'' of the kraft paper process, containing
rosins, fatty acids, long chain alcohols and phytosterols (Ref. 44).
FDA is proposing to use the term ``tall oil'' in lieu of ``byproducts
of the kraft paper pulping process.''
The phytosterols derived from tall oil are predominantly sterols.
These wood-derived plant sterols are hydrogenated to convert a
predominantly plant sterol product to plant stanols. The available
scientific evidence includes five of six intervention studies that
demonstrated cholesterol-lowering effects of conventional foods
containing plant sterols derived from tall oil (Refs. 21, 24, 32, 37,
and 43) (see table 1 at the end of this document). Jones (Ref. 34) did
not observe a significant reduction in total or LDL cholesterol levels
when 1.8 g of nonesterified sterols from tall oil was consumed in a
nonfat or low fat beverage. The composition of the phytosterols used in
these intervention studies was approximately 85 to 90 percent sterols
and 10 to 15 percent stanols. FDA concurs with the comments that argued
that there is no justification for not including plant sterols derived
from byproducts of the kraft paper pulping process. FDA is proposing to
amend the nature of the substance paragraph in current Sec.
101.83(c)(2)(ii) to specify that the source for any phytosterol
eligible for the claim may be either vegetable oils or tall oil.
Amended Sec. 101.83(c)(2)(ii) would specify that eligible plant
sterols and stanols are derived from vegetable oils or from tall oil.
4. Designation of Substance as Phytosterols
Current Sec. 101.83(c)(2)(i)(D) requires that the claim statement
identify the substance as either ``plant sterol esters,'' or ``plant
stanol esters,'' except that if the sole source of the plant sterols/
stanols is vegetable oil, the claim may use the term ``vegetable oil
sterol esters'' or ``vegetable oil stanol esters.'' Because FDA is now
proposing to expand the substance that is the subject of the health
claim to include, in addition to plant sterol/stanol esters,
nonesterified phytosterols and mixtures of sterols and stanols, the
agency is proposing to replace the terms ``plant sterol esters'' and
``plant stanol esters'' with the single term ``phytosterols''
throughout Sec. 101.83.
In addition, FDA does not believe that requiring the claim to
distinguish plant sterol esters from nonesterified plant sterols would
provide meaningful information to the average consumer. On the other
hand, it is likely that consumer recognition of the potential health
benefit of phytosterol-enriched foods would be served by encouraging
consistent use of a single term to identify the variations of
phytosterol substances proposed to be included in the health claim. FDA
believes that permitting the health claim statement to use the term
``phytosterol'' to identify all forms of the substance rather than
distinguishing between sterol and stanol forms of esterified and
nonesterified forms would encourage manufacturers to take that
approach.
Therefore the agency proposes amending current Sec.
101.83(c)(2)(i)(D) to include the single term ``phytosterols.'' To be
consistent with other revisions made to substances eligible for the
health claim in this proposal, we are also proposing to permit accurate
use of the terms ``plant sterols,'' ``plant stanols,'' or ``plant
sterols and stanols,'' and to permit ``vegetable oil phyosterols'' or
``vegetable oil sterols and stanols'' if the sole source of the plant
sterols or stanols is vegetable oil.
5. Determining the Amount and Nature of the Substance
Current Sec. 101.83(c)(2)(ii)(A)(2) and (c)(2)(ii)(B)(2) specify
that, when FDA measures phytosterols in foods bearing the claim, it
will use particular analytical methods, which are the methods specified
in the original health claim petitions. The analytical methods
specified in the current regulation are direct saponification/gas
[[Page 76533]]
chromatographic methods for the determination of phytosterols in
various food matrices. FDA is proposing to amend the health claim to
revise the analytical methods for phytosterols, because the current
methods would be inadequate to measure phytosterols in the range of
foods eligible to bear the health claim under the proposed amendments
to the regulation.
In table 3 of this document, FDA has summarized the key features of
several recent methods used for quantitation of phytosterols. Analytes,
sample handling, matrices studied, and types and lengths of gas
chromatography columns are listed. The types of validation data
obtained for these methods are also listed. Each of these methods
provides starting points for possible extensions to other analytes and
other food matrices. The validation data provide guidelines regarding
the types of validation that would be needed should these methods be
extended or modified.
The agency solicited comments on the suitability of the
petitioners' analytical methods for ensuring that foods bearing the
health claim contain the qualifying levels of phytosterol esters (65 FR
54686 at 54706 and 54707). Comments received from several manufacturers
recommended that, until a general method is developed and validated for
determining the phytosterol content of foods, the regulation should
allow manufacturers to use any reliable analytical method for
determining the amount of phytosterols in their products and that the
records of their testing, or records of other reliable methods to
verify phytosterol content such as production records, should be
available to FDA upon request.
FDA emphasizes that the purpose for identifying a specific
analytical method in a health claim regulation is not to bind
manufacturers to the use of any one analytical method. Rather, the
purpose is to inform manufacturers of the analytical method that will
be used by FDA to verify that foods bearing the claim comply with the
requirements of the claim. Because there is no Association of Official
Analytical Chemists (AOAC) Official Method for phytosterols in foods,
FDA has considered the comments from manufacturers that the agency
could review manufacturers' records (production and/or testing) as a
method of determining compliance with the requirements of the claim
regulation. A specific quantitative analytical method for the substance
that is the subject of the health claim is one means for verifying
compliance with the requirements of a health claim, although it is not
an absolute requirement for a health claim regulation. In the absence
of a validated analytical method for determining the amount of a
substance in a food, FDA has previously included a record inspection
requirement to determine the amount and nature of a substance in the
food to assure that it was in compliance with the requirements of the
health claim. In the soy protein/CHD health claim regulation (Sec.
101.82(c)(2)(ii)(B)), manufacturers of foods bearing the claim must
maintain records sufficient to substantiate the level of soy protein
when the food contains other sources of protein and make such records
available to FDA upon request.
Although FDA recognizes that using food manufacturers' production
and/or analytical records is one option for compliance verification,
recent developments in analytical methodology have provided an
additional possibility for verifying compliance with the claim
requirements. For the reasons discussed below, FDA is proposing to
replace both the Unilever and McNeil methods specified in the current
regulation with AOAC Official Method 994.10, ``Cholesterol in Foods''
(Ref. 45) as modified by Sorenson and Sullivan (Ref. 46) for assaying
phytosterols. FDA recognizes that this method may need to undergo
further validation studies if analytes other than those already studied
are included in the analyses.
When adopted in the IFR, as the analytical methods FDA would use
for determining plant stanol ester content of foods, neither the McNeil
nor the Unilever methods had been subjected to validation through a
collaborative study or peer-verified validation process, nor had they
been published in the scientific literature (65 FR 54686 at 54706 and
54707). FDA is not aware that this situation has changed for the McNeil
methods. The Unilever analytical method has subsequently been validated
through a collaborative study and published (Ref. 47). However, this
method quantifies total 4-desmethyl sterol content only and is not
recommended for identification of unknown sterols. As such, this method
is not suitable for one of the primary analytical needs for determining
compliance with the claim requirements (i.e., identifying the
phytosterols present in a food). Further, the method was validated only
for measurement of plant sterols in vegetable oil blends and plant
sterol concentrates. For these reasons, FDA is proposing to remove the
McNeil and Unilever methods cited in Sec. 101.83(c)(2)(ii)(A)(2) and
(c)(2)(ii)(B)(2) from the regulation.
Table 3--Summary of Key Features of Several Recent Methods Used for Quantitation of Phytosterols
----------------------------------------------------------------------------------------------------------------
Analytes, Validation data
Method Description analytical ranges, available, Comments
other features matrices studied
----------------------------------------------------------------------------------------------------------------
1. McNeil--Sec. Direct Analytes: In-house Method is
101.83(c)(2)(ii)(B)(2). saponification, sitosterol, validation data applicable to the
silyl sitostanol, on linearity, determination of
derivatization, campesterol, accuracy, added
GC. campestanol. precision, and phytosterols.
Lipids are Ranges: 3-8 g/100 reproducibility. Alkaline
saponified at g dressing; 6-18 Matrices: saponification
high temp with g/100 g tub dressings, tub hydrolyses sterol-
ethanolic KOH. spread; 2.5-7.5 g/ spreads, snack ester bonds;
The 100 g snack bars; bars, softgel analytes are
unsaponifiable 464-696 mg/ capsules. nonesterified
fraction is softgel capsules. sterols.
extracted into
hexane. Sterols
are derivatized
to trimethylsilyl
(TMS) ethers and
quantified by
capillary GC with
FID.
Internal standard:
5[beta]-cholestan-
3[alpha]-ol
System
suitability
standards:
cholestanol +
stigmastanol.
Column: capillary,
30 m x 0.32 mm x
0.25 [mu]m film
thickness; cross-
linked 5% phenyl-
methyl silicone
or methyl
silicone gum (HP-
5).
2A. Unilever--Sec. Direct
101.83(c)(2)(ii)(A)(2). saponification,
no
derivatization,
GC.
[[Page 76534]]
Lipids are Analytes: total 4- Validation results Method has been
saponified at desmethyl sterols. for recovery, and validated through
high temp with Range: 7-60 g/100 repeatability. a collaborative
ethanolic KOH.. g product. Matrices: study; however,
Unsaponifiable margarines, this method
fraction is dressings, fats, quantifies total
extracted into fat blends, and 4-desmethyl
heptane. phytosterol ester sterol content
Quantitation by concentrates. only and is not
GC with FID. recommended for
Internal standard: identification of
[beta]- unknown sterols.
cholestanol (CAS Method is not
No. 80-97-7). suitable for one
Column: capillary, of the primary
10 m x 0.32 mm x analytical needs
0.12 [mu]m film for determining
thickness; CP-Sil- compliance with
5CB. the claim
requirements
(i.e.,
identifying the
phytosterols
present in a
food). Method
validated only
for measurement
of plant sterols
in vegetable oil
blends and plant
sterol
concentrates.
----------------------------------------------------------------------------------------------------------------
2B. Duchateau et al., 2002 (Ref. Direct Analytes: International Method is that of
47). saponification, cholesterol, collaborative Unilever (2A).
no brassicasterol, study performed Phytosterols
derivatization, campesterol, with 8 samples analyzed as
GC. stigmasterol, from 4 different nonesterified
Sample is [beta]- products and sterols.
saponified with sitosterol, batches.
ethanolic KOH at [Delta]5- Validation data
70[deg] C for 50 avenasterol. for recovery,
min. Ranges: 15-20 g/ accuracy, and
Unsaponifiable 100 g vegetable repeatability.
fraction is oils; 8 g/100 g Instrument
extracted into vegetable oil details (GC
heptane. spreads; 60 g/100 brand, type;
Quantitation by g phytosterol columns, injector
GC with FID. ester type, temperature
Internal standard: concentrates. program) for all
[beta]- participants
cholestanol provided.
(5[alpha]-
cholestane-
3[beta]-ol).
Reference
standards:
cholesterol,
campesterol,
stigmasterol,
[beta]-sitosterol.
Column: capillary,
10 m x 0.32 mm x
0.12 [mu]m film
thickness; CP-Sil-
5CB.
----------------------------------------------------------------------------------------------------------------
3. AOAC Official Method 994.10 Direct Analyte: Collaborative The method is
``Cholesterol in Foods.'' saponification, cholesterol Test study matrices: applicable to the
Direct saponification-gas silyl sample should Butter cookies, determination of
chromatographic method (Ref. derivatization, contain <= 1 g vegetable bacon >= 1 mg
45). GC. fat or <= 5 g baby food, cholesterol/100 g
Lipids are water. Suggested chicken vegetable of foods, food
saponified at sample weights baby food, products.
high temperature provided for pure skinless wieners, Collaborative
(not specified) oils, salad NIST egg powder study reference:
with ethanolic dressings, (SRM 1845) Journal of AOAC
KOH. substances with commercial International,
Unsaponifiable high moisture powdered eggs, 78(6):1522-1525,
fraction content.. Cheese Whiz. 1995. (Ref. 48).
containing LOQ: 1.0 mg/100 g
cholesterol and Calibration curve
other sterols is 2.5-200 [mu]g/ml.
extracted with
toluene. Sterols
are derivatized
to TMS ethers and
quantified by GG
with FID.
Internal standard:
5[alpha]-
cholestane.
Column: capillary,
25 m x 0.32 mm x
0.17 [mu]m film
thickness; cross-
linked 5% phenyl-
methyl silicone
or methyl
silicone gum (HP-
5, Ultra 2 of HP-
1).
[[Page 76535]]
4. Sorenson and Sullivan, 2006 Direct Analytes: Single laboratory Full collaborative
(Ref. 46). saponification, campesterol, validation: study said to be
silyl stigmasterol, precision, in progress.
derivatization, [beta]-sitosterol. stability,
GC. LOQ: 1.0 mg/100 g accuracy, and
Modification of Calibration ruggedness.
AOAC Official curve: 2.5-200 Matrices: powdered
Method 994.10 [mu]g/ml. saw palmetto
(see item 3. of berry, saw
this table) to palmetto dried
include fruit CO2
determination of extracts, saw
phytosterols. palmetto 45%
Lipids are powdered extract,
saponified at dietary
high temperature supplement
(not specified) samples.
with ethanolic
KOH.
Unsaponifiable
fraction
containing
cholesterol and
other sterols is
extracted with
toluene. Sterols
are derivatized
to TMS ethers and
quantified by GG
with FID.
Internal standard:
5[alpha]-
cholestane.
Column: capillary,
25 m x 0.32 mm x
0.17 [mu]m film
thickness; cross-
linked 5% phenyl-
methyl silicone
or methyl
silicone gum (HP-
5, Ultra 2 of HP-
1).
----------------------------------------------------------------------------------------------------------------
5. Quaker Method 210 Direct extraction, Analytes: In-house Intended for use
(Ref. 49). silyl sitosterol, validation data in only
derivatization, sitostanol, for specificity, relatively low-
GC. campesterol, accuracy fat foods
Lipids are campestanol.. linearity, enriched with
extracted from Range: 0.7-2.25 g/ precision, and nonesterified
homogenized food 100 g bars; 0.13- stability.. plant sterols/
sample into 0.38 g/100 g Matrices: food stanols.
toluene. Sterols beverages; 3-9 g/ bars, beverages, Applicable for
are derivatized 100 g cereals. ready-to-eat determination of
to TMS ethers and cereals. added
quantified by nonesterified
capillary GC with phytosterols.
FID.
Internal standard:
5[alpha]-
cholestane (CAS
No. 481-21-0).
Reference
standards:
mixture of
nonesterified
sitosterol,
sitostanol,
campesterol,
campestanol.
Column: capillary,
30 m x 0.25 mm x
0.25 [mu]m film
thickness; (DB-5).
----------------------------------------------------------------------------------------------------------------
6. Toivo, J. et al. 2001 (Ref. Acid hydrolysis, Analytes: Single laboratory Intended for use
50). saponification, cholesterol, validation in determining
silyl sitosterol, includes method levels of
derivatization, sitostanol, optimization, endogenous
GC. campersterol, accuracy, and phytosterols in
First step uses campestanol, repeatability.. foods.
HCL hydrolysis to stigmasterol, Matrices: flour, Acid hydrolysis
liberate [Delta]5- canola oil, corn step included to
glycosylated avenasterol. meal, dried release
phytosterols Range: 0.5-800 mg/ onion, sunflower conjugated forms
bound in food 100 g for seed, diet of phytosterols.
matrices. Lipids individual composite. Important for
are extracted phytosterols. grains, flours;
into not so for oils.
hexane:ether, Use of acid
dried and the hydrolysis prior
lipid extract is to or following
saponified at lipid extraction
high temp with discussed.
ethanolic KOH. Method has been
Unsaponifiable used for analysis
fraction is of hundreds of
extracted into foods to create
cyclohexane. database of
Sterols are phytosterol in
derivatized to foods.
TMS ethers and
quantified by
capillary GC with
FID.
Internal standard:
dihydrocholestero
l (cholestanol).
Reference
standard:
dihydrocholestero
l (cholestanol),
cholesterol,
cholesteryl
palmitate, and
mixture of
soybean steryl
glucosides
containing
sitosterol,
campesterol, and
stigmasterol as
their glucosides.
Column: capillary,
60 m x 0.25 mm x
0.1 [mu]m film
thickness; cross-
linked 5%
diphenyl-95%
dimethyl
polysiloxane.
----------------------------------------------------------------------------------------------------------------
ABREVIATIONS: GC--gas chromatography; TMS--trimethylsilyl; FID--flame ionization detector; KOH--potassium
hydroxide; CAS--Chemical Abstract Service; LOQ--limit of quantitation.
[[Page 76536]]
At the present time, the method that appears to be the most
appropriate for the current regulation is that of Sorenson and Sullivan
(2006) (Ref. 46). This method, which has undergone AOAC's single
laboratory validation procedures, is a modification of AOAC Official
Method 994.10 for the determination of cholesterol in foods. AOAC
Official Method 994.10 was validated in a variety of food matrices
(Ref. 48) and, with the modifications and validation data provided by
Sorenson and Sullivan (Ref. 46), can likely be extended further to
include campestanol and sitostanol and additional food matrices.
At this time, FDA is not aware of any publicly available analytical
methods that have already been validated through collaborative studies
that apply to a wider range of food matrices and that adequately
resolve the specific phytosterols that are the subject of this health
claim (i.e., [beta]-sitosterol, campesterol, stigmasterol, sitostanol,
and campestanol) from other phytosterols potentially present in foods.
FDA is therefore requesting submission of validation data for any
analytical methods that may apply to a wider range of food matrices or
more fully validated for separation and quantitation of the specific
phytosterols of this health claim.
FDA is tentatively concluding that the modification of AOAC
Official Method 994.10 provided by Sorenson and Sullivan (Ref. 46) for
the evaluation of campesterol, stigmasterol, and beta-sitosterol is an
appropriate method for use to assess compliance for this health claim
for those foods for which such method has been validated. This method
will need to be validated to include campestanol and sitostanol and to
include additional matrices for other foods that may be eligible for
this claim. Method validation is a process that is used to establish
that, if the method is performed properly, it produces results which
are of acceptable quality. The validation process involves determining
statistical parameters of a method to decide if the method is fit for a
specified purpose. Methods documented by published interlaboratory
validation data are generally selected over those that are not.
Attributes of methods include the following: Range, limit of detection,
limit of quantitation, accuracy, precision (repeatability and
reproducibility), specificity (selectivity), sensitivity, robustness
(ruggedness), practicality, and applicability. We request comment on
whether validated methods are available for analytes and matrices that
are not included in the Sorenson and Sullivan method. If so, FDA may
adopt such methods in a final rule. If no other validated methods are
available, FDA would likely require, in a final rule, a requirement for
manufacturers to maintain records to demonstrate that the method used
to identify the presence of the phytosterols in its product, that bears
the phytosterol health claim, and the level of each phytosterol source
in such product, is capable of accurately quantifying phytosterols in
the product. FDA also would likely require that manufacturers maintain
records of test results. Further, FDA would likely require that the
manufacturer make such records available to FDA upon request.
FDA is proposing to replace the analytical methods now specified in
current Sec. 101.83 (Unilever's method in Sec. 101.83(c)(2)(ii)(A)(2)
and McNeil's methods in Sec. 101.83(c)(2)(ii)(B)(2)) with Sorenson and
Sullivan's modifications of AOAC Official Method 994.10 (Ref. 46), for
those foods for which the Sorenson and Sullivan method has been
validated.
B. Nature of the Claim
1. Effective Cholesterol-Lowering Daily Dietary Intake
Current Sec. 101.83(c)(2)(i)(G) requires that the health claim
specify the daily dietary intake of plant sterol or stanol esters that
is necessary to reduce the risk of CHD and the contribution one serving
of the product makes to the specified daily dietary intake level.
Current Sec. 101.83(c)(2)(iii)(A) further specifies that the amount of
plant sterol or stanol esters that a food product eligible to bear the
health claim is required to contain per RACC. Such amount is one half
of the daily dietary intake level associated with reduced CHD risk
(i.e., the total daily intake divided between two meals). FDA concluded
in the IFR that the daily dietary intake levels of plant sterol and
stanol esters that are associated with reducing the risk of CHD, based
on the consistently demonstrated effective lowering of blood total and/
or LDL cholesterol, were at least 1.3 g per day of plant sterol esters
(equivalent to 0.8 g per day expressed as plant sterol) and at least
3.4 g per day of plant stanol esters (equivalent to 2 g per day
expressed as plant stanols) (65 FR 54686 at 54704).
In its original health claim petition, Unilever (then acting under
its subsidiary Lipton) proposed 1.6 g per day of plant sterol esters
(equivalent to 1 g per day expressed as nonesterified plant sterols) as
the daily dietary intake level of plant sterols necessary to justify a
claim about reduced risk of CHD. The agency agreed that an intake level
of 1 g per day of nonesterified plant sterols had been demonstrated to
consistently reduce blood total and LDL cholesterol, but the agency
also considered three intervention studies (Refs. 29, 30, and 51) in
which a daily intake level of approximately 0.8 g per day plant sterols
was reported to significantly lower blood cholesterol. The agency
therefore concluded that the intake level of plant sterols consistently
shown to lower blood total and LDL cholesterol was 0.8 g per day or
more of nonesterified plant sterols (equivalent to 1.3 g per day or
more expressed as plant sterol esters) (65 FR 54686 at 54704).
McNeil proposed a total daily intake of at least 3.4 g per day of
plant stanol esters (equivalent to 2 g per day expressed as
nonesterified plant stanols), which represents an amount that had been
consistently shown to be effective in reducing blood cholesterol (65 FR
54686 at 54704). The agency found no consistent scientific evidence for
blood cholesterol-lowering associated with plant stanol ester intake
levels less than 3.4 g per day. Although one study (Refs. 28 and 52)
reported significant lowering of blood cholesterol at 1.36 g plant
stanol esters per day (equivalent to 0.8 g per day expressed as
nonesterified stanols), another study (Ref. 53) reported no significant
reduction of blood cholesterol levels at approximately the same plant
stanol ester intake level.
FDA requested comment on the determination of the daily intake of
plant sterol esters and plant stanol esters associated with the risk of
CHD (65 FR 24686 at 24704). A majority of comments to the IFR suggested
that the efficacy of plant sterols and stanols was similar and that the
daily intake levels should be the same for both substances. Many of
these comments suggested that the equivalent amount should be in line
with the minimum effective level for plant sterol esters. Some comments
argued for adopting approximately 2 g per day (expressed as
nonesterified phytosterols) as a more highly effective level, but most
comments favored the lower level. Some comments provided scientific
data and analysis to support this contention; others did not.
The phytosterol intervention studies that FDA considered in this
reevaluation (see table 1 at the end of this document) included dietary
phytosterol intervention levels ranging between 0.45 g per day (Ref.
54) and 9 g per day (Ref. 55). Most commonly, phytosterol intake levels
ranged from 1 to 3 g per day. Intervention studies demonstrated
statistically significant reductions in total and/or LDL
[[Page 76537]]
cholesterol levels for plant sterol intake levels ranging from 1 to 3 g
per day. Similar to plant sterols, intervention studies demonstrated
statistically significant reductions in total and/or LDL cholesterol
levels for plant stanol intake levels ranging from 1.6 to 3 g per day.
