Toxicology 221 (2006) 17–27

The importance of GRAS to the functional food

and nutraceutical industries
George A. Burdock a,∗ , Ioana G. Carabin b , James C. Griffiths c
a Burdock Group, 888 17th Street NW, Suite 810, Washington, DC 20006, USA
b Women in Science, 3785 7th Lane, Vero Beach, FL 32968, USA
c Burdock Group, 2001 9th Ave, Suite 301, Vero Beach, FL 32960, USA

Received 2 December 2005; received in revised form 5 January 2006; accepted 6 January 2006

Abstract
At a time when 150 million Americans spend over $20.5 billion on functional foods, nutraceuticals and dietary supplements, the
Food and Drug Administration (FDA) is doing little to ensure that all the safe and efficacious products that could come to the market
are allowed to do so. FDA has only responded slowly and reluctantly to Congressional action and to mandates from the Courts to
implement the law. Additionally, FDA had set the bar too high for Health Claims and was forced by the Courts to implement a
more reasonable standard, but the response, Qualified Health Claims, has failed to gain the confidence of the public because of the
confusing wording of the claims demanded by FDA.
Congressional efforts to assure consumer access to dietary supplements have been met with similar resistance from FDA. The
Dietary Supplement Health and Education Act (DSHEA) was the product of a compromise with a lower threshold for demonstration
of safety (reasonable expectation of no harm) that would be met by consumer self-policing and assumption of some risk. FDA has
thwarted this effort by raising the bar for New Dietary Ingredient Notifications (NDIN) to what appears to be the higher threshold for
the safety of food ingredients (reasonable certainty of no harm)—FDA apparently sees these two safety thresholds as a distinction
without a difference. As a result, increasing numbers of dietary supplement manufacturers, unwilling to gamble the future of their
products to a system that provides little hope for the FDA’s response of “no objection”, have committed the additional resources
necessary to obtain Generally Recognized As Safe (GRAS) status for their supplements.
The pressure on FDA and Congress for change is again building with increased dissatisfaction among consumers as the result of
confusing labels. A second force for change will be a need to uncouple the FDA mandated substance–disease relationship and return
to the substance–claim relationship to allow for progress in nutrigenomics and metabolomics, which will result in an increasing
number of substance-biomarker claims.
© 2006 Elsevier Ireland Ltd. All rights reserved.

Keywords: Generally recognized as safe (GRAS); FDA; Dietary Supplement Health and Education Act (DSHEA); Nutraceuticals; Functional foods;
New dietary ingredient notifications (NDIN)

Evolution of Health Care (Rowe, 1999)

2000 BCE Here, eat this root

850 AD That root is heathen; here, say this prayer
1000 AD That prayer is superstition; here, drink this potion
∗ 1940 AD That potion is snake oil; here, swallow this pill
Corresponding author. Tel.: +1 772 562 3900;
1985 AD That pill is ineffective; here, take this antibiotic
fax: +1 772 562 3908.
2000 AD That antibiotic doesn’t work anymore; here, eat this root
E-mail address: gburdock@burdockgroup.com (G.A. Burdock).