There are also five intervention studies of cross-over design that
directly compared the cholesterol-lowering effects of similar intake
levels of plant sterols and plant stanols within each study and at
intake levels ranging from 1.8 and 3 g per day across the five
intervention studies (Refs. 22, 35, 39, 40, and 41). All five of these
intervention studies demonstrated that both plant sterols and plant
stanols significantly reduce blood total and/or LDL cholesterol levels.
Three of the five intervention studies reported that equivalent intake
levels of plant sterols and stanols were equally effective in lowering
of blood LDL cholesterol levels (Refs. 22, 39, and 41). The other two
intervention studies reported that plant sterols resulted in a greater
reduction in LDL cholesterol compared to an equivalent intake level of
plant stanols (Refs. 35 and 40).
Based on the scientific evidence regarding the relationship of
consuming phytosterols with a reduced risk of CHD, FDA tentatively
concludes that 2 g of phytosterols per day is the daily dietary intake
necessary to achieve the claimed effect. Two g per day of plant sterols
is the midpoint of the daily intake range of 1 to 3 g used in the
majority of intervention studies designed to evaluate their
effectiveness in lowering cholesterol. Two g of phytosterols per day is
also at the lower end of the daily intake range in the intervention
studies designed for evaluating the effectiveness of plant stanols and
mixtures of plant stanols and sterols. In addition, 2 g per day is
commonly cited as an optimal level for cholesterol-lowering effects
(Refs. 3, 56, 57, and 58) and FDA's own evaluation of the publicly
available evidence supports that conclusion. FDA has thus tentatively
determined that, for purposes of authorizing a health claim relating
phytosterol consumption and CHD risk, the daily dietary intake
necessary to achieve the claimed effect for phytosterols is 2 g per
day. The agency invites comments on this tentative determination.
Current Sec. 101.83(c)(2)(i)(G) identifies the daily dietary
intake levels of plant sterols/stanols in terms of ``------ grams or
more per day * * *.'' Likewise, the model health claims provided in the
IFR preface the daily dietary intake levels with the phrase ``at
least,'' e.g., ``Food containing at least 1.7 g per serving * * * for a
total daily intake of at least 3.4 g * * *'' (Sec. 101.83(e)). The
agency is also proposing to eliminate the ``or more'' and ``at least''
qualifications from the specification of the daily dietary phytosterol
intake level. The agency is proposing to amend Sec. 101.83(c)(2)(i)(G)
to require that a claim that is the subject of this regulation specify
that the daily dietary intake of phytosterols that is necessary to
justify the CHD risk reduction claim is 2 g per day.
2. Servings per Day
Current Sec. 101.83(c)(2)(i)(H) requires the health claim to
specify that the daily dietary intake of plant sterol or stanol esters
should be consumed in two servings eaten at different times of the day
with other foods. FDA explained that the conditions for the consumption
of phytosterols to be specified in the claim were consistent with the
way phytosterols were used in those intervention studies showing
significant blood cholesterol-lowering effects of phytosterols. In
these intervention studies, the study subjects were instructed to
consume the daily intake of phytosterols divided over two or three
servings at different times of the day or were instructed to replace a
portion of their typical dietary fat with equal portions of
phytosterol-enriched test margarines over the course of the day,
usually during meals (65 FR 54686 at 54705). FDA also noted that given
the limited variety of phytosterol-enriched foods to be included in the
claim, it would be difficult for many consumers to eat more than two
servings of phytosterol-enriched foods per day. FDA further noted that
recommending more than two servings per day of phytosterol-enriched
foods would not be appropriate, considering the fat content of the
phytosterol-enriched conventional foods (primarily fat-based foods) to
be eligible to bear the claim (65 FR 54686 at 54708).
FDA requested comments on whether it was reasonable, in light of
the fat content of products eligible to bear a claim and the limited
number of available products, to divide the daily dietary intake of
plant sterol esters and plant stanol esters by two and specify that the
product should be consumed in two servings eaten at different times of
the day (65 FR 54686 at 54707 and 54708, respectively). Some comments
supported the agency's requirement that the label specify that the
daily dietary intake of phytosterols should be consumed in two servings
at different times during the day. Several comments stated that the
claim statement should state ``at least two * * *'' or ``two or more *
* *'' servings a day rather than two servings per day and asserted that
consumers would benefit more from consuming phytosterols on more
occasions during the day. Most comments disagreed with the agency's two
servings per day requirement. Some of these comments noted that,
because the technology exists to disperse phytosterols into non-fat
foods, there is no reason to deviate from the usual assumption that the
total daily intake of a food component is divided among four eating
occasions. Several comments requested that the claim make the servings
per day statement optional rather than a mandatory component of the
claim. One comment said that optional claim language about the number
of servings of phytosterol-enriched foods per day could vary, depending
on the phytosterol content of a food.
The 2006 Unilever petition (Docket No. FDA-2006-P-0033 (formerly
Docket No. 2006P-0316)) asserted that there is now significant
scientific agreement that phytosterols will significantly reduce
cholesterol levels when consumed once per day. The petition requested
that Sec. 101.83 be amended to permit a food containing 2g of
phytosterols to state that consuming phytosterols once per day has been
associated with a reduced risk of CHD. FDA is proposing to amend Sec.
101.83 to permit the health claim Unilever requested.
The design of most phytosterol intervention studies specified that
the daily intake of phytosterols be divided between two or three
servings eaten at different times with meals. However, scientific
evidence that has become available since issuance of the IFR
demonstrates that dividing the daily intake over two or more servings
is not necessary for the cholesterol-lowering effect of phytosterols.
Seven of the more recently completed phytosterol intervention studies
had their study subjects consume all phytosterol-enriched test foods in
one serving per day (Refs. 8, 35, 38, 42, 43, 59, and 60) (see table 1
at the end of this document).
Six of the seven ``once-per-day'' studies that FDA considered
reported significant reductions of total and/or LDL cholesterol in
phytosterol groups compared to the control group (Ref. 38). AbuMweis et
al., 2006 reported no cholesterol-lowering effect, at 1.0 to 1.8g per
day, when the phytosterols were incorporated into margarine and
consumed as part of the breakfast meal for 4 weeks. Each of the six
studies that reported once-per-day consumption of phytosterols to be
effective in reducing cholesterol had incorporated the phytosterols
into test foods (margarine,
[[Page 76538]]
bread, low fat milk, cereal, yogurt, or ground beef) that were consumed
with a meal. These once-per-day studies reported that daily intakes
ranging from 1.6 to 3 g per day resulted in reductions in cholesterol
of between 5.6 and 12.4 percent compared to controls. The cholesterol-
lowering effect from ``once-per-day'' consumption was similar to the
cholesterol reductions observed for comparable daily intake levels
divided over multiple servings eaten at different times of the day.
Based on this evidence, FDA tentatively concludes that the
requirement for the health claim to specify that the daily dietary
intake of phytosterols should be consumed in two servings eaten at
different times during the day is no longer consistent with the
available scientific evidence for the cholesterol-lowering effect of
phytosterol consumption. FDA also notes that the other reasons cited in
the IFR for requiring the claim statement to specify that phytosterols
should be eaten in two different servings (i.e., the health claim was
to be available to a limited number of foods and the conventional foods
were mostly high fat content), would no longer be valid arguments due
to other changes in the claim criteria that are being proposed at this
time.
Therefore the agency is proposing to amend Sec. 101.83(c)(2)(i)(H)
by removing the requirement that the health claim include a
recommendation that phytosterols be consumed in two servings eaten at
different times of the day.
3. Consuming Phytosterols With Meals
Current Sec. 101.83(c)(2)(i)(H) requires that the health claim
specify that phytosterols should be consumed in two servings eaten at
different times of the day with other foods. As discussed in section
V.B.2 of this document, FDA has concluded that requiring the claim to
state that the total daily dietary intake of phytosterols should be
divided over two servings eaten at different times is no longer
supported by available scientific evidence. The agency is also
proposing to amend Sec. 101.83 to require the claim to recommend that
phytosterols be consumed with ``meals.''
The design used in a majority of phytosterol intervention studies
specified that the phytosterol-enriched test foods were to be consumed
with meals. The experimental design of most all other intervention
studies that did not specify the phytosterol-enriched test foods were
to be consumed ``with meals'' involved fat-based phytosterol-enriched
test foods (margarine, butter, mayonnaise) and specified that the
phytosterol test food be used to replace an equivalent amount of the
subjects' typical daily fat consumption. As such, it is likely that in
these studies the phytosterol-enriched foods would have been consumed
with other foods. One intervention study investigated the impact of
consuming phytosterols with meals (Ref. 43). The study subjects in this
study were instructed to consume a daily single serving of phytosterol-
enriched yogurt either in the morning at least 0.5 hour before
breakfast, or with lunch. Significant lowering of total and LDL
cholesterol was reported for both phytosterol-enriched yogurt consumed
while fasting and when consumed with a meal; however, the cholesterol-
lowering effect was significantly greater when consumed with a meal
than when not consumed with a meal (Ref. 43).
Intestinal absorption of cholesterol requires cholesterol be
incorporated into mixed micelles of the intestinal digesta. Intestinal
micelles form when dietary fatty acids, pancreatic juice, and bile
salts come together at the same time in the small intestine. The
process of eating food stimulates secretion of pancreatic juice and of
bile salts into the intestine. The presumptive primary site of
phytosterol interaction with cholesterol is within the micelles, where
phytosterols are thought to block the transfer of cholesterol from
micelles to intestinal mucosal cells. This mechanism supports the
theory that the effectiveness of dietary phytosterols in reducing blood
cholesterol levels depends upon the phytosterols being consumed
concurrently with food and dietary fat to ensure maximal incorporation
of phytosterols into intestinal micelles. Current Sec. 101.83
authorizes a health claim only for phytosterols esterified with fats
and incorporated into types of fat-based foods (margarines and salad
dressings) that typically are consumed with other foods and therefore
the theoretical conditions that facilitate interference with
cholesterol absorption (i.e., phytosterols consumed with food and with
dietary fat) would be met.
Changes to current Sec. 101.83 in this proposed rule include: (1)
Expanding the substance of the claim to include nonesterified
phytosterols in conventional foods, (2) removing restrictions on types
of conventional foods eligible for the claim such that fat-free foods
and beverages will not be precluded from making the claim, and (3)
removing the requirement that the claim statement specify that
phytosterols should be consumed in two servings eaten at different
times during the day. The cholesterol-lowering efficacy of
phytosterols, when not consumed with dietary fat and a substantial
amount of food, has not been demonstrated. Without a recommendation
that phytosterols be consumed with meals or snacks, it is probable that
the types of foods (including dietary supplements) likely to be
enriched with phytosterols for the purpose of bearing the health claim
would be consumed without sufficient dietary fat or amounts of food to
be consistent with the circumstances under which phytosterols are
likely to be effective in lowering cholesterol.
FDA is proposing to amend Sec. 101.83(c)(2)(i)(H) to require that
the health claim specify that phytosterol-enriched foods should be
consumed ``with meals or snacks.'' The ``with meals or snacks''
specification will replace the current requirement that the claim
specify the daily dietary phytosterol intake should ``be consumed in
two servings eaten at different times of the day with other foods.''
C. Nature of the Food Eligible To Bear the Claim
1. Qualifying Amount of Phytosterols per Serving
Current Sec. 101.83(c)(2)(iii) requires that, in order to bear the
health claim, a product must contain at least 0.65 g of plant sterol
esters (equivalent to 0.4 g nonesterified plant sterols) or 1.7 g of
plant stanol esters (equivalent to 1 g nonesterified plant stanols)
that comply with paragraphs Sec. 101.83(c)(2)(ii)(A)(1) and
(c)(2)(ii)(B)(1) respectively, per RACC. These values are one-half of
the plant sterol/stanol ester daily intake specified in the IFR as that
necessary to achieve the CHD risk-reduction benefit. As discussed in
section V.B.2 of this document, FDA is proposing to amend Sec. 101.83
to remove the current requirement that the health claim specify that
phytosterols should be consumed in two servings at different times of
the day. Also, the proposed changes to Sec. 101.83 would result in a
greater variety of phytosterol-enriched foods eligible for the claim
than now included in current Sec. 101.83, including conventional foods
with a lower fat content. Therefore, FDA is reconsidering the initial
decision to base the minimum amount of phytosterol in a food eligible
to use the health claim on two servings per day.
The agency generally assumes that a typical food consumption
pattern includes three meals and one snack per day (see 58 FR 2302 at
2379, January 6, 1993). Currently available evidence demonstrates that
it is feasible and effective to enrich low fat and fat free foods with
phytosterols. Due to the
[[Page 76539]]
wider variety of conventional foods that may potentially be fortified
with phytosterols (as evidenced by the variety of phytosterol-enriched
test foods used in intervention study reports published since 2000), it
may be feasible for consumers to select four servings per day without
having to depend exclusively on conventional foods with a high fat
content. As a result, FDA believes it would be reasonable to base the
minimum qualifying amount of phytosterol in a food on four servings per
day. As discussed in section V.B.1 of this document, FDA has
tentatively concluded that, for the purpose of the health claim, the
phytosterol daily dietary intake necessary to achieve the claimed
effect is 2 g per day. Dividing this daily intake over four servings
per day, the minimum eligible phytosterol content of a food would be
0.5 g per RACC, expressed as the weight of nonesterified phytosterols.
Therefore, the agency is proposing to amend Sec.
101.83(c)(2)(iii)(A) to permit health claims on foods that contain at
least 0.5 g per RACC of phytosterols, expressed as the weight of
nonesterified phytosterols, and that comply with paragraph (c)(2)(ii)
of this section. Further, the agency is proposing to add new Sec.
101.83(c)(2)(iii)(C) to limit the claim to conventional foods
containing phytosterols for which the agency has received a GRAS
notification, to which it had no further questions, and the conditions
of use are consistent with the eligibility requirements for the health
claim. We note that not all conventional foods for which a GRAS
notification for phytosterols was submitted, to which the agency had no
further questions, are under conditions of use in food that would be
consistent with the eligibility requirements for the health claim,
e.g., certain foods may contain phytosterols at a level that is less
than the minimum of 0.5 g per RACC. Such foods would not be eligible to
bear the health claim if the rule is finalized as proposed.
2. Nature of the Food
Current Sec. 101.83(c)(2)(iii)(A)(1) limits the plant sterol
ester-enriched food products eligible to bear the health claim to
spreads and dressings for salad. Current Sec. 101.83(c)(2)(iii)(A)(2)
limits the plant stanol ester-enriched food products eligible to bear
the health claim to spreads, dressings for salad, snack bars, and
dietary supplements in softgel form. The term ``spreads'' was used in
the IFR to include both margarine and vegetable oil spreads resembling
margarine but having a fat content less than that required by the food
standard for margarine (Sec. 166.110 (21 CFR 166.110)). The term
``dressings for salad'' was used in the IFR to include both salad
dressing and similar vegetable oil-based food products with vegetable
oil content less than that required by the food standard for salad
dressing (Sec. 169.150 (21 CFR 169.150)), which is typically a product
that resembles mayonnaise.
FDA explained in the IFR that the use of the plant sterol ester
claim was being restricted to the labeling of spreads and dressings for
salads because of the following: (1) The petitioner limited its
requested health claim to those two types of foods, (2) the petitioner
had satisfied the requirement of Sec. 101.14(b)(3)(ii) only with
respect to the use of plant sterol esters as an ingredient in spreads
and dressings for salads, and (3) the petitioner had provided a
quantitative analytical method for measurement of plant sterol esters
only in spreads and dressings for salads (65 FR 54686 at 54707). FDA
noted that it would consider broadening the types of plant sterol
ester-containing foods eligible to bear the claim if data were
submitted to establish the use of plant sterol esters in other food
products at levels necessary to justify the claim is safe and lawful
and if a validated analytical method that permits accurate
determination of the amount of plant sterol esters in other types of
foods was available (65 FR 54686 at 54707). The agency advanced
analogous reasoning for limiting the foods eligible to bear the
authorized health claim for plant stanol esters to spreads, dressings
for salad, snack bars and dietary supplements in softgel form (65 FR
54686 at 54708).
Many comments received in response to the IFR addressed the
restrictions on the types of foods eligible for the claim. Most of the
comments objecting to the IFR's specification of eligible food
categories recommended that the final rule be expanded to include
additional types of foods or asserted that the final rule need not
restrict the types of food eligible for the claim. These comments
argued: (1) That evidence now available from clinical trials
established the cholesterol-lowering effectiveness of phytosterols when
incorporated into many types of foods, including low fat and fat free
foods, and (2) that thus there was no evidence to suggest that the food
matrix chosen to carry the phytosterol will have an effect on
cholesterol-lowering efficacy. Some comments asserted that it is
unnecessary to limit the claim to fat-based food matrices because the
technology is available to disperse nonesterified plant sterols and
stanols in a wide variety of non-fat food matrices and because the key
factor is that the plant sterols be consumed with fat, not that the
plant sterols be dispersed in fat. Other comments noted that a growing
number of GRAS notifications, to which the agency has not objected,
expand the categories of food in which phytosterols may be used safely
and lawfully beyond the foods listed in current Sec. 101.83. Some
comments urged authorizing the health claim for other categories of
foods, subject to availability of validated quantitative analytical
methodology for phytosterols in other food matrices. Other comments
argued that it is not necessary to restrict use of the claim to types
of foods for which the petitioners had provided product-specific
phytosterol analytical methods. Rather, these comments contended, that
it is feasible to measure phytosterols in other food matrices using
established general sterol methods and the food industry should be
permitted to use any reliable methods, including maintaining production
records, to document compliance with the phytosterol content
requirements of the claim. Some comments asserted that making more
types of foods eligible for use of the claim would encourage consumer
use of phytosterol-enriched foods through a broader array of food
options accommodating a greater variety of consumer tastes. One comment
opposed broadening of the categories of foods eligible to bear the
claim, arguing that proliferation of the types of foods bearing the
claim would likely result in phytosterol intake exceeding acceptable
daily intake levels and that the long-term safety of higher intake
levels has not been evaluated.
Finally, some comments received in response to the IFR requested
that FDA expand the regulation to permit health claims for plant
sterol/stanol ester-containing dietary supplements in a variety of
forms including tablets, capsules, softgel capsules, and chewable
wafers. Others were concerned that products in ``pill'' form and
intended for use to help lower blood cholesterol looked too much like
over the counter drugs.
a. Conventional foods. All the intervention studies involving
phytosterol-enriched conventional foods cited in the IFR were studies
in which the phytosterols were added to the diet as phytosterol-
enriched margarines, butter, mayonnaise, or shortening. Subsequently,
evidence from intervention studies employing a wider variety of
phytosterol-enriched conventional foods has become available (see table
1 at the end of this document). Phytosterol-enriched conventional foods
used in intervention studies now include the following: Margarine and
reduced-fat spreads
[[Page 76540]]
resembling margarine, shortening, dressings for salad, mayonnaise,
grain products (bread, croissants, muffins, and breakfast cereal),
dairy products (yogurt, reduced-fat cheese, butter, and dairy-based
beverage), beverages (orange juice, fat-free lemon-flavored drink, and
unspecified fat-free drink), meat (ground beef and cold cuts), and
chocolate. The more recent intervention studies showed that daily
dietary phytosterol (nonesterified and esterified) intake of
approximately 1 to 3 g per day from a variety of types of food enriched
with phytosterols, including fat-free foods, resulted in significant
cholesterol-lowering comparable to that resulting from consuming
phytosterol-enriched spreads and margarines (see table 1 at the end of
this document). The data from available intervention studies show the
average percent reduction of blood LDL cholesterol resulting from a
daily phytosterol of intake between 1 and 3 g per day is independent of
the types of foods enriched with phytosterols. FDA therefore concurs
with the comment that, with respect to conventional foods, there is no
scientific evidence to suggest the food matrix into which the
phytosterols are added is an important factor affecting the
cholesterol-lowering efficacy of phytosterols.
Therefore, the agency is proposing to amend Sec.
101.83(c)(2)(iii)(A) by eliminating the enumeration of specific
conventional foods that may bear a health claim and thereby broadening
the conventional foods eligible to bear the claim to those meeting the
other requirements of paragraph (c)(2)(iii).
b. Dietary supplements. While there is an abundance of evidence
from intervention studies to demonstrate the cholesterol-lowering
efficacy of phytosterol-enriched conventional foods, relatively few
trials have been conducted with dietary supplements containing
phytosterols. There is scientific evidence from four intervention
studies to demonstrate the cholesterol-lowering efficacy of dietary
supplements containing phytosterol esters (Refs. 61, 62, 63, and 64).
In the intervention study conducted by Rader and Nguyen (Ref. 61) (see
table 2 at the end of this document), participants were moderately
hypercholesterolemic, but otherwise healthy adults. They consumed three
phytosterol ester or placebo softgel capsules daily for 3 weeks. The
phytosterol ester-containing softgel capsules provided 1 g of
phytosterols per day. A significantly greater reduction in blood total
and LDL cholesterol was reported in the phytosterol ester group than in
the placebo group.
The cholesterol-lowering efficacy of dietary supplements containing
phytosterols esters has also been confirmed in three additional
intervention studies (Ref. 62, 63, and 64). Woodgate et al. (Ref. 64)
provided six softgel supplements that provided phytosterol esters
equating to 1.6 g of nonesterified phytosterols for 4 weeks. There was
a significantly greater reduction in total cholesterol levels in the
group that received the phytosterol-ester supplement compared to the
placebo group. Participants in the trial by Acuff et al. (Ref. 62) were
hypercholesterolemic, but otherwise healthy adults. They consumed two
phytosterol ester or placebo capsules daily for 4 weeks. The sterol
ester-containing capsules provided 0.8 g per day phytosterols. A
significant blood LDL cholesterol reduction in the sterol ester group
relative to the placebo group was reported. Earnest et al. (Ref. 63)
provided four sterol ester-containing capsules or a placebo for 12
weeks. The sterol ester-containing capsule provided 2.6 g per day of
phytosterols. There was a significantly greater reduction in blood
total and LDL cholesterol in the group that received the sterol ester-
containing capsules compared to the placebo group. Statistical
differences in the change in blood LDL cholesterol between the sterol
ester and placebo group was not determined. In conclusion, esterified
phytosterols were effective in reducing total and/or LDL cholesterol
levels in the blood in all three studies.
There have been three intervention studies published on the
efficacy of nonesterified phytosterols in reducing blood cholesterol
levels (Refs. 65, 66, and 67) (see table 2 at the end of this
document). Nonesterified phytosterols consumed as ingredients in a
gelatin capsule supplement were reported to have no effect on blood
cholesterol (Ref. 65). The intervention study supplemented moderately
hypercholesterolemic men, consuming a Step I diet, with 3 g of
nonesterified phytosterols per day. The phytosterols were suspended in
safflower oil (20 percent sitostanol by weight in safflower oil)
contained within gelatin capsules and consumed with meals. No changes
in either blood total or LDL cholesterol were observed between Step I
diet alone and a Step I + sitostanol supplements. The concentration of
20 percent sitostanol in the gelatin capsule is much greater than the
solubility of sitostanol of 1 percent (Ref. 68). Thus, it has been
speculated that much of the sitostanol was undissolved (Ref. 57), and
therefore not adequately dispersed in the intestinal contents.
Although a nonesterified phytosterol/soy lecithin emulsion
formulation has been shown to be effective in lowering cholesterol
under certain circumstances (Refs. 66 and 67), the results have been
inconsistent and highlight how difficult it is to predict the
effectiveness of nonesterified phytosterols in lowering cholesterol
when consumed as ingredients in dietary supplements. McPherson et al.
(Ref. 66) reported that consumption of 1.26 g stanols per day as the
spray-dried phytostanol/lecithin emulsion tablet formulation resulted
in a significant lowering of LDL cholesterol in humans; whereas,
consumption of 1 g per day as the spray-dried phytostanol/lecithin
emulsion capsule formulation had no significant effect on blood
cholesterol. This study identified several physical differences between
the capsule and tablet preparations, but does not provide data
sufficient to identify the physical characteristics responsible for the
differences between capsule and tablet preparations in their abilities
to affect cholesterol absorption. However, the effectiveness of
nonesterified phytosterol/soy lecithin vesicle tablets (1.8 g per day)
on blood cholesterol reduction was confirmed in a subsequent
intervention study done with subjects taking statin drugs for
hypercholesterolemia (Ref. 67). The available scientific evidence for
the cholesterol-lowering effects of phytosterols in dietary supplements
shows that formulation of the supplement product is an important factor
in the effectiveness of the product in lowering cholesterol and that
esterifying the phytosterol is one way to ensure effectiveness. One
explanation for the inconsistent results obtained from dietary
supplements containing nonesterified phytosterols may be the importance
of phytosterol dispersal and solubility in the gastrointestinal tract.
The effectiveness of phytosterols to interfere with cholesterol
absorption depends on their ability to be soluble, adequately dispersed
within the intestinal contents, and incorporated into the mixed
micelles (Refs. 57 and 61).
Because nonesterified phytosterols have poor solubility,
manufacturers must use a technique such as esterification to facilitate
absorption and dispersal of the phytosterols in the conventional food
itself. For example, as noted in section V.A.1 of this document, the
solubility of phytosterols in rape seed oil mayonnaise increased about
ten-fold when esterified with fatty acids (Ref. 28). No such techniques
are necessarily required, as a practical
[[Page 76541]]
matter, for adding phytosterols to dietary supplements, which commonly
come in tablets or capsules. Esterification, however, still serves to
make the phytosterols more soluble and thus suitable for dispersal in
the gastrointestinal tract and incorporation into the mixed micelles.
The available scientific evidence shows that esterified
phytosterols are effective in lowering cholesterol and thus reducing
the risk of CHD. At this time, however, FDA finds that the totality of
available scientific evidence for the cholesterol-lowering effects of
nonesterified phytosterols in dietary supplements is inconsistent and
tentatively concludes that the scientific evidence for a relationship
between dietary supplements containing nonesterified phytosterols and
CHD does not meet the significant scientific agreement standard. FDA is
therefore proposing to amend Sec. 101.83(c)(2)(iii)(B) to make the use
of the health claim available to phytosterol ester-containing dietary
supplements that meet all the specific requirements of the claim stated
in Sec. 101.83 and the general health claim requirements of Sec.
101.14. However, FDA is not proposing to include nonesterified
phytosterol-containing dietary supplements as foods eligible for the
claim.
FDA invites submission of additional data that demonstrate the
cholesterol-lowering efficacy of nonesterified phytosterols consumed as
ingredients in dietary supplements. At this time, there are no USP
standards for disintegration and dissolution for dietary supplements
containing phytosterols. Therefore, FDA is also requesting data to
provide a justification for inclusion or exclusion of specific dietary
supplement formulations using USP standards. FDA will reevaluate its
tentative conclusion regarding the eligibility of dietary supplements
containing both esterified and nonesterified phytosterols in light of
any additional data received.
3. Other Requirements
a. Disqualifying total fat level. Under the general requirements
for health claims, foods are ineligible for health claims if they
contain more than 13 g of total fat: (1) Per RACC; (2) per labeled
serving size; and (3) when the RACC is small (30 g or less or 2
tablespoons or less), per 50 g of food (Sec. 101.14(a)(4) and
101.14(e)(3)). FDA may waive this disqualifying level for an individual
nutrient in a health claim based on a finding that the claim will
assist consumers in maintaining healthy dietary practices despite the
content of that nutrient in the food (Sec. 101.14(e)(3)). FDA had
concluded in the IFR that permitting the use of the phytosterol health
claim on labels of spreads and dressings for salad would assist
consumers to develop a dietary approach that would result in
significantly lower cholesterol levels and an accompanying reduction in
the risk of heart disease. Consequently current Sec. 101.83(c)(1) and
(c)(2)(iii)(C) permit the disqualifying level for total fat level on a
``per 50 g'' basis for foods with a small RACC (i.e., more than 13 g of
fat per 50 g) to be waived for spreads and dressings for salad, which
ordinarily have a high fat content, provided the label bears a
disclosure statement that complies with Sec. 101.13(h) (i.e., ``See
nutrition information for fat content'') (65 FR 54686 at 54706).
Current Sec. 101.83 does not exempt spreads and dressings for salads
from the total fat disqualifying level per RACC, and per label serving
size.
The agency requested comments to the IFR on its decision to exempt
phytosterol-enriched spreads and dressings for salad from the
disqualifying level for total fat per 50 g (65 FR 54686 at 54710). The
agency also suggested that, despite its reluctance to grant broad
exceptions to the disqualifying levels, it was willing to consider
additional exemptions on a limited case-by-case basis and said that
manufacturers of products other than spreads and dressings for salad
may submit comments with supporting information or petition the agency
for an exemption from the total fat disqualification levels in Sec.
101.14(e)(3).
FDA received a variety of comments in response to this aspect of
the IFR. Some comments agreed with FDA's exemption for spreads and
dressings for salad from the disqualifying level for total fat per 50
g, while other comments asserted that this exemption was not justified
and argued that foods with a high fat content should not be eligible
for a health claim. Some comments suggested that the exemption should
be extended to other foods, such as vegetable oils, which have a
similar nutrient composition to the foods currently exempted by Sec.
101.83(c)(2)(iii)(C), or extended to include all foods with a small
serving size. Some comments asserted that there should be an expedited
approach to permit additional exemptions to the fat-disqualifying
level.
The agency believes that the limited exemption from the
disqualifying level of total fat on a per 50 g basis for foods with a
small reference amount continues to be appropriate for dressings for
salads and for spreads that resemble margarine. One of the factors in
FDA's decision to provide a limited exemption to the total fat
disqualifying level under Sec. 101.14(a)(4) was that, without this
exemption for spreads and dressings for salad, the number of foods
eligible for this health claim would be limited to such an extent that
the public health value of the claim would be undermined (65 FR 54686
at 54710). FDA is now proposing to remove the current restrictions on
food categories eligible to bear the phytosterol/CHD health claim.
Consequently the variety of phytosterol-enriched foods not high in
total fat and eligible to bear the health claim available to consumers
would significantly increase. Therefore, the agency does not find it
necessary to expand the limited total fat ``per 50 g'' disqualifying
level exemption to other foods with small servings out of concern that
the number of foods eligible for the claim is limited. The type of food
identified as ``spreads'' in current Sec. 101.83 was intended by the
agency to be specifically vegetable oil spreads resembling margarine
formulated with a reduced total fat content relative to the minimum 80
percent fat content required under the standard of identity for
margarine (Sec. 166.110). FDA realizes that without additional
specification, the term ``spread'' could be interpreted to include
other types of foods as well, such as mayonnaise and peanut butter-type
spreads. Because FDA has tentatively concluded that it is not necessary
to extend the limited exemption from disqualifying total fat level per
50 g beyond the limited food categories initially included, the agency
is proposing to clarify in amended Sec. 101.83(c)(2)(iii)(D) that the
spreads that are exempt from Sec. 101.14(a)(4) are vegetable oil
spreads that resemble margarine.
Some comments recommended an exemption from the total fat
disqualifying level be made to provide for the use of the health claim
by liquid vegetable oils. These comments argued that liquid vegetable
oils have fat composition as do the vegetable oil spreads and dressings
for salads that can use the health claim. FDA recognizes that providing
for disclosure of the total fat level rather than disqualification
reflects an evolution in expert opinion on total fat intake and risk of
CHD. The ``Dietary Guidelines for Americans, 2005'' (Ref. 69)
recommends that Americans limit fat intake to between 20 to 35 percent
of calories, with most fats coming from sources of polyunsaturated and
monounsaturated fatty acids such as fish, nuts and vegetable oils, and
limit intake of fats and oils high in saturated and/or trans fatty
acids. Substituting liquid vegetable oils,
[[Page 76542]]
containing predominantly unsaturated fatty acids, for solid fats high
in saturated fat and cholesterol is one dietary modification that can
contribute to reducing dietary saturated fat and cholesterol.
Several current qualified health claims (see FDA's 2003 Consumer
Health Information for Better Nutrition Initiative (Ref. 70)) are about
a relationship of the unsaturated fatty acids of certain vegetable oils
(olive oil, canola oil, and corn oil) used to replace similar amounts
of saturated fat without increasing calories consumed, and CHD risk
(Refs. 71, 72, and 73). When deliberating the merits of these vegetable
oil unsaturated fatty acid qualified health claims, FDA concluded that
there was credible but limited scientific evidence that label
statements informing consumers that they might lower their risk of CHD
by consuming foods high in unsaturated fatty acids, such as vegetable
oils, in place of similar foods high in saturated fatty acids, without
increasing calorie consumption, is information that can help consumers
develop a dietary approach to lower CHD risk. FDA also concluded that
such information is consistent with current dietary guidelines, which
emphasize that consuming diets low in saturated fat and cholesterol is
more important in reducing CHD risk than is consuming diets low in
total fat. FDA therefore decided that the disqualifying total fat level
for health claims would not be a criterion in permitting the qualified
health claims for unsaturated fats of vegetable oils. Consistent with
the position taken in permitting the unsaturated fatty acids in
vegetable oils and CHD qualified health claims, FDA finds that rather
than disqualifying phytosterol-enriched liquid vegetable oils on the
basis of total fat content, disclosure of the total fat content along
with the phytosterol health claim, will help consumers develop a
dietary approach to lowering blood cholesterol levels.
Liquid vegetable oils are composed entirely of fat, and the amount
of fat in a RACC (1 tablespoon, about 13.6 g) exceeds the disqualifying
total fat level of 13 g. The limited exemption from the disqualifying
total fat level on a per 50 g basis provided for spreads and dressings
for salads, if extended to liquid vegetable oils, would still not make
liquid vegetable oils eligible for a health claim. Therefore, FDA is
proposing to exempt liquid vegetable oils from the total fat
disqualifying level on a per RACC, per label serving size, and per 50 g
basis.
The agency is proposing to amend Sec. 101.83(c)(2)(iii)(D) to
specify that the limited exemption from the disqualifying total fat
level ``per 50 g basis'' for ``spreads'' applies specifically to
vegetable oil spreads resembling margarine and not to other spreadable
food products such as peanut butter and mayonnaise. In addition to the
current exemption per 50 g for dressings for salad, the agency is also
proposing to exempt liquid vegetable oils from the requirement per
RACC, per labeled serving, and per 50 g.
b. Low saturated fat and low cholesterol criteria. Current Sec.
101.83(c)(2)(iii)(B) requires foods that bear the health claim to meet
the nutrient content requirements in Sec. 101.62 for a ``low saturated
fat'' and ``low cholesterol'' food.
One comment to the IFR objected to the ``low saturated fat''
requirement for the phytosterol CHD health claim on the basis that it
would severely limit the availability of sterol/stanol containing
foods. The comment recommended that the requirement for ``low'' amounts
of saturated fat are not appropriate for foods that contain equal
amounts of saturated fat, monounsaturated fat, and polyunsaturated fat.
There is strong and consistent scientific evidence that diets high
in saturated fat and cholesterol are associated with elevated total and
LDL cholesterol, and that elevated blood cholesterol levels are a major
modifiable risk factor for CHD. The ``Dietary Guidelines for Americans,
2005'' recommends lowering dietary saturated fat and cholesterol as a
primary lifestyle change for reducing heart disease risk (Ref. 69).
The variety of phytosterol-enriched foods tested in intervention
studies since publication of the IFR indicates a range of food
products, many of which are low fat or fat-free, that manufacturers
contemplate marketing. There also are a number of foods in the food
categories now eligible for the health claim under current Sec. 101.83
that can qualify as ``low saturated fat'' and ``low cholesterol.'' As a
result, FDA does not agree that requiring foods bearing the claim be
``low saturated fat'' and ``low cholesterol'' would significantly limit
the number of food products eligible to use the claim. Consequently,
the agency is not proposing to amend the requirement that foods
eligible for the claim be ``low in saturated fat'' and ``low in
cholesterol.''
c. Trans fat considerations. FDA is concerned about the presence of
trans fats in foods bearing the phytosterols and risk of coronary heart
disease claim. There is a positive linear trend between trans fatty
acid intake and LDL cholesterol concentration, and therefore there is a
positive relationship between trans fatty acid intake and the risk of
CHD (Ref. 74). In the Institute of Medicine (IOM) report, Dietary
Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids,
Cholesterol, Protein, and Amino Acids, in the discussion on dietary
fats, total fat and fatty acids, the IOM states that trans fatty acids
are not essential and provide no known benefit to human health (Ref.
74). The IOM sets tolerable upper intake levels (UL) for the highest
level of daily nutrient intake that is likely to pose no risk of
adverse health effects to almost all individuals in the general
population. In their 2005 report, the IOM does not set a UL for trans
fatty acid because any incremental increase in trans fatty acid intake
increases the risk of CHD (Ref. 74).
Trans fats are naturally occurring in some foods made from ruminant
animals (e.g., cattle and sheep) such as dairy products and meats (Ref.
69). Trans fatty acids are created when unsaturated fatty acids are
chemically changed through the process of hydrogenation \12\ to create
a more solid food product (Ref. 69). Sources of trans fatty acids
include partially hydrogenated and hydrogenated vegetable oils used in
making shortening, margarine, baked goods such as biscuits and pie
crusts, snack foods, fried foods, and margarine (Ref. 69). Since trans
fats are naturally occurring in some foods that contribute essential
nutrients such as protein, calcium and vitamin D, consuming zero
percent of energy as trans fats would require substantial adjustments
to the diet that may have undesirable effects (Ref. 74). To date, there
have been no reports issued by authoritative sources that provide a
level of trans fat in the diet above which there is a known increased
risk of CHD and below which there is no risk of CHD. Recommendations
are for Americans to limit trans fat as much as possible while
consuming a nutritionally adequate diet (Refs. 3 and 74).
---------------------------------------------------------------------------
\12\ Hydrogenation is the addition of a carbon-carbon double
bond to a chain of unsaturated fatty acids. This produces a single
carbon-carbon bond with two hydrogens attached to each carbon. This
process converts liquid oils into more solid fats, which are used in
making products such as margarine and shortening. Trans fats are a
by-product of hydrogenation of vegetable oils (Ref. 75).
---------------------------------------------------------------------------
The agency is taking several approaches to address trans fats. On
July 11, 2003 (68 FR 41507), FDA published an advance notice of
proposed rulemaking (ANPRM), in part, to solicit information and data
that
[[Page 76543]]
could potentially be used to establish new nutrient content claims
about trans fatty acids; to establish qualifying criteria for trans fat
in current nutrient content claims for saturated fatty acids and
cholesterol, lean and extra lean claims, and health claims that contain
a message about cholesterol-raising lipids; and, in addition, to
establish disclosure and disqualifying criteria to help consumers make
heart-healthy food choices. On March 1, 2004 (69 FR 9559), FDA reopened
the comment period to allow interested persons to consider the report
issued by the Institute of Medicine of the National Academy of Science
in December 2003 entitled ``Dietary Reference Intakes: Guiding
Principles for Nutrition Labeling and Fortification.'' FDA extended the
comment period on April 19, 2004 (69 FR 20838) to receive comment on a
Food Advisory Committee Nutrition Subcommittee meeting discussing the
scientific evidence for determining a maximal daily intake value of
trans fat and how trans fat compares to saturated fat with respect to
reducing coronary heart disease. Specifically, the agency requested
comment on whether the available scientific evidence supported listing
the percent Daily Value (DV) for saturated fat and trans fat together
or separately on the Nutrition Facts label and what the maximal daily
intake of trans fat may be. In addition, the agency published an ANPRM
on November 2, 2007 (72 FR 62149) to request, in part, comment on what
new reference values the agency should use to calculate the DV for a
number of nutrients and what factors the agency should consider in
establishing such values. FDA asked specific questions in the November
2, 2007 ANPRM about trans fat labeling. Comments are being reviewed by
the agency from these ANPRMs for consideration in defining nutrient
content claims for trans fat and in deciding what levels of trans fat
may be appropriate in foods bearing health claims about a reduced risk
of coronary heart disease.
FDA received a citizen petition from the Center for Science in the
Public Interest (CSPI) in 2004 and one from Dr. Fred Kummerow in 2009
asking the agency to revoke the GRAS status of partially hydrogenated
oils. The agency is in the process of reevaluating the GRAS status of
partially hydrogenated oils in response to the two citizen petitions.
Finally, the agency is evaluating current analytical methods for the
detection of trans fat in foods and is working on improving the
sensitivity of these methods so that trans fat may be reliably detected
at lower levels in foods.
The agency is concerned that products containing phytosterols and
bearing the health claim may also contain significant amounts of trans
fat that could undermine the beneficial effects from consumption of the
phytosterols in the product. The agency is not aware of any studies
that were designed to determine the amount of trans fat that could
offset the beneficial effects of phytosterols. Based on the available
data, 0.8g/day of trans fat was the highest intake level from margarine
at which there was a significant reduction in total and LDL cholesterol
levels when the consumption of phytosterols was approximately 2 g/day
(Ref. 41). The agency requests comment on whether these data, alone or
in combination with other data or information, would support a
limitation on the level of trans fat in foods, as an eligibility
criterion, for foods that could bear the phytosterol and risk of
coronary heart disease claim. Foods that contain more than this level
of trans fat would be disqualified from bearing a claim. In addition,
the agency requests comment on whether there are data that may support
another level of trans fat that the agency should consider as an
eligibility criterion for foods bearing such a claim. The agency also
requests comment on available information that provides clarification
on the effect of trans fat in products that also contain phytosterols.
d. Minimum nutrient contribution requirement. Current Sec.
101.83(c)(2)(iii)(D) requires that a conventional food bearing a health
claim for phytosterol esters meet the minimum nutrient contribution
requirement specified in Sec. 101.14(e)(6), unless it is a dressing
for salad. Section 101.14(e)(6) requires that, except for dietary
supplements or where provided in other health claim regulations, foods
eligible to bear a health claim contain 10 percent or more of the
Reference Daily Intake or Daily Reference Value for vitamin A, vitamin
C, iron, calcium, protein, or fiber per reference amount prior to any
nutrient addition. The minimum nutrient contribution requirement is
necessary to ensure that the value of a health claim will not be
trivialized or compromised by its use on a food of little or no
nutritional value. In the IFR, the agency concluded that, while
important, the minimum nutrient requirement for dressings for salad is
outweighed by the public health importance of communicating the
cholesterol-lowering benefits from consumption of plant sterol/stanol
esters (65 FR 54686 at 54711). FDA found that the value of the health
claim would not be trivialized or compromised by its use on dressings
for salad because dressings for salad are typically consumed with foods
rich in fiber and other nutrients. However, the agency decided that
there was not a sufficient rationale to justify an exemption from this
requirement for the remaining phytosterol-enriched foods that would
have otherwise been eligible to bear the health claim. Id.
The agency requested comments in the IFR on its decision to exempt
only dressings for salad from the minimum nutrient requirement. FDA
further stated that manufacturers of foods that do not meet the minimum
nutrient requirement may submit comments with supporting information by
a petition to the agency requesting an exemption from this requirement.
Id.
Comments were mixed as to whether the minimum nutrient contribution
requirement should be applied to other foods eligible for the health
claim. Some agreed with FDA's exemption from the minimum nutrient
contribution requirement for dressings for salad, while other comments
suggested that no foods should be exempt. Other comments suggested
additional specific foods such as fruit drinks, smoothies, liquid
vegetable oils, vegetable oil spreads or snack bars or groups of foods
such as small servings to which the minimum nutrient requirement
exemption might be extended either through fortification or waiving of
the requirement.
The purpose of the minimum nutrient contribution requirement is to
ensure that health claims are used to promote only those foods that are
consistent with dietary guidelines and to ensure that health claims are
not to be trivialized or compromised by their use on foods of little or
no nutritional value (e.g., jelly beans) (58 FR 2478 at 2481 and 2521).
FDA exempted dressings for salad from the minimum nutrient requirement
in current Sec. 101.83 in recognition that dressings for salad are
typically consumed with other foods (specifically salads and
vegetables) that are rich in a number of important nutrients and fiber.
FDA is not persuaded by the rationales put forward for other foods, as
a general matter. It does, however, concur that extending the exemption
from this requirement for certain vegetable oil spreads and liquid
vegetable oils is justified because they provide unsaturated fatty
acids that can be used in place of saturated fatty acids in the diet.
A key recommendation of the ``Dietary Guidelines for Americans,
2005'' (Ref. 69) is that most fats in the diet should
[[Page 76544]]
come from sources of polyunsaturated and monounsaturated fatty acids
such as fish, nuts, and vegetable oils. Using liquid vegetable oils in
the diet as substitutes for solid and hardened fats is an approach to
developing a heart-healthy diet that is consistent with the ``Dietary
Guidelines for Americans, 2005.'' Liquid vegetable oils, like dressings
for salad, will likely be consumed in small portions with foods rich in
fiber and other nutrients. Vegetable oils contain none of the six core
nutrient components of the minimum nutrient content requirement for
health claims and therefore are ineligible for health claims unless an
exemption is provided in a specific health claim regulation. The agency
has concluded that the public health benefit of providing for use of
the health claim on labels of certain liquid vegetable oil outweighs
the concerns that health claims are trivialized by their use with foods
of little nutritional value, and therefore is proposing that liquid
vegetable oils be exempt from the minimum nutrient requirement in
amended Sec. 101.83. As noted in section V.C.2.a of this document, FDA
is proposing to also exempt liquid vegetable oils from the
disqualifying level for total fat; however liquid vegetable oils will
be subject to the requirement that foods bearing the phytosterol/CHD
health claim be ``low saturated fat'' foods.
Margarine, a standardized food under Sec. 166.110 including those
that are nutritionally modified and labeled under 21 CFR 130.10 must
contain not less than 10 percent of the recommended dietary allowance
(RDA) for vitamin A per reference amount customarily consumed.
Margarine substitutes may need to be fortified with Vitamin A to be
nutritionally equivalent to margarine to avoid being categorized as
``imitation'' margarine (Sec. Sec. 101.3(e)(2) and 104.20(e) (21 CFR
101.3(e)(2) and 104.20(e))). As FDA stated in the rulemaking for Sec.
101.14, permitting foods to be fortified with nutrients for the sole
purpose of making a health claim that complies with the minimum
nutrient requirement would be misleading and inconsistent with FDA's
fortification policy in Sec. 104.20 (58 FR 2478 at 2521). FDA also
stressed, however, that ``the exclusion of fortification pertains only
to fortification to specifically meet the requirements of this
provision and not to the fortification of the food itself'' (id.).
Vegetable oil spreads that resemble and substitute for margarine may be
required to be fortified with Vitamin A to avoid being categorized as
an ``imitation'' (as explained in this paragraph) and those not
required to be so fortified may be optionally fortified under Sec.