0300-483X/$ – see front matter © 2006 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.tox.2006.01.012
18 G.A. Burdock et al. / Toxicology 221 (2006) 17–27
1. Introduction
In the past, food was only thought of as something
having taste, aroma or general nutrition. Today, how-
ever, most consumers recognize additional categories of
foods, including “functional foods” and “nutraceuticals,”
located somewhere along a continuum of substances that
have more benefit than simple foods and are probably on
a par with officially recognized “vitamins”. The precise
value that any consumer would place on these substances
likely bears directly on the consumer’s self-image. That
is, a hypothetical functional foods/nutraceuticals con-
sumer might see himself/herself as normally existing
within a range of 80–90% efficiency; a range in which
one feels in equilibrium with one’s surroundings. Below
80% efficiency there is no longer the ‘good feeling’ about
oneself (i.e., no longer in equilibrium); and even lower,
one feels ‘sick’, prompting a need for some sort of ther-
apeutic treatment (i.e., a drug). The upper end of this
range, 90%, is the best one could expect to feel, given
healthy lifestyle habits and ordinarily available foods.
The goal is to maintain oneself in the 80–90% range, but
given the conventional environment of only a limited
food selection or restrictions on physical activity, stay-
ing within this optimal range can only be accomplished
as the result of an exogenous influence and; functional
foods or nutraceuticals may put that goal within easier
reach.
There are likely a variety of other reasons for con-
suming these added value substances and may include
a concern about the high cost of prescription drugs,
a quest for more natural remedies or simply engaging
in preventative measures (e.g., fiber), but there is no
doubt that consumption of functional substances is on
the rise. According to a recent Bill in Congress, over
158,000,000 Americans regularly consume these added
value substances and consumer expenditures on dietary
supplements (alone) reached a reported $20,500,000,000
in 2004, more than double the amount spent in 1994.1
To food formulators, functional foods and nutraceu-
ticals have a slightly different meaning, as being those
foods that contain some health-promoting component(s)
beyond traditional nutrients. To the Food and Drug
Administration (FDA), these terms have no meaning in
regulation or the law and, in fact, are regarded as “fanci-
ful” (Table 1). This seeming inflexible posture by FDA is
the result of the mandate to the Agency from Congress to
protect the public from “snake oil” salesmen and “health
1 http://thomas.loc.gov/cgi-bin/query/D?c109:1:./temp/∼
c109VQ5aX0: (site visited 24 November 2005).
Table 1
Regulatory vs. “Fanciful”a terms
Regulatory terms Other terms
Drug Nutraceutical
Food Aquaceutical
Food ingredient (food additive or GRAS) Functional food
Food for special dietary use Herbal supplement
Medical food Cosmeceutical
Nutrient supplementb Natural food
Dietary supplement
Cosmetic
a “. . . an arbitrary or fanciful name which is not false or misleading
in any particular.” http://www.cfsan.fda.gov/∼lrd/FCF133.html (site
visited 24 November 2005).
b 21 CFR 170.3(o)(20) [substances] “that are necessary for the
body’s nutritional and metabolic processes.”
crusaders” with outlandish claims for healing foods.2
That is, for foods, FDA must ensure that the substance
does not touch upon the definition of a drug (so there
is no potential to defraud the consumer), according to
the definition of a drug in the Federal Food Drug and
Cosmetic Act (FFDCA):
“. . . articles intended for use in the diagnosis, cure,
mitigation, treatment, or prevention of disease in man
or other animals [or] articles (other than food* )
intended to affect the structure or any function of
the body of man or other animals.” (§201(g)(1)(B)
FFDCA)
* Emphasis added
Sometimes, however, when an article (food) is a
nutrient, it can act like a drug when it prevents a dis-
ease (scurvy), cures or prevents (starvation) and treats
(hypovitaminosis). Nutrients, however, have regulations
governing them and all must be approved as such by
the Food and Drug Administration,3 as well as any food
substance for which a health claim (or qualified health
claim) is to be made. Likewise, in the definition of a drug,
there is a provision that a substance is not necessarily a
drug because the label contains a health claim; this pro-
vides flexibility for certain foods, which may contain a
2 See: Worton, J.C., 1982. Crusaders for Fitness. The History of
American Health Reformers. Princeton University Press, Princeton,
NJ.
3 21 U.S.C. 343(r)(4). “According to the Nutrition Labeling and Edu-
cation Act (NLEA, 1990), a nutrient must have an established amount
that exerts a beneficial effect, such as a RDI. However, the food com-
ponents being studied today for their beneficial effects [e.g., fiber or
broccoli with high amounts of sulforanes] may not yet have recognized
levels and therefore may not meet the NLEA standard for a nutrient”
(Anonymous, 1999).
 G.A. Burdock et al. / Toxicology 221 (2006) 17–27
Table 2
Five types of health-related statements or claims are allowed on food
and dietary supplement labels
1. Nutrient content claims indicate the presence of a specific
nutrient at a certain level.
2. Structure and function claims describing the effect of dietary
components on the normal structure or function of the body.
3. Dietary guidance claims describing the health benefits of broad
categories of foods.
4. Qualified health claims conveying a developing relationship
between components in the diet and risk of disease, as approved
by the FDA and supported by the weight of credible scientific
evidence available.
5. Health claims confirming a relationship between components in
the diet and risk of disease or health condition, as approved by
FDA and supported by significant scientific agreement.
health claim on their label. Claims permitted for food are
shown in Table 2.
There are as well, “foods for special dietary use”4
and “medical foods;”5 however, there are no efficacy
standards for either of these categories nor is there a
requirement for pre-market approval by FDA.
Recently, FDA has given voice to a possible new
group of “bioactive” food ingredients (Rulis, 2005).
Examples of this new category from the Generally
Recognized As Safe (GRAS) notification list include:
vegetable oil sterol esters, phytostanol esters, lactofer-
rin, fructooligosaccharides, small planktivorous pelagic