104.20. Such spreads usually serve as substitutes for products higher
in saturated fats and cholesterol. Thus, the agency believes that
permitting vegetable oil spreads resembling margarine to meet the
minimum nutrient contribution requirement through the addition of
Vitamin A is consistent with FDA's fortification policy and appropriate
as an exemption to the requirement in Sec. 101.14(e)(6) that the food
contain 10 percent or more of a nutrient prior to any nutrient
addition.
The agency is not convinced that additional modifications to
current Sec. 101.83(c)(1) and (c)(2)(iii)(D) to provide exemptions
from the minimum nutrition contribution requirement for additional
foods are warranted. Because the agency is proposing to drop the
limitation on eligible food categories and extend the claim to include
nonesterified phytosterols and mixture of plant sterols and stanols,
there would be a greater variety of lower fat, heart healthy
phytosterol-enriched foods that would be able to bear the health claim
without extending the minimum nutrient contribution requirement.
Further, the agency believes that dropping the requirement in Sec.
101.14(e)(6) altogether could lead to indiscriminate use of health
claims on foods with little or no nutritional value such as snack and
confectionary items. Therefore, the agency is not proposing to provide
further exemptions to the minimum nutrient contribution requirement.
While FDA will consider any further requests for exemptions that it
receives via the petition process as expeditiously as possible, it
still expects that any such request will be accompanied with adequate
justification for the exemption. The agency does not plan to set up an
expedited notification process for such a review.
In short, the agency is proposing to amend Sec.
101.83(c)(2)(iii)(E) to permit liquid vegetable oils to be exempt from
the minimum nutrient requirement. FDA is also proposing to amend this
provision to permit the minimum nutrient contribution requirement for
vegetable oil spreads resembling margarine to be met by the addition of
vitamin A consistent with FDA's fortification policy.
D. Model Claims
Current Sec. 101.83(c)(2)(i) prescribes specific requirements for
health claims that link plant sterol/stanol esters to reduced risk of
CHD. Current Sec. 101.83(e) provides examples of model health claims
that may be used to comply with the requirements in Sec.
101.83(c)(2)(i). As discussed in previous sections of this document, we
are proposing modifications to Sec. 101.83 that would entail revision
of specific requirements for health claims and the examples of model
health claims. Consequently, the agency is proposing to revise Sec.
101.83(c)(2)(i) and (e) accordingly.
E. Cautionary Statements
Current Sec. 101.83 does not require cautionary or advisory
statements regarding the potential effect of consuming phytosterols on
the absorption of other nutrients or on certain subpopulation groups,
and FDA did not address the use of such statements in the IFR. However,
the agency subsequently became aware that regulatory bodies in other
countries had concluded that requiring such statements on the labels of
products containing phytosterols or limiting the use of phytosterols in
food was necessary to guard against such effects. When the IFR comment
period was reopened, FDA requested comments on ``whether changes to
[Sec. 101.83], advisory labeling, or other actions are needed'' to
address concerns regarding the effect of consuming plant/sterol esters
on the absorption of beta-carotene and on certain subpopulation groups
(66 FR 50824 at 50826).
Some comments focused on the safety of consuming plant/sterol
esters for certain subpopulation groups, such as those taking drugs to
lower cholesterol or those suffering from phytosterolemia, an autosomal
recessive disorder characterized by increased intestinal absorption of
dietary cholesterols and phytosterols. Those comments disagreed whether
the labels of foods bearing the health claim should provide an advisory
statement. Other comments asserted that consuming phytosterols inhibits
intestinal absorption of fat soluble vitamins and carotenoids and that
requiring an advisory statement on foods bearing the health claim is
necessary to prevent adverse health consequences, especially in
vulnerable subpopulation groups, such as children or pregnant or
lactating women.
Section 201(n) of the act states that, in determining whether
labeling is misleading, the agency shall take into account not only
representations made about the product, but also the extent to which
the labeling fails to reveal facts material in light of such
representations made or suggested in the labeling with respect to
consequences which may result from use of the article to which the
labeling relates under the conditions of use as are customary or usual
(see 21
[[Page 76545]]
CFR 1.21). Thus, the omission of certain material facts from the label
or labeling on a food causes the product to be misbranded within the
meaning of sections 403(a)(1) and 201(n) of the act. Under that
authority, FDA has considered the use of cautionary statements to
address each of the public health issues identified by other regulatory
bodies and the similar concerns raised in comments.
With respect to the comments about the effects of consuming
phytosterols on individuals suffering from rare conditions that make
them hyper-sensitive to phytosterols, FDA tentatively concludes that no
cautionary statement regarding those effects in the labeling of foods
bearing the health claim or any other action is necessary. For the
consumers at whom such a cautionary statement would be directed, i.e.,
those aware that they have a phytosterol-sensitive condition, the
health claim itself and the required ingredient declaration (see 21 CFR
101.4(a)) should provide sufficient warning that the product contains
phytosterols. Such consumers could consult with their medical
practitioner regarding the possible consequences of consuming
phytosterols.
As for a cautionary statement regarding potential adverse
interactions with cholesterol-lowering drugs, FDA tentatively concludes
that Sec. 101.83 should not require such a statement in the labeling
of food bearing the health claim. FDA is unaware of any scientific
evidence demonstrating that consuming phytosterols while on
cholesterol-lowering drugs results in any adverse health consequences.
The agency thus sees no justification for requiring a statement
specific to consumers taking cholesterol-lowering drugs. We invite the
submission of any data or other evidence demonstrating adverse health
consequences under such circumstances.
With respect to the comments about the potential effect of
phytosterols on the absorption of certain nutrients in the population
as a whole or in certain subpopulation groups, FDA tentatively
concludes that the available scientific evidence does not support a
need for a cautionary statement regarding that potential effect. As
noted in this section of the document, the potential effect of
phytosterol-enriched foods on lowering plasma fat soluble vitamins and
carotenoids has been a concern to regulatory bodies in some other
countries. The European Commission (EC) Scientific Committee on Food
(SCF) recommended that the beta-carotene lowering effect of
phytosterol-enriched foods be communicated to the consumer, together
with appropriate dietary advice regarding the regular consumption of
fruits and vegetables (Refs. 76 and 77). As a result, EC regulations
for the labeling of foods with added phytosterols require a label
statement stating that: (1) Phytosterol-enriched foods may not be
nutritionally appropriate for pregnant or breastfeeding women and
children under the age of 5 years; and (2) phytosterol-enriched foods
should be used as part of a balanced and varied diet, including regular
consumption of fruit and vegetables to help maintain carotenoid levels
(Refs. 78 and 79). Similarly, Food Standards Australia New Zealand
(FSANZ) requires that phytosterol-enriched foods have a label statement
advising that the product should be consumed in moderation as part of a
diet low in saturated fat and high in fruits and vegetables, and that
the product is not recommended for infants, children, or pregnant or
lactating women unless under medical supervision (Ref. 80).
FDA reviewed 19 intervention studies that evaluated the effect of
phytosterol intake on the intestinal absorption of fat soluble vitamin
and carotenoid, by measuring plasma levels (Refs. 24, 26, 35, 37, 39,
41, 51, 55, 59, 81, 82, 83, 84, 85, 86, 87, 88, 89, and 90).
Collectively, these studies provided phystosterols ranging from 0.8 to
9 g per day. After adjusting for plasma total or LDL cholesterol
levels, only one study showed that vitamin E levels were significantly
reduced with phytosterol intake (3 g per day) (Ref. 88). Vitamin E
levels were not altered at higher phytosterol intake levels (3.2 to 9 g
per day) (Refs. 51, 55, 88, and 89). There was no effect of phytosterol
intake on adjusted levels of other fat soluble vitamins (i.e., vitamin
A, vitamin D, vitamin K).
While phytosterol intake was shown in some studies to reduce
adjusted levels of beta-carotene (the major pro-vitamin A carotenoid)
to a statistically significant degree at phytosterol intake levels
ranging from 3 to 9 g per day (Refs. 51, 55, 87, 88, 89, and 90) there
was no effect on serum retinol levels (a biomarker of vitamin A
status). Some studies also showed a reduction in carotenoids such as
lutein and lycopene, but these food components likewise do not have an
established health benefit at a particular level. Thus, FDA has no
basis for concluding that any reduction in the intestinal absorption of
these nutrients caused by consuming phytosterols amounts to an adverse
health consequence.
FDA has determined that available scientific evidence does not
demonstrate that consuming phytosterols has an effect on intestinal
absorption of fat soluble vitamins. Furthermore, although there is some
evidence that consuming phytosterols reduces plasma levels of
carotenoids such as beta-carotene, lutein, and lycopene, those
carotenoids have no established health benefits at particular levels.
Therefore, the agency is not proposing that Sec. 101.83 require a
cautionary statement regarding a potential effect on fat soluble
vitamins or carotenoids.
In conclusion, the agency finds that the failure of a food bearing
the health claim to include any of the foregoing cautionary statements
would not render the food's labeling misleading under section 403(a)(1)
of the act. We are therefore not proposing that Sec. 101.83 require
any of the foregoing cautionary statements. Furthermore, the available
science does not persuade FDA that the use of phytosterols at the
levels necessary to justify the claim render the food unsafe or
unlawful under the relevant safety provisions of the act, even in the
absence of such cautionary statements. But FDA again notes that
authorization of a health claim for a substance should not be
interpreted as an affirmation that the substance is safe and lawful for
all uses.
F. Status Under Section 301(ll) of Foods Containing Nonesterified and
Esterified Phytosterols
Section 301(ll) of the act (21 U.S.C. 331(ll)) prohibits the
introduction or delivery for introduction into interstate commerce of
any food that contains a drug approved under section 505 of the act (21
U.S.C. 355), a biological product licensed under section 351 of the
Public Health Service Act (42 U.S.C. 262), or a drug or a biological
product for which substantial clinical investigations have been
instituted and their existence made public, unless one of the
exemptions in section 301(ll)(1)-(4) applies. In this proposal to amend
the regulation authorizing a health claim on the relationship between
plant sterol esters and plant stanol esters and reduced risk of CHD for
use on food labels and in food labeling, FDA did not consider whether
section 301(ll) of the act or any of its exemptions would apply to
foods containing nonesterified or esterified phytosterols. Accordingly,
this proposed rule should not be construed to be a statement that foods
that contain nonesterified or esterified phytosterols, if introduced or
delivered for introduction into interstate commerce, would not violate
section 301(ll) of the act. Furthermore, this language is included in
all health claim proposed
[[Page 76546]]
and final rules and should not be construed to be a statement of the
likelihood that section 301(ll) of the act applies.
VI. Enforcement Discretion
Pending issuance of a final rule, FDA intends to consider the
exercise of its enforcement discretion on a case-by-case basis when a
health claim regarding phytosterols is made in a manner that is
consistent with the proposed rule. Beginning 75 days from the date the
proposed rule publishes, FDA does not intend to exercise its
enforcement discretion based on the letter issued in 2003 (Ref. 1). The
act's enforcement provisions commit complete discretion to the
Secretary of Health and Human Services (and by delegation to FDA) to
decide how and when they should be exercised (see Heckler v. Chaney,
470 U.S. 821 at 835 (1985); see also Shering Corp. v. Heckler, 779 F.2d
683 at 685-86 (DC Cir. 1985) (stating that the provisions of the act
``authorize, but do not compel the FDA to undertake enforcement
activity'')). Until the agency issues a final rule amending the
requirements of Sec. 101.83, the agency believes that its exercise of
enforcement with respect to claims that do not comply with current
Sec. 101.83 but do comply with the proposed rule is appropriate. Food
bearing the health claim would be required to comply with any revised
requirements established in the final rule when the final rule becomes
effective.
VII. Environmental Impact
FDA has determined under 21 CFR 25.32(p) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
VIII. Analysis of Economic Impacts
Preliminary Regulatory Impact Analysis
FDA has examined the impacts of the proposed rule under Executive
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612), and
the Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). The agency believes that
this proposed rule is not a significant regulatory action as defined by
the Executive order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because the costs to all businesses would be low and
will not likely have a significant economic impact on a substantial
number of small businesses, the agency believes that the proposed rule
will not have a significant economic impact on a substantial number of
small entities.
Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires
that agencies prepare a written statement, which includes an assessment
of anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and Tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $135 million, using the most current (2009) Implicit
Price Deflator for the Gross Domestic Product. FDA does not expect this
proposed rule to result in any 1-year expenditure that would meet or
exceed this amount and has determined that this proposed rule does not
constitute a significant rule under the Unfunded Mandates Reform Act.
A. Need for the Rule
The scientific evidence relating to phytosterols and the risk of
CHD has developed to warrant proposing to amend the existing health
claim for plant sterol/stanol esters and CHD. If finalized, this rule
would allow manufacturers of products that meet certain conditions to
provide the most scientifically reliable, up-to-date information on the
relationship between diets that include phytosterols and the risk of
CHD. In addition, this rule would allow an increased number of foods to
be eligible to make this health claim, by including foods other than
the limited number in the current regulation, and increasing the
variety of composition of the phytosterol ingredients included under
the regulation, i.e., inclusion of plant sterol and plant stanol
mixtures, inclusion of forms of phytosterols in conventional foods
other than those esterified with fatty acids, and inclusion of
additional forms of dietary supplements. The greater availability of
foods containing the required minimum amounts of phytosterols and with
up-to-date information on their labels would provide additional health
benefits for consumers that are consistent with the current state of
scientific evidence. FDA announced, in February 2003, its decision to
consider exercise of enforcement discretion, within certain parameters,
in regards to the use of the phytosterol/CHD health claim in order to
provide greater flexibility in the application of the claim than that
allowed under the IFR. The proposed rule would reduce any uncertainty
that may arise on the part of manufacturers from the real and perceived
lack of permanency inherent in the policy of enforcement discretion.
B. An Overview of the Changes in Behavior From the Regulatory Options
FDA's benefit-cost analysis assumes the existing regulatory
requirements of Sec. 101.83, rather than upon the 2003 enforcement
discretion criteria, as the baseline upon which to measure the impact
of this proposed rule. The regulatory options considered are as
follows:
Option 1--Take no new regulatory action,
Option 2--Implement the proposed rule,
Option 3--Restrict coverage of the proposed option to only
conventional foods and not allow dietary supplements to make a
phytosterols/CHD health claim, and
Option 4--Restrict the proposed option to require
manufacturers of any product claiming reduced risk of CHD from
phytosterols consumption, for which the analytical method for
determining the quantity of phytosterols is different than either the
McNeil or Unilever methods, to provide FDA with access to documentation
substantiating the amount of phytosterols contained in the food
product.
There would be no changes from current behavior by consumers and
manufacturers for option 1. No products would need to be re-labeled or
reformulated, and consumer information on the relationship between
diets containing phytosterols and the risk of CHD currently found on
food labels would remain unchanged.
For option 2, the proposed rule, manufacturers of vegetable
spreads, salad dressings, snack bars, and dietary supplements in
softgel form that currently use the plant sterol/stanol esters health
claim would be required to re-label their products to conform to the
claim language required under the proposed rule. Manufacturers of plant
sterol ester-enriched products would also be required to reformulate
these products if they contain no more than the minimum 0.65 g sterol
ester/RACC (equivalent to 0.4 g nonesterified plant sterol) required
under the IFR for plant
[[Page 76547]]
sterol esters, and if they want to continue to make the claim. The IFR
requires a minimum of 1.7 g/RACC of plant stanol esters (equivalent to
1 g of nonesterified plant stanol), so manufacturers of plant stanol
ester-enriched products, including dietary supplements in softgel form
that currently make a phytosterols/CHD health claim, would not be
required to reformulate to continue to make the claim. Consumers would
benefit from more up-to-date information on food labels, the increase
in the intake of phytosterols, and the wider range of foods and dietary
supplements that would likely contain phytosterols, which may
contribute to an increase in the intake of phytosterols and a reduction
in the risk from CHD.
For ensuring compliance with the labeling requirements for
vegetable spreads, salad dressings, snack bars, and dietary supplements
in softgel form, the protocol for sampling and testing the products
directly for phytosterols content would be changed to the Sorenson and
Sullivan method from the McNeil or Unilever methods. The Sorenson and
Sullivan method would also be used to ensure compliance with the
labeling requirements for the variety of products newly allowed to
claim a relationship between diets containing phytosterols and the
reduction in risk from CHD.
Option 3 would restrict coverage of the proposed requirements to
only conventional foods, so that manufacturers of some plant stanol
ester-containing dietary supplements in softgel form that currently
claim reduced risk of CHD from plant sterol/stanol esters consumption
would no longer be allowed to make that claim. These manufacturers are
assumed to re-label their products to either make no claim or to make a
structure/function claim. Benefits from the consumption of dietary
supplements in softgel form may be reduced.
For option 4, the behavioral changes by manufacturers and consumers
are assumed to be the same as those from the proposed option. To ensure
compliance with the labeling requirements for vegetable spreads, salad
dressings, snack bars, and dietary supplements, sampling and testing
the products directly for phytosterols content using either the McNeil
or Unilever methods would be used. Ensuring compliance with the
labeling requirements for the variety of food products and dietary
supplements that would be newly allowed to claim benefits from the
relationship between phytosterols consumption and the risk of CHD, for
which the analytical method for making this determination is different
than either the McNeil or Unilever methods would require FDA access to,
and analyses of, documents that substantiate the amount of phytosterols
contained in these products.
C. Costs of Option 2 (the Proposed Rule)
The costs of the proposed rule are from the re-labeling required of
products that currently make the plant sterol/stanol esters-CHD health
claim to conform to the claim language required under the proposed
rule. Manufacturers of plant sterol ester-enriched products may also
incur reformulation costs associated with the increase in the
phytosterols content required to make the health claim under the
proposed rule.
Vegetable spreads, salad dressings, snack bars, and dietary
supplements that currently make a plant sterol/stanol esters and CHD
health claim would have to be re-labeled because of this rule. All
current manufacturers of these products would bear the costs of unused
label inventory as well as the costs of designing and printing new
labels to comply with the updated health claim requirements. Some
manufacturers of plant sterol ester-enriched vegetable spreads and
salad dressings will decide to reformulate their products in order to
meet the higher minimum amounts of phytosterols per serving required
for plant sterol esters to make a phytosterols-CHD health claim under
the proposed rule. Moreover, some manufacturers of plant stanol ester-
enriched snack bars may decide not to make a phytosterols-CHD health
claim due to the required new language that specifies that the daily
dietary intake of phytosterols should be consumed with meals; snack
bars may be less likely than vegetable spreads or salad dressings to be
consumed with meals.
FDA does not have any information on how many labels would have to
be redesigned, or the number of products that would be reformulated
because of the proposed rule. Many existing products would not need to
reformulate because the qualifying amount of plant stanol content in
the IFR--1.7 g plant stanol esters per RACC, or the equivalent of 1 g
of nonesterified stanols--is higher than the qualifying amount of
phytosterols (plant sterols/stanols) per RACC in this proposed rule
(0.5 g per RACC). Some products that currently enrich with plant sterol
esters in order to make the plant sterol/stanol esters and CHD health
claim may need slight reformulation since the qualifying amount in the
IFR--0.65 g plant sterol esters per RACC, or the equivalent of 0.4 g of
nonesterified sterols--is slightly lower than the qualifying amount of
phytosterols per RACC required in this proposed rule. However, there is
evidence suggesting that some food products now enriching with plant
sterol esters are formulated with more than 0.5 g phytosterol per RACC.
For example, the phytosterol content of the sterol ester-enriched
product Benecol spread (Ref. 111) exceeds the 0.5 g per RACC and would
not need to reformulate.
The agency uses the FDA Labeling Cost Model to estimate the costs
of redesigning the labels and the costs of lost label inventory for
estimated small fractions of the vegetable spreads, salad dressings,
snack bars and dietary supplements sectors (Ref. 112). In order to use
the FDA Labeling Costs Model to estimate the re-labeling costs, FDA
estimates the percentage of each of the sectors that would incur costs
from the proposed rule. These percentages are then applied to the
sector-wide results obtained by the Labeling Cost Model.
For estimating the percentage of the dietary supplements sector
that currently make a plant sterol/stanol esters and CHD health claim,
FDA uses information from the 1999 report by Research Triangle
Institute for FDA entitled ``Dietary Supplements Sales Information''
(Ref. 113). Research for that report found that of the approximately 20
categories of claims made by dietary supplements, approximately 20
percent make a claim regarding circulatory system benefits. FDA assumes
that 67 percent of the claims regarding circulatory system benefits are
either structure/function claims or nutrient content claims, and 50
percent of the remaining 33 percent address the risk of CHD, then about
3.3 percent of all dietary supplements address the risk of CHD (i.e.,
20 percent x 33 percent x 50 percent).
FDA uses representative scanner data on sales and forms that
dietary supplements take over the period 2001-2005, to estimate that 2
percent of all dietary supplement sales are in softgel form. Consistent
with the estimated percent for dietary supplements overall, FDA assumes
that 3.3 percent of all dietary supplements in softgel form may have a
health claim that addresses the risk of CHD, and that no more than 10
percent of those with health claims that address the risk of CHD may
make a phytosterols health claim. Consequently, FDA estimates that
between 0 and 0.007 percent of dietary supplements sold may currently
make a plant sterol/stanol esters and CHD health claim and would be re-
labeled (2 percent of all dietary supplements x 3.3
[[Page 76548]]
percent that make a claim that addresses CHD x 0 to 10 percent that may
make a phytosterols-CHD health claim).
To estimate the percent market shares of conventional food products
to apply to the Labeling Cost Model, the agency uses results from FDA's
2001 Food Label and Package Survey (FLAPS), from which LeGault, et al.
report that 4.4 percent of all food products sold make at least one of
the FDA-approved health claims (Ref. 114). In order to estimate the
market share of foods that may make a plant sterol/stanol esters and
CHD health claim, FDA takes the estimated percentage of total sales of
products that make any claim (4.4 percent) and multiply it by the
percentage of health claims that were found to address the risk of CHD
(41.7 percent). FDA assumes that 10 percent of all packaged food sales
with claims that address the risk of CHD may make a phytosterols-CHD
health claim. Consequently, FDA estimates that approximately 0.2
percent of all food sales in the vegetable spreads and salad dressings
sectors may make a plant sterol/stanol esters and CHD health claim
(i.e., 4.4 percent x 41.7 percent x 10 percent, rounded to the nearest
tenth of a percent).
To account for the smaller likelihood that manufacturers of snack
bars that currently make a plant sterol/stanol esters and CHD health
claim will continue to do so under the proposed rule, FDA divides the
estimate for vegetable spreads by 2 to obtain the market share for the
snack bar sector that would incur re-labeling costs.
While the names of most of the sectors used by both the Labeling
Cost Model and Reformulation Cost Model correspond closely with those
that are currently identified in the IFR, there is no snack bar sector
identified in the models. Consequently, FDA uses the labeling costs for
the ``Salty Snacks--Other'' category to approximate those for the snack
bar category. FDA assumes that firms will have 1 year to come into
compliance. The estimated low, medium, and high costs of re-labeling
generated by the labeling cost model for these sectors made assuming a
12-month compliance period are provided in table 4 of this document.
Because 12 months represents a compliance period likely to be shorter
than the actual period, actual costs may be lower.
Table 4--Re-Labeling Costs Assuming a 12-Month Compliance Period
----------------------------------------------------------------------------------------------------------------
Product group Low Medium High
----------------------------------------------------------------------------------------------------------------
Salty Snacks--Other............................................. $27,000 $38,000 $52,000
Margarines...................................................... 3,000 4,000 8,000
Fats and Oils................................................... 25,000 35,000 57,000
Salad Dressings and Toppings.................................... 30,000 42,000 67,000
Dietary Supplements--Liquid..................................... 900 1,000 2,000
-----------------------------------------------
Total....................................................... 86,000 121,000 186,000
----------------------------------------------------------------------------------------------------------------
FDA uses the Reformulation Cost Model to estimate the costs of
reformulating products for estimated fractions of the vegetable
spreads, salad dressings, snack bar, and dietary supplement sectors in
which it is likely that firms currently make a plant sterol/stanol
esters and CHD health claim (Ref. 115). FDA assumes that most
conventional food products that currently make a plant sterol/stanol
esters and CHD health claim currently meet the minimum per-serving
requirements in the proposed rule. FDA assumes that some conventional
food products that enrich with plant sterol esters will have to be
reformulated in order to meet the minimum per-serving requirements. FDA
assumes that 25 percent of conventional food products that currently
make a plant sterol/stanol esters and CHD health claim will reformulate
to keep the claim. FDA assumes that no dietary supplements in softgel
form that currently make a plant sterol/stanol esters and CHD health
claim would have to reformulate in order to meet the minimum per-
serving requirements in the proposed rule.
FDA assumes that any reformulation costs incurred by manufacturers
of these products will involve minor changes to recipes and
ingredients. The estimated costs of reformulating generated by the
reformulation cost model for sectors that correspond closely with those
identified in the IFR used to compute labeling costs are made assuming
a 12-month compliance period and are provided in Table 5 of this
document. Discarded inventories are the primary cost of reformulation
when the model is computed under these assumptions. FDA requests
comments on the magnitude of the reformulation cost generated by the
model, as well as the assumption that discarded inventories would be
the primary source of reformulation costs.
To characterize uncertainty about the total reformulation costs,
FDA assumes that the estimated total reformulation costs is distributed
normally with a mean equal to the addition of all of the costs
estimated for the individual sectors ($5,200), and a standard deviation
equal to that for the data across sectors ($650). FDA requests comments
on these estimates. The confidence interval that contains the true
amount of total reformulation costs with 95 percent probability under
the stated assumptions is reported in the bottom row of Table 5.
Table 5--Reformulation Costs Assuming a 12-Month Compliance Period
------------------------------------------------------------------------
Product group Reformulation costs
------------------------------------------------------------------------
Salty Snacks--Other...................... $500.
Vegetable oils........................... $1,500.
Margarines............................... $1,500.
Salad Dressings--Refrigerated............ $150.
Salad Dressings--Bottled, Unrefrigerated. $1,500.
------------------------------
Total................................ Between $700 and $9,000.
------------------------------------------------------------------------
D. Benefits of Option 2 (the Proposed Rule)
1. The Importance of the Health Risk Addressed by the Claim
CHD is the leading cause of death and permanent disability in the
United States (Ref. 116). The National Center for Health Statistics in
the Centers for Disease Control and Prevention (CDC) reports that in
2002 there were approximately 23 million non-institutionalized adults
diagnosed with CHD, resulting in approximately 700,000 deaths.
According to the same source, CHD patients made approximately 20.8
million office-based
[[Page 76549]]
physician visits and approximately 1.1 million hospital outpatient
visits in that year. In addition, there were approximately 4.4 million
hospital discharges of CHD patients, with average lengths of stay of
approximately 4.4 days. As an indication of the extent to which this
disease is disabling, CDC reports that approximately 66 percent of
heart patients fail to fully recover (Refs. 116 and 117).
2. The Benefits Model
The benefit of the proposed rule relative to the IFR is the reduced
risk of CHD that may result from consumers substituting a greater
number of foods containing phytosterols for currently consumed
alternatives that do not reduce the risk of CHD. The proposed rule
would increase the number of food products eligible to use the
phytosterols-CHD health claim from only foods enriched with esterified
sterols and stanols, to include conventional foods enriched with
nonesterified and esterified phytosterols, as well as mixtures of
sterols and stanols, and additional forms of dietary supplements.
Consequently, a wide variety of low and non-fat foods that are
currently not authorized to make the plant sterol/stanol esters-CHD
health claim may do so under the proposed rule.
FDA anticipates that foods for which GRAS notifications for
phytosterols use have been submitted may be qualified to make a
phytosterols-CHD health claim under this proposed rule. Phytosterol
GRAS notifications to which FDA has no objections include, but are not
limited to, the use of phytosterols as ingredients in: Margarine and
vegetable oil spreads, salad dressings, mayonnaise, edible vegetable
oils, snack bars, dairy and dairy-like substitutes (including those for
yogurt, ice cream, cream cheese, and milk and milk based beverages),
baked foods, ready-to-eat breakfast cereals, pasta and noodles, sauces,
salty snacks, processed soups, puddings, confections, white breads and
white bread products, vegetable meat analogues, fruit and vegetable
juices, and coffee. The increase in the number of conventional foods in
which phytosterol-enrichment has been self-determined to be GRAS and
that may be qualified to make a health claim under the proposed rule,
suggests an increase in consumption of conventional foods with
phytosterols-CHD health claims.
The higher effective daily intake of phytosterols required to be
communicated on the health claim may also increase the dietary intake
of phytosterols. The effective daily intake of phytosterols that must
be stated in the health claim has been increased to 2 g per day of
phytosterols (expressed as weight of nonesterified phytosterols) for
both plant sterols and plant stanols in the proposed rule. The IFR
specified effective daily intake levels of 1.3 g per day of plant
sterol esters (equivalent to 0.8 g of nonesterified plant sterols) and
3.4 g per day of plant stanol esters (equivalent to 2 g of
nonesterified plant stanols).
FDA assumes that the proposed change in the minimum amount of
phytosterols required for eligible foods to 0.5 g of phytosterols per
RACC would have no impact on the number of plant stanol-enriched foods
that make the claim because the 0.5 g of phytosterols per RACC required
minimum in this proposed rule is less than the qualifying amount of
plant stanol esters required under the IFR (1 g/RACC as nonesterified
stanol). FDA also assumes that the proposed change in the minimum
amount of phytosterols required for eligible foods would have no impact
on the number of plant sterol-enriched foods that make the claim
because the 0.5 g of phytosterols per RACC required minimum in this
proposed rule is only slightly higher than the qualifying amount
required under the IFR for plant sterol esters (0.4 g/RACC as
nonesterified sterol). Finally, the proposed new claim language
specifying that phytosterols should be consumed with meals, rather than
specifying that phytosterols should be consumed in two servings eaten
at different times of day with other foods, may result in fewer snack
foods making the health claim.
3. The Increase in Dietary Intake of Phytosterols
FDA estimates the increase in the market share of newly labeled
products that may make a phytosterols-CHD health claim as a first step
to model the increase in dietary intake of phytosterols. The agency
refines this estimate of the increase in dietary intake to account for
the possibility that increased consumption of foods newly permitted to
make a health claim under this proposed rule contain the same levels of
phytosterols as foods currently consumed but not allowed to make a
claim. FDA further refines its estimate of the increase in dietary
intake of phytosterols from this proposed rule to account for the
consumption of meals away from home that are not subject to packaged
food labeling regulations; the portion of dietary intake of
phytosterols from meals away from home is assumed to not be affected by
the proposed rule.
The increase in dietary intake of phytosterols will be less than
the increase in the market share of packaged food products that may
make a health claim if meals are consumed away from home and
consequently not subject to packaged food labeling regulations, or if
consumption of foods newly permitted to make a health claim under this
proposed rule contain the same levels of phytosterols as foods
currently consumed that are not allowed to make a claim. FDA uses data
from the U.S. Department of Agriculture (USDA) to estimate the fraction
of total food consumption (both in-home as well as away-from-home
consumption) that is subject to packaged food labeling requirements.
Food consumed at home accounts for about 57 percent of all food
expenditures (Ref. 118). FDA assumes that half of the remaining sales
of newly labeled foods that may make a phytosterols-CHD health claim
will reflect purchases of existing products that contain threshold
levels of phytosterols but are not currently allowed to make a
phytosterols-CHD health claim. If FDA applies these estimates to the
0.2 percent for the market share of packaged food products that may
make the health claim permitted by this proposed rule, FDA estimates
that the percent increase in dietary intake of phytosterols as a result
of this proposed rule may be 0.06 percent (i.e., (0.2 percent x 57
percent)/2) of current levels.
Finally, the increase in dietary intake of phytosterols does not
necessarily lead to health benefits for all consumers. Healthful
characteristics, including the phytosterols content, are just some of
several considerations consumers use when making food purchases.
Consumers who choose newly formulated foods that make the phytosterols-
CHD health benefits over foods that do not contain phytosterols may
include both those at risk of CHD as well as those who are not at risk.
If a substantial number of those who are at risk of CHD will increase
their intake of phytosterols because of the phytosterols-CHD health
claims permitted by this proposed rule, then FDA can expect some
positive effects on public health.
E. Costs and Benefits of Option 3
Option 3 would restrict coverage of the proposed requirements to
only conventional foods, so that manufacturers of some plant stanol
ester-containing dietary supplements in softgel form that currently
claim reduced risk of CHD from plant sterol/stanol esters consumption
would no longer be allowed to make that claim. These manufacturers
would need to re-label their products to either make no
[[Page 76550]]
claim or to make a structure/function claim. Benefits from the
consumption of dietary supplements in softgel form may be reduced.
There would be re-labeling costs for some dietary supplements in
softgel form that currently make the plant stanol esters-CHD health
claim based on the current regulation, but are no longer permitted to
make that claim in the proposed rule. The re-labeling costs incurred
for the dietary supplements under option 3 will be larger than those
incurred by dietary supplement manufacturers under the proposed option;
all dietary supplements that currently make a plant sterol/stanol
esters and CHD health claim would have to be re-labeled to either make
no claim or to make a structure/function claim--either of which implies
larger changes to the label. FDA assumes the costs of a full label
redesign will be incurred by manufacturers of dietary supplements that
currently make a plant sterol/stanol esters and CHD health claim.
Because dietary supplements would no longer be permitted to make the
plant sterol/stanol esters and CHD health claim, there may also be
reformulation costs incurred by manufacturers of some dietary
supplements that choose to reduce current levels of phytosterols
contained as an ingredient in the final product. However, these costs
are considered to be a voluntary reallocation of resources rather than
compliance costs.
F. Costs and Benefits of Option 4
FDA assumes that manufacturers of any product making the
phytosterols-CHD health claim, for which the analytical method for
determining the quantity of phytosterols is different than either the
Unilever or McNeil methods, may incur costs from the requirement to
provide access to documentation that substantiates the amount of
phytosterols in a food product. FDA considers the costs incurred for
requiring FDA to have access to these documents for an estimated small
number of firms to be a reallocation of resources rather than
compliance costs, since claiming the health benefits from phytosterols
is strictly voluntary; any product for which a testing method different
than either the Unilever or McNeil methods is required would be
different than a vegetable spread, salad dressing, or snack bar and
would have voluntarily chosen to make a phytosterols-CHD health claim
following passage of this proposed rule. The costs of ensuring
compliance with phytosterols-content requirements in products for which
the analytical method for making this determination is different than
either the McNeil or Unilever methods would be higher than for the
proposed rule if the FDA inspection resources required to access and
analyze documents that substantiate the amount of phytosterols
contained in products were greater than those required to sample and
test the products directly with the Sorenson and Sullivan method.
IX. Small Entity Analysis (or Initial Regulatory Flexibility Analysis)
FDA has examined the economic implications of this proposed rule as
required by the Regulatory Flexibility Act (5 U.S.C. 601-612). If a
rule has a significant economic impact on a substantial number of small
entities, the Regulatory Flexibility Act requires the agency to analyze
regulatory options that would minimize the economic impact of the rule
on small entities.
Small businesses that are currently making a plant sterol/stanol
esters and CHD health claim may incur re-labeling costs to satisfy the
change in the language required on the health claim, and reformulation
costs to satisfy the increased minimum per-serving quantity of
phytosterols required for a product to make a health claim. FDA uses
the 2002 Economic Census to estimate the number of small businesses in
the vegetable spreads, salad dressings, snack bars, and dietary
supplements sectors that may incur costs from this proposed rule as
well as the costs that they would incur. Based on the Economic Census
there are approximately 3,065 firms in the sectors described by North
American Industry Classification System (NAICS) codes 311225 (Fats and
oils refining and blending), 311941 (Mayonnaise, dressing, and other
prepared sauce manufacturing, 311942 (Spice and extract manufacturing),
311919 (Other snack food manufacturing), 311999 (All other
miscellaneous food manufacturing), and 325412 (Pharmaceutical
preparation manufacturing). Approximately 95 percent of these firms
have fewer than 500 employees and are considered small (Ref. 119).
Moreover, FDA estimates from this data that firms with fewer than 500
employees account for approximately 75 percent of the sales revenues
from these sectors.
In order to estimate the number of food manufacturers that may make
a plant sterol/stanol esters and CHD health claim, FDA assumes that
half of the small firms from the sectors described in the previous
paragraph manufacture a product that is eligible to make a health
claim. Consistent with FDA's 2001 FLAPS (Ref. 114), FDA multiplies
those making a health claim by the percentage of health claims that
were found to address the risk of CHD (41.7 percent). FDA assumes that
10 percent of all packaged food sales with claims that address the risk
of CHD may make a phytosterols-CHD health claim.
Consequently, FDA estimates that 128 firms with fewer than 500
employees would manufacture one product that makes the plant sterol/
stanol esters and CHD health claim and would incur compliance costs
from this proposed rule (i.e., 95 percent of 3,065 food and dietary
supplements manufacturers, multiplied by 50 percent for only those that
manufacture products making a health claim, multiplied by 41.7 percent
for manufacturing products that make a health claim addressing the risk
of CHD, and multiplying by 10 percent for making the plant sterol/
stanol esters and CHD health claim. Because each individual food
product currently making the plant sterol/stanol esters and CHD health
claim would need to be re-labeled, fewer labels would need to be
redesigned or discarded for a small manufacturer than for a large
manufacturer. FDA uses data from the 2002 Economic Census indicating
that 75 percent of total sales revenue--and by extension re-labeling
costs--for the entire sector can be attributed to small manufacturers.
FDA multiplies the re-labeling cost estimates for the entire sector of
between $86,000 and $186,000 obtained in the cost-benefit analysis by
75 percent, and then divides by the number of small firms to obtain the
cost per small firm. Consequently, FDA estimates that the average one-
time re-labeling cost per small business would be between approximately
$700 and $1,500.
FDA assumes that only some manufacturers that currently enrich
conventional food products with plant sterol esters will incur
reformulation costs. FDA assumes that 25 percent of small manufacturers
of conventional food products that make a plant sterol/stanol esters
and CHD health claim would need to reformulate a product as a result of
this proposed rule. Consistent with the earlier discussion in this
document, FDA estimates that 95 percent of the reformulation costs, or
approximately $5,000, would be incurred by approximately 30 small
manufacturers with fewer than 500 employees. FDA obtains an estimate of
the reformulation costs per small manufacturer of approximately $160.
FDA requests comments on the estimate of reformulation costs per
manufacturer. Small businesses that currently are not making a plant
sterol/stanol esters and CHD health claim will incur labeling and
reformulation costs only if they
[[Page 76551]]
choose to take advantage of the marketing opportunity presented by this
proposed rule.
X. Paperwork Reduction Act of 1995
FDA concludes that the labeling provisions of this proposed rule
are not subject to review by the Office of Management and Budget
because they do not constitute a ``collection of information'' under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). Rather, the
food labeling health claim on the association between consumption of
phytosterols and CHD risk is a ``public disclosure of information
originally supplied by the Federal Government to the recipient for the
purpose of disclosure to the public'' (see 5 CFR 1320.3(c)(2)).
XI. Federalism
FDA has analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. Section 4(a) of the
Executive order requires agencies to ``construe * * * a Federal statute
to preempt State law only where the statute contains an express
preemption provision or there is some other clear evidence that the
Congress intended preemption of State law, or where the exercise of
State law conflicts with the exercise of Federal authority under the
Federal statute.'' Federal law includes an express preemption provision
that preempts ``any requirement respecting any claims of the type
described in [21 U.S.C. 343(r)(1)] made in the label or labeling of
food that is not identical to the requirement of [21 U.S.C. 343(r)] * *
*.'' 21 U.S.C. 343-1(a)(5). However, the statutory provision does not
preempt any State requirement respecting a statement in the labeling of
food that provides for a warning concerning the safety of the food or
component of the food (Pub. L. 101-535, section 6, 104 Stat. 2353
(1990)). If this proposed rule is made final, the final rule would
create requirements for various health claims for phytosterols in the
label or labeling of food under 21 U.S.C. 343(r).
XII. Comments
Interested persons may submit to the Division of Dockets Management
(see ADDRESSES) either electronic or written comments regarding this
document. It is only necessary to send one set of comments. It is no
longer necessary to send two copies of mailed comments. Identify
comments with the docket number found in brackets in the heading of
this document. Received comments may be seen in the Division of Dockets
Management between 9 a.m. and 4 p.m., Monday through Friday.
XIII. References
The following references have been placed on display in the
Division of Dockets Management (see ADDRESSES) and may be seen between
9 a.m. and 4 p.m., Monday through Friday, except on Federal Government
holidays. (FDA has verified the Web site addresses, but is not
responsible for any subsequent changes to the Web sites after this
document publishes in the Federal Register.)
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List of Subjects in 21 CFR Part 101
Food labeling, Incorporation by reference, Nutrition, Reporting and
recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act and under
authority delegated to the Commissioner of Food and Drugs, it is
proposed that 21 CFR part 101 be amended as follows:
PART 101--FOOD LABELING
1. The authority citation for 21 CFR part 101 continues to read as
follows:
Authority: 15 U.S.C. 1453, 1454, 1455; 21 U.S.C. 321, 331, 342,
343, 348, 371; 42 U.S.C. 243, 264, 271.
2. Section 101.83 is revised to read as follows:
Sec. 101.83 Health claims: phytosterols and risk of coronary heart
disease (CHD).
(a) Relationship between diets that include phytosterols and the
risk of CHD. (1) Cardiovascular disease means diseases of the heart and
circulatory system. Coronary heart disease (CHD) is one of the most
common and serious forms of cardiovascular disease and
[[Page 76555]]
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. Lowering of blood total and/or LDL cholesterol has been shown
conclusively to lower risk for CHD, and thus is the primary target of
cholesterol-lowering therapy. The relationship between total and LDL
cholesterol levels and CHD risk is continuous over a broad range of LDL
cholesterol levels from low to high. 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. Borderline high risk
blood cholesterol levels range from 200 to 239 mg/dL (5.17 to 6.18
mmol/L). An optimal blood LDL cholesterol level is less than 100 mg/dL
(2.6 mg/L); borderline high LDL levels range from 130 to 160 mg/dL (3.4
to 4.1 mmol/L); and a high LDL cholesterol level is above 160 mg/dL.
(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) Phytosterols (plant sterols) are structurally similar to
cholesterol. Although there are many different phytosterols found in
plants, the phytosterols most abundant in the diet are beta ([beta])-
sitosterol, campesterol, and stigmasterol. Phytosterols usually have a
double bond at the 5 position of the core ring structure. Phytosterols
that have been saturated to remove the double bond in the ring
structure are sometimes referred to as ``stanols.'' This regulation
uses the term phytosterol as inclusive of both sterol and stanol forms.
(4) Scientific evidence demonstrates that diets that include
phytosterols may reduce the risk of CHD.
(b) Significance of the relationship between diets that include
phytosterols 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) The scientific evidence establishes that including phytosterols
in the diet helps to lower blood total and LDL cholesterol levels.
(c) Requirements--(1) General. All requirements set forth in Sec.
101.14 shall be met, except Sec. 101.14(a)(4), as specified in
paragraph (c)(2)(iii)(C) of this section, for disqualifying levels of
total fat in vegetable oil spreads resembling margarine, dressings for
salad, and liquid vegetable oils and Sec. 101.14(e)(6), as specified
in paragraph (c)(2)(iii)(D) of this section, for minimum nutrient
contribution requirements with respect to vegetable oil spreads
resembling margarine, dressings for salad, and liquid vegetable oils.
(2) Specific requirements--(i) Nature of the claim. A health claim
associating diets that include phytosterols 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 phytosterols should be consumed as part
of a diet low in saturated fat and cholesterol;
(B) The claim states that diets that include phytosterols ``may''
or ``might'' reduce the risk of heart disease;
(C) In specifying the disease, the claim uses the following terms:
``heart disease'' or ``coronary heart disease'';
(D) In specifying the substance, the claim accurately uses the term
``phytosterols,'' ``plant sterols,'' ``plant stanols,'' or ``plant
sterols and stanols,'' except that if the sole source of the plant
sterols or stanols is vegetable oil, the claim may so specify, e.g.,
``vegetable oil phytosterols'' or ``vegetable oil sterols and
stanols'';
(E) The claim does not attribute any degree of risk reduction for
CHD to diets that include phytosterols;
(F) The claim does not imply that consumption of diets that include
phytosterols is the only recognized means of achieving a reduced risk
of CHD;
(G) The claim specifies the daily dietary intake of phytosterols
that is necessary to reduce the risk of CHD and the contribution one
serving of the product makes to the specified daily dietary intake
level. The daily dietary intake level of phytosterols that has been
associated with reduced risk of CHD is 2 grams (g) per day, based on
the nonesterified weight of phytosterols; and
(H) The claim specifies that the daily dietary intake of
phytosterols should be consumed with meals or snacks.
(ii) Nature of the substance. (A) The substance may be derived from
either vegetable oils or from tall oils and shall contain at least 80
percent beta-sitosterol, campesterol, stigmasterol, sitostanol, and/or
campestanol (combined weight). For conventional foods, the substance
may be esterified with food-grade fatty acids; for dietary supplements,
the substance must be esterified with food-grade fatty acids.
(B) The Food and Drug Administration (FDA) will measure
phytosterols by the Association of Official Analytical Chemists (AOAC)
Official Method 994.10, ``Cholesterol in Foods,'' as modified for
assaying phytosterols by Sorenson and Sullivan (Journal of AOAC
International, Vol. 89, No. 1, 2006). These methods are incorporated by
reference in accordance with 5 U.S.C. 552(a) and 1 CFR part 51. Copies
may be obtained from the Center for Food Safety and Applied Nutrition,
Food and Drug Administration, 5100 Paint Branch Pkwy., College Park, MD
20740, or at the National Archives and Records Administration (NARA).
For information on the availability of this material at NARA, call 202-
741-6030, or go to http://www.archives.gov/federal_register/code_of_federal_regulations/ibr_locations.html.
(iii) Nature of the food eligible to bear the claim. (A) The food
product shall contain at least 0.5 g of phytosterols, based on the
nonesterified weight of phytosterols that comply with paragraph
(c)(2)(ii) of this section per reference amount customarily consumed;
(B) If the food product is a dietary supplement, the phytosterols
shall be esterified with food-grade fatty acids;
(C) If the food product is a conventional food, the use of the
phytosterols in such food has been submitted to FDA in a generally
recognized as safe (GRAS) notification, to which the agency had no
further questions, and the conditions of use are consistent with the
eligibility requirements for the health claim;
(D) The food shall meet the nutrient content requirements in Sec.
101.62 for a ``low saturated fat'' and ``low cholesterol'' food;
(E) The food shall meet the limit for total fat in Sec.
101.14(a)(4), except that, if the label of the food bears a disclosure
statement that complies with Sec. 101.13(h), vegetable oil spreads
resembling margarine and dressings for salad are not required to meet
the limit for total fat per 50 g and liquid vegetable oils are not
required to meet the limit for total fat per reference amount
customarily consumed, per label serving size, and per 50 g; and
(F) The food shall meet the minimum nutrient contribution
requirement in Sec. 101.14(e)(6) unless it is a liquid vegetable oil
or dressing for salad. The minimum nutrient contribution requirement
for vegetable oil spreads
[[Page 76556]]
resembling margarine may be met by added vitamin A.
(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 include phytosterols 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
include phytosterols and the risk of CHD and the significance of the
relationship.
(4) The claim may include information from the following paragraph
on the relationship between saturated fat and cholesterol in the diet
and the risk of CHD: 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. 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 keep total fat intake
between 20 to 35 percent of calories. 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.
(5) The claim may state that diets that include phytosterols and
are low in saturated fat and cholesterol are consistent with ``Dietary
Guidelines for Americans.'' U.S. Department of Agriculture (USDA) and
Department of Health and Human Services (DHHS), Government Printing
Office (GPO).
(6) 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.
(7) 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
for Health, or ``Dietary Guidelines for Americans,'' U.S. Department of
Agriculture (USDA) and Department of Health and Human Services (DHHS),
Government Printing Office (GPO).
(e) Model health claims. The following model health claims may be
used in food labeling to describe the relationship between diets that
include phytosterols and reduced risk of heart disease:
(1) Foods containing at least 0.5 g per serving of phytosterols
[plant sterols, plant stanols, or plant sterols and stanols] eaten with
meals or snacks for a daily total intake of 2 g as part of a diet low
in saturated fat and cholesterol, may reduce the risk of heart disease.
A serving of [name of the food] supplies----g of phytosterols [plant
sterols, plant stanols, or plant sterols and stanols].
(2) Diets low in saturated fat and cholesterol that include 2 g per
day of phytosterols [plant sterols, plant stanols, or plant sterols and
stanols] eaten with meals or snacks may reduce the risk of heart
disease. A serving of [name of food] supplies----g of [phytosterols
plant sterols, plant stanols, or plant sterols and stanols].
Dated: November 24, 2010.
Leslie Kux,
Acting Assistant Commissioner for Policy.
Tables 1 and 2 to Preamble
Note: These tables will not appear in the Code of Federal
Regulations.
Table 1--Randomized Clinical Trials of Phytosterols in Conventional Foods and Total and LDL Cholesterol Concentration
--------------------------------------------------------------------------------------------------------------------------------------------------------
Study Design Population Intervention Diet Results
--------------------------------------------------------------------------------------------------------------------------------------------------------
AbuMweis et al., 2006 (Ref. 38) Randomized single- Healthy adults 38 One serving/d test Controlled diet; all Total-C (mg/dL)
blind, placebo- enrolled, 30 margarine, eaten food and beverage Baseline: 228
controlled, crossover completed with breakfast. PS prepared/provided by After 4-wk test
trial; five 29-d test Mean age dose: 22 mg/kg body study; American diet period:
periods, separated by sd. wgt (about 1.7 g PS/ w/30% energy from C 222
2-4 wk washout 59 10 y.. d) \1\ fat I1 219
periods n = 30/phase.......... C = margarine w/o I2 220
Inclusion criteria: added PS. I3 224
LDL-C >100 mg/dL, BMI I1 = ~1.7 g PS/d as I4 223
22-34, age 40-85 y, nonesterified plant LDL-C (mg/dL)
no chronic disease or sterols in PS- Baseline: 147
lipid-lowering RX. enriched margarine. After 4-wk test
USA................... I2 = ~1.7 g PS/d as period:
plant sterol esters C 141
(sunflower oil fatty I1 139
acids) in PS- I2 139
enriched margarine. I3 145
I3 = ~1.7 g PS/d as I4 143
plant sterol esters No significant
(fish oil n-3 LC changes of Total-C
PUFA) in PS-enriched or LDL-C compared to
margarine. control
I4 = ~1.7 g PS/d as
nonesterified plant
sterols fish oil.
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76557]]
Doornbos et al., 2006 (Ref. 43) Randomized double- Mildly Single serving Habitual diet........ Total-C (mg/dL)
blind, placebo- hypercholesterolemic bottled yogurt drink Baseline: 234
controlled, parallel adults (100 g) consumed Total-C % change
trial with 5 groups; 191 randomized, 184 with a meal, or compared to control:
4-wk run-in followed Included in analysis. while fasting I1 [darr] 7.0%*
by 4-wk test period Mean age C = drink w/o added I2 [darr] 4.1%*
sd. PS. I3 [darr] 6.5%*
57 2 y... I1 = 3.2 g PS/d in I4 [darr] 4.7%*
n = 33(C)............. low-fat yogurt (0.1 *p < 0.05
n = 38 (I1)........... g dairy fat, 2.2 g LDL-C (mg/dL)
n = 38 (I2)........... fat in the stanol/ Baseline: 155
n = 39 (I3)........... sterol ester) w/meal. LDL-C % change
n = 36 (I4)........... I2 = 3.2 g PS/d in compared to control:
Inclusion criteria: low-fat yogurt (0.1 I1 [darr] 9.5%*
BMI 18-32 kg/m\2\; g dairy fat, 2.2 g I2 [darr] 5.1%*
total-C 193-309 mg/dL fat in the stanol/ I3 [darr] 9.3%*
TG < 355 mg/dL. sterol ester) w/o I4 [darr] 6.9%*
The Netherlands....... meal. *p < 0.05
I3 = 2.8 g tall oil
PS/d in regular-fat
yogurt (1.5 g dairy
fat, 2.1 g fat in
the stanol/sterol
ester) w/meal.
I4 = 2.8 g PS/d in
regular-fat yogurt
(1.5 g dairy fat,
2.1 g fat in the
stanol/sterol ester)
w/o meal.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jauhiainen et al., 2006 (Ref. 89).. Randomized double- Mildly 50 g/d hard cheese Habitual diets....... Total-C (mg/dL)
blind, placebo- hypercholesterolemic divided into 2 Baseline:
controlled parallel adults portions consumed C 224
trial, 1-wk run-in, 5- 67 enrolled, 67 with two major meals I 218
wk test period completed. C = cheese w/o added Total-C % change
n = 34 (C)............ phytosterols. compared to placebo:
n = 33 (I)............ I = 2.0 g PS/d as I [darr] 5.7% (p <
Age range 25-65 y..... plant stanol ester 0.05)
Inclusion criteria:... in PS-enriched hard LDL-C (mg/dL)
Total-C 193-251....... cheese. Baseline:
mg/dL, TG < 266....... C 139
mg/dL................. I 138
Finland............... LDL-C % change
compared to control:
I [darr] 10.1% (p <
0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Korpela et al., 2006 (Ref. 37)..... Randomized double- Mildly 150 g low-fat yogurt, Habitual diets plus Total-C (mg/dL)
blind, placebo- hypercholesterolemic 50 g low-fat hard low-fat yogurt and Baseline:
controlled, parallel adults. 170 enrolled, cheese, and 50 g low- low-fat hard/fresh C 247
trial; 3-wk run-in, 6- 164 completed fat fresh cheese cheese I 247
wk test period n = 82/group.......... C = yogurt and cheese % change compared to
Mean age w/out added PS. control: I [darr]
sd. I= 1.65-2.0 g PS/d as 6.5% (p < 0.05)
57 8 y nonesterified sterol/ LDL-C (mg/dL)
(C). stanol in enriched Baseline:
58 9 y yogurt and cheeses. C 155
(I). I 159
Inclusion criteria: % change compared to
Total-C 193-329 mg/ control: I [darr]
dL, TG < 354 mg/dL. 11.0% (p < 0.05)
Finland...............
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jakulj et al., 2005 (Ref. 90)...... Randomized double- Healthy moderately 25 g/d test margarine Habitual diets....... Total-C (mg/dL)
blind, crossover hypercholesterolemic on sandwiches or Baseline: 261
design for PS adults 40 enrolled, mixed with food in a At end of 4 wk test
component, and open- 39 Included in hot meal period:
label RX tmt; 2x2 analyses C = spread w/o added C 249
factorial trial. 2-wk Mean age PS. I1 235
run-in followed by sd. I1 = 2.0 g PS/d as I2 208
four consecutive 4-wk 55.5 7.9 plant sterol on PS- I3 204
test periods y. enriched spread. Total-C % change
n = 39................ Information not compared to control:
Inclusion criteria: provided as to I1 [darr] 5.2%*
plasma LDL-C 135-193 whether I2 [darr] 15.7%*
mg/dL; TG < 355 mg/dL. nonesterified or I3 [darr] 17.2%*
The Netherlands....... esterified. *p < 0.05
I2 = Ezetimibe....... LDL-C (mg/dL)
I3 = Ezetimibe + PS- Baseline: 174
enriched spread. At end of 4-wk:
C 157
I1 148
I2 121
I3 116
% change compared to
control:
I1 [darr] 5.1%*
I2 [darr] 20.9%*
I3 [darr] 23.8%*
*p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76558]]
Clifton et al. 2004 (Ref. 88)...... Randomized single- Mildly One serving/d each 4 Habitual diets Total-C (mg/dL)
blind, placebo- hypercholesterolemic of test foods supplemented by one Baseline: 241
controlled, adults 63 enrolled, (bread, milk, serving daily of % change compared to
incomplete crossover 58 completed cereal, and yoghurt) yoghurt, low-fat placebo:
trial; four n = 58 (C)............ consumed with meals milk, bread, and I1 [darr] 5.6%*
consecutive 3-wk test n = 36 (I1)........... C = test foods w/o muesli-type cereal. I2 [darr] 8.5%*
periods, no washout n = 40 (I2)........... added PS. No changes in I3 [darr] 3.2%*
periods n = 58 (I3)........... I1 = 1.6 g/d PS as reported intakes of I4 [darr] 6.3%*
n = 40 (I4)........... soy sterol esters in energy, fat, CHO, or *p < 0.05
Mean age 54 y......... 2 slices of PS- protein across LDL-C (mg/dL)
Inclusion criteria: enriched bread. treatment periods or Baseline: 156
BMI < 31, no RX that I2 = 1.6 g/d PS as between centers % change compared to
affect lipids, total- soy sterol esters in control:
C 193-290 mg/dL. 500 ml of 2% PS- I1 [darr] 10.4%*
Australia............. enriched milk. I2 [darr] 13.2%*
I3 = 1.6 g/d PS as I3 [darr] 6.0%*
soy sterol esters in I4 [darr] 10.4%*
45 g of PS-enriched *p < 0.05
cereal.
I4 = 1.6 g/d PS as
soy sterol esters
200g of PS-enriched
yogurt.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Devaraj et al., 2004 (Ref. 33)..... Randomized double- Healthy mildly 2 servings/d of test Habitual diets. No Total-C (mg/dL)
blind, parallel trial hypercholesterolemic orange juice, with other orange juice, Baseline:
with 2 groups; 2-wk adults meals. citrus fruit, or PS- C 209
run-in period 75 enrolled; 72 C = orange juice w/o enriched margarine I 207
followed by 8-wk test completed. added PS. allowed. 3-day diet Total-C % change
period Mean age I=2 g PS/d as records at beginning compared to control:
sd. nonesterified sterol and end of study I [darr] 5.3% (p <
44 13 y in PS-enriched 0.05)
(C). orange juice. LDL-C (mg/dL)
41 13 y Baseline:
(I). C 140
n = 36/group.......... I 137
Inclusion criteria: LDL-C % change
LDL-C >100 mg/dL; no compared to control:
Rx that affect I [darr] 7.3% (p <
lipids, no smoking, 0.05)
no HX of CVD.
USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Thomsen et al., 2004 (Ref. 26)..... Randomized double- Mildly 2 servings/d of 1.2%- Habitual Danish diet Total-C (mg/dL)
blind, crossover hypercholesterolemic fat test milk w/ with limits on Baseline: 271
trial, with three adults meals certain fatty foods; Total-C % change
consecutive 4-wk 81 subjects Randomized C = milk w/o added PS e.g., 20 g/d cheese, relative to control:
periods; no run-in or 69 completed. I1 = 1.2 g PS/day as 2 portions of I1 [darr] 4.73%*
wash-our periods Mean age nonesterified plant crustaceans and I2 [darr] 7.05%*
sd. sterols in PS- mollusks per wk * p < 0.0001
60 5 y... enriched milk. LDL-C (mg/dL)
n = 69................ I2 = 1.6 g PS/day as Baseline: 169
Inclusion criteria: no nonesterified plant LDL-C % change
RX that affect sterols in PS- relative to control:
lipids, total-C 217- enriched milk. I1 [darr] 7.1%*
325 mg/dL, TG < 310 I2 [darr] 9.6%*
mg/dL. * p < 0.0001
Denmark...............
--------------------------------------------------------------------------------------------------------------------------------------------------------
Cleghorn et al., 2003 (Ref. 91).... Randomized double- Mildly Test butter (20 g/d) Self-selected low-fat Total-C (mg/dL)
blind, placebo- hypercholesterolemic or test margarine diets. Test At end of 3 wk test
controlled, crossover adults; (25 g/d) substance (butter or period:
trial; 3-wk run-in 58 subjects enrolled, B = Butter w/o added margarine) added to B 235
period, 3-wk test 53 completed. PS. low-fat diet M 227
period Mean age M = margarine w/o I 215
sd. added PS. Total-C % change
46.7 10.5 I = 2 g PS/d PS as relative to control:
y. plant sterol esters I [darr] 5.45% (p <
n = 53................ in PS-enriched 0.05)
Inclusion criteria: margarine. LDL-C (mg/dL)
total-C 193-290 mg/ At end of 3 wk test
dL, TG < 266 mg/dL; period:
no cholesterol-lowing B 154
RX. M 145
New Zealand........... I 135
LDL-C % change
compared to control:
I [darr] 7.2% (p <
0.01)
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76559]]
Homma et al., 2003 (Ref. 82)....... Randomized double- Healthy adult Japanese 2 or 3 servings/d of Habitual Japanese Total-C (mg/dL)
blind, placebo- 105 enrolled, 104 low-fat test spread, diet. Diets were Baseline:
controlled, parallel completed. eaten w/meals. assessed with 2 day C 238
trial, 4-wk test Mean age C = spread w/o added diet analysis at I1 235
period, and 4-wk post- sd. PS, 3 servings/d. start and end of I2 232
trial follow-up 46 14 y I1 = 2 g PS/d as trial Total-C % change
period (P). plant stanol esters compared to control:
47 13 y in PS-enriched I1 [darr] 5.7%*
(I1). spread, 2 servings/d. I2 [darr] 4.9%*
49 12 y I2 = 3 g PS/d as *p < 0.001
(I2). stanol esters in PS- LDL-C (mg/dL)
n = 33-34/group....... enriched spread, 3 Baseline:
Inclusion criteria: servings/d. C 157
age >20 y, total-C I1 153
209-278 mg/dL, TG < I2 153
345 mg/dL. LDL-C % change
Japan................. compared to control:
I1 [darr] 8.9%*
I2 [darr] 6.6%*
*p < 0.001
--------------------------------------------------------------------------------------------------------------------------------------------------------
Ishiwata et al., 2002 (Same Randomized double- See Homma et al. 2003 2 or 3 servings/d of Habitual Japanese Total-C (mg/dL)
subjects as Homma et al., 2003) blind, placebo- n = 30-31/group....... low-fat test spread, diet Baseline:
(Ref. 92). controlled, parallel Analysis stratified by eaten w/meals C ApoE3 236
trial, 4-wk test apolipoprotein E C = spread w/o added C ApoE4 241
period, and 4-wk post- phenotype. PS, 3 servings/d. I1 ApoE3 237
trial follow-up I1 = 2 g PS/d as I1 ApoE4 231
period plant stanol esters I2 ApoE3 234
in PS-enriched I2 ApoE4 233
spread, 2 servings/d. Total-C % change
I2 = 3 g PS/d as compared to control:
stanol esters in PS- I1 ApoE3 [darr] 7.1%*
enriched spread, 3 I1 ApoE4 [darr] 6.3%*
servings/d. I2 ApoE3 [darr] 5.9%*
I2 ApoE4 [darr] 4.7%
* p < 0.05
LDL-C (mg/dL)
Baseline:
C ApoE3 153
C ApoE4 161
I1 ApoE3 155
I1 ApoE4 148
I2 ApoE3 155
I2 ApoE4 151
LDL-C % change
compared to control:
I1 ApoE3 [darr] 9.2%*
I1 ApoE4 [darr]
11.0%*
I2 ApoE3 [darr] 8.7%*
I2 ApoE4 [darr] 6.4%
* p < 0.01
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jones et al., 2003 (Ref. 34)....... Randomized double- Mildly 3 servings/d of Typical American Total-C (mg/dL)
blind, crossover hypercholesterolemic nonfat or low fat diet. Controlled Baseline:
trial; three 3-wk adults test beverage intake; all food/ C 237
controlled feeding 15 enrolled, 15 consumed w/meals beverage prepared/ I1 242
test periods completed. C = nonfat beverage w/ provided by study I2 229
separated by 4-wk age range 22-68 y..... o added PS. Total-C % change at 3
washout periods n = 15................ I1 = 1.8 g PS/d as wk:
Inclusion criteria: nonesterified plant C [darr] 8.5%
BMI 22-32 kg/m\2\, tall oil sterol/ I1 [darr] 11.6%
LDL-C 126-232 mg/dL, stanol in PS- I2 [darr] 10.1%
HDL < 31 mg/dL, TG < enriched nonfat no significant
355 mg/dL. beverage. differences between
Canada................ I2 = 1.8 g PS/d as control and PS
nonesterified plant periods
tall oil sterol/ LDL-C (mg/dL)
stanol in PS- Baseline:
enriched low fat C 155
beverage. I1 160
I2 150
LDL-C % change at 3
wk:
C [darr] 5.0%
I1 [darr] 10.4%
I2 [darr] 8.5%
no significant
differences between
P and PS periods
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76560]]
Naumann et al., 2003 (Ref. 42)..... Randomized double- Healthy adults, 44 1 serving/d of test Habitual diets; food Total-C (mg/dL) At
blind, placebo- enrolled, 42 margarine frequency end of 3 wk:
controlled, crossover completed C = margarine w/o questionnaires C 173
trial; three Mean age added PS. assessed diet at end I1 167
consecutive 3-wk test sd. I1 = 2 g PS/d as of each period. No I2 168
periods 32 14 y F phytosterol ester, margarine was Total-C % difference
37 16 y M 1:1 sterol/stanol allowed other than compared to control:
n = 42................ ester ratio in PS- the provided test I1 [darr] 3.4%*
Inclusion criteria: BP enriched margarine. margarine. Study I2 [darr] 2.7%*
< 160/95, BMI < 30, I2 = 2 g PS/d as provided sunflower *p < 0.05
stable body wgt, age phytosterol ester, oil shortening (w/o LDL-C (mg/dL)
18-65 y, Total-C < 3:1 sterol/stanol added plant sterols At end of 3 wk
309 mg/dL, TG < 355 ester ratio in PS- and stanols) to C 109
mg/dL. enriched margarine. control unintended I1 102
The Netherlands....... plant sterol and I2 102
stanol intake LDL-C % difference
compared to control
3 wk:
I1 [darr] 6.0%*
I2 [darr] 6.7%*
*p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Qu[iacute]lez et al., 2003 (Ref. Randomized double- Healthy subjects, 61 2 test bakery Habitual diets with Total-C (mg/dL)
93). blind, placebo- enrolled, 57 competed products/d (1 test foods replacing Baseline:
controlled, parallel Mean age muffin, 1 croissant) usual bakery product C 162
trial; 2 groups, 8 wk sd. eaten at any time of consumption I 167
test period 30.9 7.2 day Total-C % change
y (C). C = bakery products w/ compared to control:
31.0 6.7 o added PS. I [darr] 8.9% (p <
y (I). I = 3.2 g PS/d as soy 0.001)
n = 29 (C)............ sterol esters; Total-C (mg/dL)
n = 28 (I)............ divided between PS- Baseline:
Inclusion criteria: enriched croissant C 93
BMI < 40, no RX or and muffin. I 97
diet that affect Total-C % change
blood lipids, total-C compared to control:
< 240 mg/dL, global I [darr] 14.6% (p <
CV risk < 20% (Eur 0.001)
Soc for
Atherosclerosis
criteria), TG < 200
mg/dL, consumers of
bakery products.
Spain.................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Seki et al., 2003 (Ref. 54)........ Randomized double- Healthy mildly 3 slices test bread/d Habitual diets; diets Total-C (mg/dL)
blind, parallel trial hypercholesterolemic C = bread made with assessed with three Baseline:
with 2 groups; 2-wk males veg oil w/o added PS. 3-d diet records C 190
run-in period 61 enrolled, 60 I = 0.45 g PS/d as I 194
followed by 12-wk completed. plant sterol esters Total-C % change
test period Mean age in PS-enriched veg compared to control:
sd. oil baked into bread. I [darr] 3%
39.4 1.4 LDL-C (mg/dL)
y. Baseline:
n = 28 (C)............ C 115
n = 32 (I)............ I 116
Inclusion criteria: LDL-C % change
healthy; total-C < compared to control:
280 mg/dL, TG < 400 I [darr] 2.1%
mg/dL. No significant
Japan................. treatment effects
--------------------------------------------------------------------------------------------------------------------------------------------------------
Spilburg et al., 2003 (Ref. 27).... Randomized double- Moderately Powdered lemonade- American Heart Total-C (mg/dL)
blind, parallel hypercholesterolemic flavored fat-free Association Step I Baseline:
trial, with 6-wk run- adults test beverage, 3 diet; diet C 200
in period followed by 26 randomized, 24 servings/d counseling to I 224
4-wk test period completed. P = beverage w/added maintain weight if % change compared to
Mean age lecithin, w/o added needed control: I [darr]
sd. PS. 10.1% (p < 0.05)
50.6 10 y I = 1.9 g PS/d as LDL-C (mg/dL)
Inclusion criteria: lecithin emulsified C 128
LDL-C 80-210 mg/dL, soy nonesterified I 148
TG < 300; no illness; stanol in PS- % change compared to
no RX except for oral enriched beverage. control: I [darr]
contraceptives, 14.3% (p < 0.05)
hormone replacement,
anti-hypertensives,
anti-depressants &
analgesics.
USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76561]]
De Graaf et al., 2002 (Ref. 32).... Randomized double- Mildly 3 servings/d of test Self-selected Step I Total-C (mg/dL)
blind, parallel hypercholesterolemic chocolate/d (10.5 g diet; supplemented w/ C 257
trial; 4 wk run-in adults each), eaten with three servings/d of I 261
period; 4-wk test 70 randomized, 62 meals chocolate Total-C% change
period completed. C = chocolate w/o compared to control:
Mean age.............. added PS. I [darr] 6.4% (p <
57.8 y (C)............ I = 1.8 g PS/day as 0.05)
56.2 y (I)............ nonesterified tall LDL-C (mg/dL)
n = 31/group.......... oil sterols/stanols C 177
Inclusion criteria: in PS-enriched I 182
age 21-75 y; total-C chocolate. LDL-C% change
213-310 mg/dL, LDL-C compared to control:
>=135 mg/dL; TG < 354 I [darr] 11.1 (p <
mg/dL; BMI < 35. 0.05)
The Netherlands.......
--------------------------------------------------------------------------------------------------------------------------------------------------------
Geelen et al., 2002 (Ref. 94)...... Randomized double- Healthy adults with One tub (35 g) test Habitual diets; Total-C (mg/dL)
blind, crossover known apolipoprotein margarine/d consumed random 24-h recall Baseline:
trial, with 2 E phenotype 31 ApoE4 in place of usual diet surveys E3/4 & E4/4 201
consecutive 3-wk test subjects; 57 ApoE3 margarine conducted during E3/3 178
periods subjects n = 88; Mean C = margarine w/o test Total-C% change
age 25.4 y added PS. compared to control:
Inclusion criteria: I = 3.2 g PS/d as I [darr] 7% (p <
age >=18 y; no vegetable oil sterol 0.05)
prescribed diets; no esters in PS- LDL-C% change
lipid-lowering RX; enriched margarine. compared to control:
total-C <=310 mg/dL; I [darr] 11%
TG < 266 mg/dL. (P<0.05)
The Netherlands.......
--------------------------------------------------------------------------------------------------------------------------------------------------------
Judd et al., 2002 (Ref. 95)........ Randomized double- Healthy adults, normal Two servings/d of Typical American Type of salad
blind, crossover or slightly elevated test salad dressing diet; Controlled dressing did not
trial; two total-C (Ranch or Italian), diet provided by affect plasma lipids
consecutive 3-wk 58 enrolled, 53 eaten w/meals study and eaten on so data was combined
intervention periods, completed. C1 = Ranch dressing w/ site Total-C (mg/dL)
no wash out Mean age o added PS. baseline: 214
sd. I1 = 2.2 g PS/d as Total-C% change
47.1 1.5 soy sterol esters in compared to control:
y. PS-enriched Ranch I [darr] 7.0% (p <
n = 53................ dressing. 0.0001)
Inclusion criteria: C2 = Italian dressing LDL-C (mg/dL)
age 25-65 y; HDL >25 w/o added PS. Baseline: 141
mg/dl (men) or >35 mg/ I2 = 2.2 g PS/d as LDL-C% change
dL (women), TG < 300 soy sterol esters in compared to control:
mg/dL. PS-enriched Italian I [darr] 9.2% (p <
USA................... dressing. 0.0001)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Matvienko et al, 2002 (Ref. 60).... Randomized double- Hypercholesterolemic One serving/d (112 g) Habitual diets w/ Total-C (mg/dL)
blind, placebo- white males. 50% of of cooked lean limits on eggs (2-3 Baseline:
controlled, parallel subjects w/family HX ground beef eaten at eggs/wk), and no red C 224
trial; single 4-wk of premature CVD & lunch meat other than that I 228
test period hyperlipidemia C = ground beef...... in the test meal. Total-C% change
36 enrolled, 34 w/o added PS........ Diets assessed by compared to control:
completed. I = 2.7 g PS/d as soy interviewer I [darr] 8.4% (p <
Mean age sterols, partially administered 0.001)
sd. esterified, in PS- questionnaires LDL-C (mg/dL)
22.23.9 y enriched beef. Baseline:
(C). C 153
23.63.9 y I 159
(I). LDL-C% change
n = 17/group.......... compared to control:
Inclusion criteria: I [darr] 13.3% (p <
total-C >197 mg/dL, 0.001)
LDL-total-C >130 mg/
dL.
USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Mensink et al., 2002 (Ref. 86)..... Randomized double- Mildly 3 servings/d of test Habitual diets Total-C (mg/dL)
blind, placebo- hypercholesterolemic yogurt, eaten w/ supplemented with 3 Baseline:
controlled, parallel adults meals servings/day test C 184
trial; 3-wk run-in 69 randomized, 60 C = yogurt w/o added yogurt. Low erucic I 193
followed by 4-wk test completed. PS. acid rapeseed oil % change compared to
period Mean age I = 3 g PS/d as plant margarine and control: I [darr]
sd. stanol esters in PS- shortening provided 8.7% (p < 0.001)
36 14 y.. enriched yogurt. to standardize fatty LDL-C (mg/dL)
n = 30/group.......... acid intake. Diet Baseline:
Inclusion criteria: no questionnaires to C 111
diets that affects assess diet I 113
lipids, no CAD HX, % change compared to
BMI < 30, total-C < control: I [darr]
251 mg/dL. 13.7% (p < 0.001)
The Netherlands.......
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76562]]
Mussner et al., 2002 (Ref. 96)..... Randomized double- Mildly Two servings/d (10 g Habitual diets; 3-day Total-C (mg/dL)
blind, crossover hypercholesterolemic each) of test dietary recalls (at Baseline: 233
trial, with 2 adults margarine, consumed beginning and end of Total-C% change
consecutive 3-wk test 63 enrolled, 62 in morning and study) to assess compared to control:
periods completed. evening, replacing diets I [darr] 3.8% (p <
Mean age usual margarine 0.05)
sd. C = margarine w/o LDL-C (mg/dL)
42 11 y.. added PS. Baseline: 152
n = 62................ I = 1.82 g PS/d as LDL-C% change
Inclusion criteria: plant sterol esters compared to control:
BMI < 30, total-C 200- in PS-enriched I [darr] 6.5% (p <
300 mg/dL, LDL-C 130- margarine. 0.05)
200 mg/dL; TG < 160
mg/dL.
Germany...............
--------------------------------------------------------------------------------------------------------------------------------------------------------
Noakes et al., 2002 (Ref. 41)...... Randomized double- Hypercholesterolemic 3 servings/d of Usual low saturated Total-C (mg/dL) After
blind, crossover adults reduced fat test fat diet; w/>=5 3-wk intervention:
trial; three 52 enrolled, 46 spread replacing servings/d of fruit C 244
consecutive 3-wk test completed. usual margarine, and vegetables, >=1 I1 229
periods, no washout Mean age consumed w/meals of which was high in I2 226
period; 1-wk run-in sd. C = spread w/o added carotenoids Total-C% change
Study 1............... 55 9.7 y PS. compared to control:
M. I1 = 2.3 g PS/d as I1 [darr] 6.0%*
58 7.3 y plant sterol esters I2 [darr] 7.3%*
F. in PS-enriched *p < 0.001
n = 46................ spread. LDL-C (mg/dL) After 3-
Inclusion criteria: I2 = 2.5 g PS/d as wk intervention:
age 20-75 y; BMI < plant stanol esters C 166
31, no RX that affect in PS-enriched I1 153
lipids, total-C 209- spread. I2 150
329 mg/dL, TG < 400 LDL-C% change
mg/dL. compared to control:
The Netherlands....... I1 [darr] 7.7%*
I2 [darr] 9.5%*
*p < 0.001
No significant
difference between
I1 and I2
--------------------------------------------------------------------------------------------------------------------------------------------------------
Randomized double- Hypercholesterolemic 3 servings/d of Diet same as in Study Total-C (mg/dL) After
blind, crossover adults reduced fat test 1 3-wk intervention:
trial; two 40 enrolled, 35 spread replacing C 233
consecutive 3-wk test completed. usual margarine, I3 218
periods, no washout n = 35................ consumed w/meals Total-C% change
period; 1-wk run-in Inclusion criteria: C = spread w/o added compared to control:
Study 2............... BMI < 31, no RX that PS. I3 [darr] 6.6%*
affect lipids, total- I3 = 2 g PS/d as LDL-C (mg/dL) After 3-
C 209-329 mg/dL, TG < plant sterol esters wk intervention:
400 mg/dL. in PS-enriched C 161
The Netherlands....... spread. I3 145
LDL-C% change
compared to control:
I3 [darr] 9.6%*
*p < 0.001
--------------------------------------------------------------------------------------------------------------------------------------------------------
Ntanios et al., 2002 (Ref. 97)..... Double-blind, placebo- Healthy adult Two servings/d low- Habitual Japanese Total-C (mg/dL) After
controlled, crossover Japanese, 53 fat test spread diet. Diets assessed 3 wks of
trial. 1-wk run-in; enrolled, 53 consumed w/meals with food frequency intervention:
Two consecutive 3-wk completed C = spread w/o added questionnaire during C 213
test periods w/o wash- Mean age PS. run-in period I 201
out period sd. I = 1.8 g PS/d as Total-C% change
45.1 10.4 plant sterol esters compared to control:
y. in PS-enriched I [darr] 5.8% (p <
n = 53................ spread. 0.01)
Inclusion criteria: LDL-C (mg/dL) After 3
age 24-67 y; BMI 19- wks of intervention
30, healthy, normal C 119
diet, no HX of CVD or I 109
[uarr] total-C. LDL-C% change
Japan................. compared to control:
I [darr] 9.1% (p <
0.001)
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76563]]
Simons et al., 2002 (Ref. 98)...... Multicenter, Hypercholesterolemic Two servings/d of American Heart Total-C (mg/dL)
randomized double- adults, some using test margarine, Association Step I Baseline:
blind, placebo- statin drugs consumed w/meals. diet; closely I1 295
controlled, parallel 154 enrolled, 152 Drug intervention: supervised by a I2 297
2 X 2 factorial trial completed. 400 [mu]g/day nutritionist I3 282
with 4-wk test period Mean age cerivastatin, or I4 298
sd. placebo tablet Total-C% change at 4
60 9 y I1 = tablet + wk relative to
(I1). margarine. baseline:
58 10 y I2 = placebo tablet + I1 [uarr]2.2%
(I2). 2 g PS/d as plant I2 [darr] 5.3%
58 11 y sterol esters in PS- I3 [darr] 23.2%
(I3). enriched margarine. I4 [darr] 28.9%
62 11 y I3 = statin + placebo Main effect of PS-
(I4). margarine. enriched margarine:
n = 37-29/group....... I4 = statin + 2 g PS/ [darr] 6.7% (p <
Inclusion criteria: d as plant sterol 0.0001)
LDL-C >=97 mg/dL, TG esters in PS- LDL-C (mg/dL)
< 400 mg/dL, age >18 enriched margarine. Baseline:
y. I1 210
Australia............. I2 209
I3 195
I4 209
LDL-C% change at 4 wk
compared to
baseline:
I1 [uarr]2%
I2 [darr] 8.2%
I3 [darr] 32.4%
I4 [darr] 38.5%
Main effect of PS-
enriched margarine:
[darr] 8.1% (p <
0.0001)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Tammi et al., 2002 (Ref. 99)....... Randomized double- Healthy children (age 20 g/d test margarine Continuation of STRIP Total-C (mg/dL)
blind, crossover 6 y) enrolled in replaced similar study diet (low sat Baseline:
trial, with two 3 Finnish STRIP* study amount of usual fat, low 158 (boys)
month test periods 81 enrolled, 79 dietary fat cholesterol) that 176 (girls)
separated by a 6-wk completed. C = margarine w/o the subjects had Total-C% change at 3-
wash out period n = 35 F.............. added PS. followed for several mo compared to
n = 44 M.............. I = 1.6 g PS/d as years control
*Special Turku plant stanol esters Iboys [darr] 6.4%*
Coronary Risk Factor in PS-enriched Igirls [darr] 4.4%*
Project; subjects margarine. *p < 0.05
enrolled as infants; LDL-C (mg/dL)
study diet aim was Baseline:
1:1:1 ratio of 98 (boys)
PUFA:MUFA:sat fats, 123 (girls)
cholesterol < 200 mg/ LDL-C% change at 3-mo
d. compared to control:
Iboys [darr] 9.1%*
Igirls [darr] 5.8%*
*p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Temme et al., 2002 (Ref. 100)...... Randomized double- Healthy adults, 42 3 portions/d of test Habitual diet........ Total-C (mg/dL) After
blind, crossover enrolled, 42 margarine eaten w/ 4 wk test period:
trial; no run-in completed meals replaced C 248
period; two Mean age habitual margarine I 231
consecutive 4-wk test sd. use Total-C% change
periods 55 9 y... C = spread w/o added compared to control:
n = 42................ PS. I [darr] 6.9%*
Inclusion criteria: I = 2.1 g PS/d as LDL-C (mg/dL) After 4
BMI < 30, no RX or plant sterol esters wk test period:
prescribed diet that in PS-enriched C 166
affect lipids. spread. I 150
Report states 70% of LDL-C % change
Belgium adult compared to control:
population is mildly I [darr] 9.6%*
hypercholesterolemic. *p < 0.05
Belgium...............
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76564]]
Vanstone et al., 2002 (Ref. 22).... Randomized double- Primary familial 3 portions/d test Controlled feeding of Total-C (mg/dL) At
blind, crossover hyperlipidemia adults butter eaten w/meals typical American end of 3 wk test
trial; no run-in 16 enrolled, 15 C = butter w/ diet, all food and period:
period; four 3-wk completed. cornstarch added to beverage prepared/ C 238
controlled test Mean age mimic appearance of provided by study, 2 I1 214
periods separated by sd. PS-enriched butter. or more meals/d I2 215
4-wk washout periods 47.8 1.9 I1 =1.8 g PS/d as eaten onsite I3 216
y. nonesterified soy Total-C % change
n = 15................ sterols in PS- compared to control:
Inclusion criteria: enriched butter. I1 [darr] 7.8%*
age 35-58 y; Total-C I2 = 1.8 g PS/d as I2 [darr] 11.9%*
201-348 mg/dL, and TG nonesterified soy I3 [darr] 13.1%*
< 310 mg/dL. stanols in PS- LDL-C (mg/dL) At end
Canada................ enriched butter. of three wk test
I3 = 1.8 g PS/d as 50/ period:
50 mix of C 155
nonesterified soy I1 139
sterols/stanols in I2 139
PS-enriched butter. I3 137
LDL-C % change at 3
wk relative to
placebo:
I1[darr]11.3*
I2[darr]13.4*
I3[darr]16.0*
*p < 0.05
No significant
difference between
I1, I2 and I3
--------------------------------------------------------------------------------------------------------------------------------------------------------
Christiansen et al., 2001 (Ref. 24) Randomized double- Hypercholesterolemic 2 servings/d of test Habitual Finnish Total-C (mg/dL)
blind, parallel adults spread (rapeseed oil diet; 7-day food Baseline: 257
design; three arm, 6- 155 enrolled, 134 margarine) in place diaries ``were kept Total-C % change
wk run-in, 6-month completed. of usual dietary fat by half of compared to control:
test period Mean age 50.7 y....... C = spread w/o added subjects.'' I1 [darr] 9%*
n = about 45/group.... PS. I2 [darr] 8.3%*
Inclusion criteria: I1 = 1.5g PS/d as *p=0.001
total-C >= 227 mg/dL, microcrystalline LDL-C (mg/dL)
TG < 266 mg/dL. wood-derived (tall Baseline: 166
Finland............... oil) nonesterified LDL-C % change
sterol/stanols in PS- compared to control:
enriched spread. I1 [darr] 11.3%*
I2 = 3 g PS/d as I2 [darr] 10.6%*
microcrystalline *p=0.002
wood-derived (tall
oil) nonesterified
sterol/stanols in PS-
enriched spread.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Davidson et al., 2001 (Ref. 55).... Randomized double- Healthy adults 2 servings/d of Habitual diet Total-C (mg/dL)
blind, parallel 84 randomized 77 reduced- fat test supplemented w/3 Baseline: 205
trial; four arm, 8-wk completed. spread, and 1 servings/d of test Total-C % change
test period Mean Age 46 y......... serving/d of reduced- foods. 3-day diet compared to control:
n = 19 (C)............ fat test salad records collected at I1 [darr] 3.9%
n = 19 (I1)........... dressing wk 0, 4, and 8 I2 [darr] 0.9%
n = 18 (I2)........... C = spread + salad I3 [darr] 4.6%
n = 21 (I3)........... dressing. LDL-C (mg/dL)
Inclusion criteria: I1 = 3 g PS/d as Baseline: 130
total-C < 300 mg/dL, sterol esters in PS- LDL-C % change
TG < 350 mg/dL, BMI < enriched spread; compared to control:
35. placebo salad C [darr] 1.3%
USA................... dressing. I1 [darr] 3.7%
I2 = 6 g PS/d as I2 [darr] 1.5%
sterol esters in PS- I3 [darr] 7.7%
enriched salad No significant
dressing; placebo treatment effects on
spread. total-C or LDL-C
I3 = 9 g PS/d as
sterol esters in PS-
enriched spread + PS-
enriched salad
dressing.
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76565]]
Maki et al., 2001 (Ref. 101)....... Randomized double- Hypercholesterolemic 2 servings/d of National Cholesterol Total-C (mg/dL)
blind, placebo- adults reduced-fat test Education Program Baseline: 238
controlled, parallel 224 enrolled, 192 spread eaten w/meals Step I, supplemented Total-C % change
trial, 4-wk run-in; 5- included in analysis. C = spread with w/o w/reduced-fat test compared to control:
wk test period n = 83 (C)............ added PS. spread I1 [darr] 5.2%*
n = 75 (I1)........... I1 = 1.1 g PS/d as I2 - 6.6%*
n = 35 (I2)........... soy sterol esters in *p < 0.001
Mean age PS-enriched spread. LDL-C (mg/dL)
sd. I2 = 2.2 g PS/d as Baseline: 158
57.5 10.8 soy sterol esters in LDL-C % change
y (C). PS-enriched spread. compared to control:
58.7 10.6 I1 [darr] 7.6%*
y (I1). I2 [darr] 8.1%*
60.4 9.7 *p < 0.001
y (I2).
Inclusion criteria: no
RX that affect
lipids, BMI < 35, LDL-
C 130-200 mg/dL, TG <
350 mg/dL, BMI < 35.
USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nestel et al., 2001 (Ref. 35)...... Randomized single- Hypercholesterolemic 3 servings/d of test Habitual low sat fat, Median Total-C (mg/
blinded, crossover adults foods (low-fat wheat low cholesterol diet dL) at 4 wk:
trial; 2-wk run-in, 22 enrolled, 22 cereal, low-fat prescribed for C 271
three 4-wk test completed. bread, spread), one cholesterol control; I1 247*
periods w/o wash-out Mean age serving eaten w/each diet assessed by 3- I2 261*
period sd. meal day FFQ during run- *p < 0.001 compared
Study 1............... 60 9 y... C = test foods, w/o in phase to control
n = 22................ added phytosterols. Median LDL-C (mg/dL)
Inclusion criteria: I1 = 2.4 g PS/d as at 4 wk:
Total-C >213 mg/dL, soy sterol esters in C 184
TG < 266 mg/dL. PS-enriched foods. I1 159*
Australia............. I2 = 2.4 g PS/d as I2 169*
nonesterified soy *p < 0.05 compared to
stanols in PS- control
enriched foods. I1 significantly
lower than I2
--------------------------------------------------------------------------------------------------------------------------------------------------------
Randomized single- Hypercholesterolemic 1 serving/d of test Habitual low sat fat, Total-C (mg/dL)
blinded, crossover adults (all Study 1 dairy spread (butter low cholesterol diet Baseline: 257
trial; 2-wk run-in participants) + margarine blend) prescribed for Total-C % change
followed by two 4-wk 15 enrolled, 15 eaten w/a meal cholesterol control compared to control:
test periods w/o wash- completed. C = spread w/o added I3 [darr] 9.8%*
out period Australia............. PS. *p < 0.001
Study 2............... I3 = 2.4 g PS/d as LDL-C (mg/dL)
soy sterol esters in Baseline: 178
PS-enriched dairy LDL-C % change
spread. compared to control:
I3 [darr] 13.0%*
*p = 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Tikkanen 2001 (Ref. 25)............ Double-blind, placebo- Hypercholesterolemic 3 servings/d of test Subjects received Total-C (mg/dL)
controlled, parallel adults foods/d (bread, individual dietary Baseline:
trial, two arms; 2-wk 78 enrolled, 71 meat, jam) advice and kept 3-d C 253
run-in period w/ completed. C = test foods w/o food diaries 5 times I 263
placebo foods, 3 Mean age added PS. during the study Total-C % change
consecutive 5-wk sd. I=1.25 g PS/d for 5 compared to control:
periods. PS dose 54 11 y wk, then 2.5 g PS/d I wk5 [darr] 4.4%
doubled w/each (C). for wks 6-10, then 5 I wk10 [darr] 6.2%
successive test 57 8 y g PS/d for wks 11- I wk15 [darr] 5.5%
period (I). 15. PS as Significant
n = 35 (C)............ nonesterified wood- difference between P
n = 36 (I)............ derived sterol/ and I by repeated
Inclusion criteria: stanol mixture in PS- measures ANOVA p <
age 25-75 y; no enriched bread, 0.05
familial [uarr]total- meats, and jam. LDL-C (mg/dL)
C, no HX of CAD Baseline:
previous 3 mos, no HX C 166
of revascularization I 173
previous 4 mo, no RX LDL-C % change
that affect lipids, compared to control:
total-C 232-310 mg/ I wk5 [darr] 5.4%
dL; TG < 355 mg/dL. I wk10 [darr] 7.9%
Finland............... I wk15 [darr] 8.9%
Significant
difference between C
and I by repeated
measures ANOVA p <
0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76566]]
Blair et al., 2000 (Ref. 102)...... Randomized double- Hypercholesterolemic 3 servings/d of test Habitual diet. Diets Total-C (mg/dL)
blind, placebo- adults on statin RX margarine in place assessed by 24-hr Baseline: 231
controlled, parallel 167 randomized, 141 of usual margarine recalls Total-C % change
trial, two arms; 8-wk completed. consumptions compared to control:
test period with Mean age C = margarine w/o I [darr] 7% (p <
additional 6-wk sd. added PS. 0.0001)
follow-up 56 10 y.. I = 3.0g PS/d as LDL-C (mg/dL)
n = 72 (C)............ stanol esters in PS- Baseline: 147
n = 69 (I)............ enriched margarine. LDL-C % change
Inclusion criteria: compared to control:
age >=20 y; LDL-C I [darr] 9.6% (p <
>=130 mg/dL, TG <=350 0.0001)
mg/dL, stable statin
dose for >90d.
USA...................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Hallikainen et al., 2000B (Ref. 39) Randomized double- Mildly 2-3 portions/d of Step I diet. Diet was Total-C (mg/dL) At
blind, crossover hypercholesterolemic test margarines assessed with 4-day end of 4 wk:
trial; 2-wk run-in adults eaten with meals food records at the C 236
period; three 42 enrolled, 34 C = margarine w/o end of each period I1 213
consecutive 4-wk test completed. added PS. I2 218
periods Mean age I1 = 2 g PS/d as Total-C % change
sd. plant stanol ester compared to control:
48.8 8.1 in PS-enriched I1 [darr] 9.2%*
y. margarine. I2 [darr] 7.3%*
n = 34................ I2 = 2 g PS/d as *p < 0.001
Inclusion criteria: plant sterol ester LDL-C (mg/dL) At end
age 30-65 y, Total-C in PS-enriched of 4 wk:
186-271 mg/dL, TG < margarine. C 162
220 mg/dL. I1 141
Finland............... I2 145
LDL-C % change
compared to control:
I1 [darr] 12.7%*
I2 [darr] 10.4%*
*p < 0.001
I1 and I2 not
significantly
different
--------------------------------------------------------------------------------------------------------------------------------------------------------
Hallikainen et al., 2000a (Ref. 53) Randomized single- Hypercholsterolemic 2-3 portions of test Subjects consumed a Total-C (mg/dL)
blind crossover adults margarine w/meals standardized Baseline:
trial; 1-wk run-in 22 entolled, 22 C = margarine w/out background diet 266 50
period, five 3-wk completed. added PS. mg/dL0
test periods Mean age 50.5 11.7. plant stanol esters. compared to control:
n = 22................ I2 = 1.6 g/d PS/d as I1 [darr] 2.8%
Inclusion criteria: plant stanol esters. I2 [darr] 6.8%*
Total-C 194-329 mg/dL. I3 = 2.4 g PS/d as I3 [darr] 10.3%*
Finland............... plant stanol esters. I4 [darr] 11.3%*
I4 = 3.2 g PD/d as LDL-C % change
plant stanol esters. compared to control:
I1 [darr] 1.7%
I2 [darr] 5.6%
I3 [darr] 9.7%*
I4 [darr] 10.4%*
*p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jones et al., 2000 (Ref. 40)....... Randomized double- Hyperlipidemic males 3 servings/d of test Controlled diet Total-C (mg/dL)
blind, crossover 18 enrolled, 15 margarine, eaten formulated to meet Baseline:
trial; no run-in included in analyses. with meals Canadian Recommended C 250
period; three 3-wk n = 15................ C = margarine w/o Nutrient Intakes. I1 247
controlled feeding Inclusion criteria: added PS. All food and I2 246
test periods Age 37-61 y; Total-C I1 = 1.84 g PS/d as beverage prepared/ Total-C % change
separated by 5-wk 232-387 mg/dL, TG < plant sterol esters provided by study; compared to control:
washout periods 266 mg/dL. in PS-enriched at least 2 meals/d I1 [darr] 9.1%*
Canada................ margarine. eaten onsite I2 [darr] 5.5%
I2 = 1.84 g PS/d as *p < 0.02
plant stanol esters LDL-C (mg/dL)
in PS-enriched Baseline:
margarine. C 172
I1 166
I2 168
LDL-C % change
compared to control:
I1 [darr] 13.2%*
I2 [darr] 6.4%* *
*p < 0.02
I1 significantly
lower than I2
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76567]]
Plat et al. 2000 (Ref. 87)......... Randomized double- Healthy, normal or One serving/d of test Habitual diets Total-C (mg/dL)
blind, placebo- mildly margarine and 3 supplemented w/test At end of 4 wk:
controlled, crossover hypercholesterolemic servings/d of test margarine and test C 194
trial. Three subjects shortening (in cookies/cake. PS- I1 182
consecutive 4-wk test 40 enrolled, 39 cookies/cakes) with free shortening was I2 181
periods, no washout completed. each meals provided to subjects Total-C % change
periods Mean age C = margarine & for baking and compared to control:
sd. shortening w/o added cooking I1 [darr] 6.4%*
31 14 y.. PS. I2 [darr] 6.6%*
n = 39................ I1 = 2.5 g PS/d as *p < 0.001
Inclusion criteria: stanol ester in PS- LDL-C (mg/dL) At end
age 18-65 y; Total-C enriched margarine of 4 wk
< 250 mg/dL; TG < eaten w/lunch. C 118
266; BMI < 30, BP < I2 = 2.5 g PS/d as I1 106
160/95, no RX or diet stanol ester in PS- I2 106
that affect lipids, enriched margarine LDL-C % change
no HX of CVD. and PS-enriched compared to control:
The Netherlands....... shortening divided I1 [darr] 9.9%*
over 3 servings w/ I2 [darr] 10.2%*
meals. *p < 0.001
--------------------------------------------------------------------------------------------------------------------------------------------------------
Vissers et al., 2000 (Ref. 36)..... Double-blind, Normal adults Test margarine, Habitual diets. Diet Total-C (mg/dL) At
crossover trial; no 60 enrolled, 60 divided over assessed each period end of 3 wks:
run-in period; three completed. multiple portions, with 24-h diet C 164
consecutive 3-wk test age range=18-59 y..... eaten with meals in recall I1 157
periods n = 60................ place of usual I2 162
Inclusion criteria: margarine Total-C % change
age >17 y; no RX or C = margarine without compared to control:
prescribed diet that added PS. I1 [darr] 4.5%*
affect lipids, Total- I1 = 2.1 g PS/d as I2 [darr] 1.2%
C < 290 mg/dL, TG < rice bran *p < 0.05
204 mg/dL. nonesterified oil LDL-C (mg/dL) At end
The Netherlands....... sterols in PS- of 3 wks:
enriched margarine C 91
(~1 g/d of 4- I1 84
desmethylsterols). I2 89
I2 = sheanut oil LDL-C % change
triterpenes in compared to control:
margarine. I1 [darr] 8.5%*
I2 [darr] 3.0%
*p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Andersson et al., 1999 (Ref. 103).. Randomized double Moderately 25 g/d margarine Consumed a test diet. Total-C % change
blind controlled hypercholesterolemic provided as 3 single compared to baseline
parallel trial; 4-wk adults servings C [darr] 8.0%
run-in period, three Age sd... C = margarine w/o I1 [darr] 15%*
8-wk test periods 55.1 7.9 added PS. *p = 0.0035
y. I1 = 2 g PS/d as LDL-C % change
n = 21 (C)............ plant stanol esters compared to baseline
n = 19 (I)............ in PS-enriched C [darr] 12%
Inclusion criteria: margarine. I1 [darr] 19%*
Total-C < 330 mg/dL, *p = 0.0158
BMI >30.
Sweden................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Ayesh et al., 1999 (Ref. 104)...... Randomized placebo- Healthy adults 40 g/d margarine Typical British diet, Total-C % change
controlled parallel 24 enrolled, 21 consumed at breakfast and dinner compared to control:
trial; 21 to 28 d run- completed. breakfast and dinner consumed under I [darr] 18%*
in, 21-28 d test Age 30-40 y........... C = margarine w/o supervision LDL-C % change
period n = 11 (C)............ added PS. compared to control:
n =10 (I)............. I = 8.6 g PS/d as I [darr] 23%*
Inclusion criteria: plant sterol esters *p < 0.0001
Total-C 158-255 mg/dL. in PS-enriched
United Kingdom........ margarine.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Gylling and Miettinen, 1999 (Ref. Randomized double- Moderately 25 g/d butter Subjects were advised Total-C % change
105). blind crossover hypercholesterolemic, C = butter w/out to replace 25 g of compared to control:
trial; 1-wk run-in postmenopausal women; added PS. their normal dietary I [darr] 8%*
period; two 5 wk test 24 enrolled I = 2.4 g PS/d as fat with butter LDL-C % change
periods Age 50-55 y........... wood sitostanol compared to control:
n = 21 butter period.. ester in PS-enriched I [darr] 12%*
Inclusion criteria: butter. *p < 0.05
Total-C between 213
and 310 mg/dL.
Finland...............
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[[Page 76568]]
Hendriks et al., 1999 (Ref. 51).... Randomized, double- Normocholesterolemic 25 g/d butter or Habitual diets. Total-C (mg/dL)
blind, crossover and mildly spread consumed at Spreads replace an Baseline:
trial; no run-in cholesterolemic lunch or dinner equivalent amount of 197 mg/dL
period, four test adults, 100 enrolled, C1 = butter w/out spreads habitually Total-C % change
periods of 3.5 wks 80 per test period added PS. used compared to C2
Age 19-58 y........... C2 = spread w/out I1 [darr] 4.9%*
n = 80................ added PS. I2 [darr] 5.9%*
Inclusion criteria: I1 = 0.8 g PS/d as I3 [darr] 6.8%*
Total-C < 290 mg/dL. plant sterol esters LDL-C % change
The Netherlands....... in PS-enriched compared to C2
spreads. I1 [darr] 6.7%*
I2 = 1.6 g PS/d as I2 [darr] 8.5%*
plant sterol esters I3 [darr] 9.9%*
in PS-enriched *p < 0.0001
spreads.
I3 = 3.2 g PS/d as
plant sterol esters
in PS-enriched
spreads.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Jones et al., 1999 (Ref. 21)....... Randomized double- Hypercholsterolemic 30 g/d test margarine Controlled feeding Total-C (mg/dL)
blind, placebo- adults, 32 enrolled, consumed with 3 regimen; a prudent Baseline:
controlled, parallel 32 completed meals fixed North American C 263
trial with 2 groups; Age 25-60 y........... C = margarine w/o diet formulated to I 260
No run-in period; 30- n = 16 (C)............ added PS. meet Canadian LDL-C % change
d test period; 20-d n = 16 (I)............ I = 1.7 g PS/d recommended nutrient compared to control:
follow-up after test Inclusion criteria: sistostanol- intakes I [darr] 15.5% (p <
period Total-C 252-387 mg/dL. containing 0.05)
Canada................ phytosterols (20%
sitostanol,
remaining plant
sterols are
sitosterol,
campesterol) as
nonesterified tall
oil.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nguyen et al., 1999 (Ref. 106)..... Multicenter Mildly 24 g/d U.S. vegetable Usual dietary habits Total-C % change
randomized, double- hypercholesterolemic oil spread (three 8 maintained compared to control:
blind, placebo- adults g servings/d) I1 [darr] 6.4*
controlled parallel Age sd... C = U.S. vegetable I2 [darr] 4.1*
trial; 4-wk run-in 51.3 12.0 oil spread w/out *p < 0.001
period, 8-wk test to 54.5 added PS. LDL-C % change
period 11.3 y. I1 = 3 g PS/d as compared to control:
n = 76 (C)............ stanol esters in I1 [darr] 10.1*
n = 71 (I1)........... U.S. vegetable oil I2 [darr] 4.1*
n = 77 (I2)........... spread. *p < 0.02
Inclusion criteria: 20 I2 = 2 g PS/d as
y, Total-C 200 and stanol esters in
280 mg/dL. U.S. vegetable oil
USA................... spread.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Sierksma et al., 1999 (Ref. 29).... Balanced, double-blind Healthy adults, 78 25 g/d Flora spread, Habitual diets. Total-C (mg/dL)
crossover trial; 1-wk enrolled, 76 with meals Phytosterol- Baseline:
run-in, 3-wk test completed C = Flora spread w/o containing spread 310 mg/dL
period Age 18-62 y........... added PS. replaced all or part Total-C (mg/dL)
n = 75................ I1 = 0.8 g PS/d as of habitual spread C 196
Inclusion criteria: < nonesterified or butter used for I1 188*
Total-C < 309 mg/dL. sterols in PS- spreading I2 194
The Netherlands....... enriched Flora LDL-C (mg/dL)
spread. C 122
I2 = 3.3 g PS/d as I1 114*
esterified sterols I2 119
in PS-enriched Flora Total-C % change
spread. compared to control:
I1 [darr] 3.8%*
LDL-C % change
compared to control:
I1 [darr] 6.0%*
*p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Westrate and Meijer, 1998 (Ref. 31) Balanced, Randomized Normocholesterolemic 30 g/d margarine Test margarine Total-C (mg/dL)
double-blind and mildly consumed at lunch replaced margarines Baseline:
crossover trial; 5-d hypercholesterolemic and dinner habitually used 207
run-in, four test adults, 100 enrolled, C = Flora spread w/o Total-C % change
periods of 3.5 wks 95 completed added PS. compared to control:
Mean age I1 = 2.7 g PS/d as I1 [darr] 7.3%*
sd. plant stanol esters I2 [darr] 8.3%*
45 12.8 y (2.7 g/d. I3 [darr] 1.1%
n = 95................ I2 = 3.0 g PS/d as I4 [darr] 0.7%
Inclusion criteria: soybean sterol LDL-C % change
Total-C < 310 mg/dL. esters. compared to control:
The Netherlands....... I3 = 1.6 g PS/d as I1 [darr] 13%*
rice bran I2 [darr] 13%*
nonesterified I3 [darr] 1.5%
sterols. I4 [darr] 0.9%
I4 = 2.9 g PS/day as *p < 0.05
sheanut
nonesterified
sterols.
Stanol source: wood..
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76569]]
Niinikoski et al., 1997 (Ref. 107). Randomized double- Normocholesterolemic 24 g margarine Habitual diet. Total-C (mg/dL)
blind, placebo- adults, 24 enrolled consumed in 3 Replace normal Baseline:
controlled parallel Age 24-52 y........... portions dietary fat with 197
trial; no run-in n = 12 (C)............ C = margarine w/out test rapeseed oil Total C % compared to
period, 5-wk test n = 12 (I)............ added PS. margarine control
period Inclusion criteria: I = 3 g PS/day as C [darr] 11
not provided. esterified I [darr] 31*
Finland............... sitostanol. *p < 0.05
--------------------------------------------------------------------------------------------------------------------------------------------------------
Pelletier et al., 1995 (Ref. 30)... Randomized, crossover Normolipidemic men 50 g/d butter as part Controlled but normal Total-C % change
trial; 1-wk run-in, Mean age of a normal diet diet compared to control:
two test periods of 4 sd. C =butter w/out added I [darr] 10%*
wks 22.7 2.6 PS. LDL-C % change
y. I = 0.74 g PS/d as compared to control:
n = 12................ soybean I [darr] 15%*
Inclusion criteria: nonesterified *p < 0.05
light smokers and sterols.
normal physical
activity.
France................
--------------------------------------------------------------------------------------------------------------------------------------------------------
Miettinen et al., 1994 (Ref. 28)... Randomized double- Hypercholesterolemic 50 g rapeseed oil Habitual diets. Total-C % change
blind, placebo- adults, 31 enrolled mayonnaise, with Advised to replace compared to control:
controlled parallel Mean age meals 50 g of typical I1 [darr] 7.7%
trial; 6-wk run-in, 9- sd. C = mayonnaise w/out daily fat with I2 [darr] 0.4%
wk test period 45 3 y... added PS. mayonnaise I3 [darr] 7.4%*
n = 31................ I1 = 0.7 g PS/d as containing rapeseed LDL-C % change
Inclusion criteria: nonesterified oil compared to control:
Total-C >232 mg/dL. sitosterol in I1 [darr] 7.0%
Finland............... mayonnaise. I2 [darr] 1.2%
I2 = 0.7 g PS/d as I3 [darr] 7.7%*
nonesterified *p < 0.05
sitostanol in
mayonnaise.
I3 = 0.8 g PS/d as
sitostanol ester in
mayonnaise.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Blomqvist et al., 1993 Vanhanen et Randomized double- Hypercholesterolemic 50 g rapeseed oil Habitual diets. Total-C % change
al., 1993 (Ref. 108). blind placebo adults, 37 enrolled mayonnaise, with Advised to replace compared to control:
controlled parallel Mean age meals 50 g of daily fat C [darr] 2.7
trial; 4-wk run-in, 6- sd. C = mayonnaise w/out intake with 50 of I [darr] 17.0*
wk test period 43-48 2 y added PS. mayonnaise LDL-C % change
n = 33 (C)............ I = 3.4 g PS/d as containing rapeseed compared to control:
n =34 (I)............. sitosterol ester in oil C [darr] 1.5
Inclusion criteria: mayonniase. I [darr] 14.3*
Total-C >232 mg/dL. *p < 0.051
Finland...............
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Weight represents nonesterified sterols or stanols.
Table 2--Randomized Clinical Trials of Phytosterols in Supplements and Total and LDL Cholesterol Concentration
--------------------------------------------------------------------------------------------------------------------------------------------------------
Study Design Population Intervention Diet Results
--------------------------------------------------------------------------------------------------------------------------------------------------------
Nonesterified Phytosterols
--------------------------------------------------------------------------------------------------------------------------------------------------------
Denke 1995 (Ref. 65)............... Non-random, non- Moderately (1) Gelatin capsules Step I diet (control) Total-C (mg/dL)
blinded, 3 sequential hypercholesterolemic containing tall oil during intervention Baseline: 239
3-mos trial periods males. sitostanol suspended and washout periods. Total-C % change
separated by 3-mos 33 enrolled, 33 in safflower oil; 3 compared to Step I
washout periods. completed. doses/d of 4 diet:
Age range 31-70 y..... capsules (total 12 I[ihel1] [darr] 0.5%
Subjects' capsules/d) taken I[ihel2] [darr] 7.1%*
characteristics: mean with meals. (2) I[ihel3] [darr] 8.9%*
LDL-C with Step I Cholestyramine LDL-C (mg/dL)
diet 175 mg/dL, TG < supplied in flavored Baseline: 175
250 mg/dL, mean BMI bars. LDL-C % change from
26.2. I[ihel1] = 3 g/d Sep 1 diet:
USA................... sitostanol\1\. I[ihel1] [darr] 1.8%
I[ihel2] = I[ihel2] [darr]
cholestyramine. 12.6%*
I[ihel3] = sitostanol I[ihel3] [darr]
+ cholestyramine. 14.8%*
*p < 0.001 compared
to preceding and
subsequent washout
periods.
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76570]]
McPherson et al., 2005 (Ref. 66)... Randomized, double Healthy adults 52 Dietary supplement of AHA heart healthy Total-C (mg/dL)
blind, placebo- enrolled, 52 rapidly diet. Baseline:
controlled, parallel completed. disintegrating CT 195
design; four arms; 6- Mean age tablets or slowly IT 186
wk trial period. sd 46.5 disintegrating CC 198
8.1 y (tablets). capsules, twice/d IC 203
50.7 12.5 with meals. Total-C % change
y (capsules). CT = lecithin- compared to control:
tablet trial.......... containing tablets w/ IT [darr] 4.8%
n = 13 (IT)........... o PS. IC [darr] 1.9%
n = 12 (PT)........... CC = lecithin- No significant
n = 27 (capsule trial) containing capsules differences between
Inclusion criteria: w/o PS. IT and IC and
LDL-C 70-190 mg/dL, IT = 1.26 g PS/d as control
TG < 300 mg/dL. spray-dried plant LDL-C (mg/dL)
USA................... stanol/lecithin Baseline:
emulsion in tablets. CT 121
IC = 1.26 g PS/d as IT 117
spray-dried plant CC 123
stanol/lecithin IC 235
emulsion in gelatin LDL-C % change
capsules. relative to placebo:
IT [darr] 10.4%*
IC [darr] 2.5%
* p < 0.05 compared
to placebo
--------------------------------------------------------------------------------------------------------------------------------------------------------
Goldberg et al., 2006 (Ref. 67).... Randomized double- Hyperlipidemic adults Soy stanols as a American Heart Total-C (mg/dL)
blind, placebo- taking statins 26 tableted stanol/ Association Heart Baseline:
controlled, parallel enrolled, 26 lecithin emulsion. Healthy Diet. C 197
trial, 1-wk run-in, 6- completed.. 225 mg PS/tablet; 4 I 193
wk test period. age range 40-78 y..... tablets twice a day Total-C % change
n = 13/group.......... before meals. Starch compared to control:
Inclusion criteria: replaced stanol/ I [darr] 5.7% (p <
Stable statin dose, lecithin complex in 0.05)
LDL-C >100 mg/dL, TG placebo tablets. LDL-C (mg/dL)
< 300 mg/dL. C = placebo tablet... Baseline:
USA................... I = 1.8 g PS/d as C 119
stanol/lecithin I 112
emulsion in tablets. LDL-C % change
compared to placebo:
I [darr] 9.1% (p <
0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Esterified Phytosterols
--------------------------------------------------------------------------------------------------------------------------------------------------------
Woodgate et al., 2006 (Ref. 64).... Randomized, double- Hyperchoelsterolemic Total of 6 softgel Habitual diets Total-C (mg/dL)
blind, placebo- adults, 30 enrolled, (glyceron) capsules Baseline:
controlled trial with 29 completed. with breakfast and C 266
2 groups; 4-wk test Age 33-70 y........... dinner. I 267
period. Inclusion criteria: no C = corn oil......... Total-C % change
diabetes, no I = 1.6 g PS/d as compared to control
cholesterol lowering stanol esters. I [darr] 8% (p <
Rx, no prior 0.05)
myocardial infarction LDL-C (mg/dL)
or heart surgery. Baseline:
C 207
I 201
LDL-C % change
compared to control
I [darr] 9% (p <
0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Acuff et al., 2007 (Ref. 62)....... Randomized, double- Hypercholesterolemic 2 dietary supplement Habitual diets, diets Total-C (mg/dL)
blind, placebo- adults, 20 enrolled, capsules/d, one not monitored. Baseline: 256
controlled, 16 completed. capsule w/lunch, After 4 wk test
sequential trial; two Mean age second capsule w/ period:
4-wk test periods sd. dinner. C 242
separated by 2-wk 51 13 y.. C = soy oil capsules. I 230
washout period. Inclusion criteria: I = 0.8 g PS/d as Total-C % change
hyperlipidemia, BMI < plant sterol esters compared to control:
30, no lipid lowering divided between 2 I [darr] 4.7% (not
RX, no diseases capsules. significant)
requiring tmt, no LDL-C (mg/dL)
hypertension. Baseline: 177
USA................... After 4 wk test
period:
C 169
I 163
LDL-C % change
compared to control:
I [darr] 3.5% (p <
0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
[[Page 76571]]
Earnest et al., 2007 (Ref. 63)..... Randomized double- Mildly 4 dietary supplement Habitual diets, diets Total-C (mg/dL)
blind, placebo- hypercholesterolemic capsules/d; 2 not monitored. Baseline:
controlled, parallel adults. capsules w/each of 2 C 232
trial with 2 groups; 54 enrolled, 54 meals. I 243
12-wk test period. completed. C = capsule w/o PS... After 4 wk test
Age 20-70 y........... I = 2.6 g PS/d as period:
Inclusion criteria: plant sterol esters C 237
LDL-C >=130 mg/dL. divided among 4 I 234
USA................... capsules. Total-C % change
compared to control:
I [darr] 6.0% (p <
0.05)
LDL-C (mg/dL)
Baseline:
P 155
I 165
After 4 wk test
period:
P 161
I 157
LDL-C % change
compared to control:
I [darr] 9.2% (p <
0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Rader and Nguyen, 2000 (Ref. 61)... Randomized, double- Hypercholesterolemic 3 dietary supplement Habitual diets Total-C (mg/dL)
blind, placebo- adults; 160 enrolled, test capsules/d with Baseline:
controlled, parallel 156 completed. meals. P 245
trial, two arm. 3-wk n = 156............... C = placebo capsules I 248
trial period. Inclusion criteria: w/o PS. Total-C % change
Total-C 220-300 mg/ I = 1 g PS/d as plant compared to control:
dL; TG <=350 mg/dL; stanol esters I [darr] 3.0% (p <
good health. divided over 3 0.05)
USA................... capsules. LDL-C (mg/dL)
Baseline:
C 154
I 155
LDL-C % change
compared to control:
I [darr] 5.2% (p <
0.05)
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ Weight represents nonesterified sterols or stanols.
Abbreviations Used in table:
C control group/period
I intervention group/period
BMI body mass index
Total-C serum total cholesterol
LDL-C serum low density lipoprotein cholesterol
wk week
y years
PS phytosterols (mixture of sterols and stanols)
mg/dL milligrams per deciliter
g gram
g/d grams per day
w/ with
w/o without
TG serum triglycerides
tmt treatment
mos months
CAD coronary artery disease
CVD cardiovascular disease
Rx prescription drugs
Hx history
Sd standard deviation
d day
RSO Rape seed oil
[FR Doc. 2010-30386 Filed 12-7-10; 8:45 am]
BILLING CODE 4160-01-P