body fish oil, fish oil concentrate, tuna oil, diacylglycerol
and inulin (Rulis, 2005). Another example of a bioactive
food ingredient that received food additive approval sev-
eral years ago is Olestra® , “the no-fat cooking oil with
the full-fat flavor.”6,7 However, is approval of Olestra®
a genuine leap in creative application of the FFDCA
or just progress in food technology? How can Olestra®
be considered more of a special category than oleomar-
garine (with no cholesterol) was over butter and the new
“no trans-fats” margarine over conventional margarine?
FDA’s creative application of the law can resolve, as in
the Olestra® example, the current conundrum of a defi-
nition and acceptance of claims for functional foods and
nutraceuticals.
4 21 CFR 105.
5 Medical foods are regarded as foods for the maintenance of a patient
as opposed to a treatment. Further, medical foods are not those foods
included within a healthy diet intended to decrease the risk of disease,
such as reduced-fat foods or low-sodium foods, nor are they weight
loss products. (http://www.cfsan.lfda.gov/∼dms/ds-medfd.html) (site
visited 24 November 2005).
6 http://www.olean.com (site visited 24 November 2005).
7 Interestingly, Olestra® is not a “Food for Special Dietary Use” (21
CFR 105.3) nor does it have a health claim.
19
Fig. 1. The struggle: players and issues.
At this point, all stakeholders (i.e., consumers, indus-
try and the FDA) have taken positions creating a tension
with the other two (Fig. 1). Consumers are demanding
greater access to products for which they see a benefit
and industry is demanding that it’s right of free speech be
not abridged by FDA. The push-back by FDA is fulfill-
ment of its mandate to protect the consumer, ensuring the
product is safe and to protect the consumer from fraud
as the result of false claims on the label.8 How did we
get to this stalemate and how can it be resolved?
2. Ontogeny and current status of the regulations
A generation or two ago, an aging population
accepted getting older, retiring to less active pursuits
and passing the baton to the next generation, but in the
current “forever-young” or “youth-mimetic” culture, the
present aging generation (the baby boomers) are less
willing to give in to the aging process and are seeking
some palliative treatment. In addition, the shear number
of aging Americans presents a forbidding burden to the
heath care system, which is more geared to treatment
than preventative measures.9 The answer to both forces
is to engage in preventative means through healthier
lifestyles and dietary choices before the inevitable onset
of age-associated disease . . . let food by thy medicine
. . . (Hippocrates, 460-377 BCE). The Japanese Min-
istry of Health Care recognized the size and gravity
of the problem in the late 1980’s and responded with
8 FTC and FDA have complementary jurisdiction over the mar-
keting of dietary supplements and similar products. Under the terms
of a 1971 liaison agreement, the FTC has primary responsibility for
regulating advertising and the FDA has primary responsibility for label-
ing. (http://www.ftc.gov/opa/1998/08/fdaadvoc.htm) (site visited 25
December 2005).
9 The 55–64 age group is expected to rise from 29 million Americans
in 2004 to 40 million in 2014. Associated Press, 8 December 2005
(http://www.msnbc.msn.com/id/10383942/) (site visited 30 December
2005).
20 G.A. Burdock et al. / Toxicology 221 (2006) 17–27
Foods for Specialized Health Uses (FOSHU)10,11 ; the
objective of which is to keep the aging population as
healthy as possible for as long as possible (Bailey, 2005).
Similarly-intended legislation was passed by Congress
with the National Labeling and Education Act (NLEA)
in 1990 (allowing health claims for foods); which was
followed in 1997 by the Food and Drug Modernization
Act (FADMA), an attempt by Congress to liberalize the
FDA’s narrow interpretation of NLEA and; the Dietary
Supplement Health and Education Act (DSHEA) in
1994.12 Each amendment to the Act permitted certain
types of claims. As public interest increased and dis-
tinctions began to be made between products, the terms
functional foods and nutraceuticals were coined. As
indicated earlier, while neither term is supported by reg-
ulation or the law, each has a certain cachet that supports
a persuasive concept.
The system of Generally Recognized As Safe, for
review and approval of ingredients for addition to food,
was included in the 1958 amendment to the FFDCA to
provide an additional avenue for approval of food ingre-
dients; a system parallel to the food additive petition
(FAP) process that is administered by FDA. A substance
is GRAS, if there is agreement “. . . among experts qual-
ified by scientific training and experience to evaluate its
safety, as having been adequately shown through scien-
tific procedures (or, in the case as a substance used in
food prior to 1 January 1958, through either scientific
procedures or experience based on common use in food)
to be safe under the conditions of its intended use.”13
That is, a GRAS expert panel examines the data rele-
vant to the safe use of a substance, including testing data
10 FOSHU are foods that are composed of functional ingredients that
affect the structure/function of the body. These foods are used to main-
tain or regulate specific health conditions, such as gastro-intestinal
conditions, blood pressure, and blood cholesterol level (Bailey, 2005).
11 The FOSHU system is authorized by the Nutrition Improvement
Law (Law No. 248, July 31, 1952, Amended by Law No. 101, 24
May 1995) and the Nutrition Improvement Law Enforcement Regula-
tions (Ministerial Ordinance No. 41, July 1991, Amendment to Min-
isterial Ordinance No. 33, 25 May 1996). (http://www.nceff.com.au/
regulatory/reg-japan.htm) (site visited 25 December 2005).
12 The Federal Trade Commission (FTC) also has an interest in polic-
ing claims, but under the memorandum of understanding of 1971, FTC
concerns itself with advertising instead of label claims. In this case, the
standard set by FTC is “competent and reliable scientific evidence,”
defined in FTC cases as “tests, analyses, research, studies, or other
evidence based on the expertise of professionals in the relevant area,
that have been conducted and evaluated in an objective manner by
persons qualified to do so, using procedures generally accepted in the
profession to yield accurate and reliable results.” The FTC does indi-
cate however, that it would defer to another agency (e.g., FDA), with
expertise in the particular area.
13 FFDCA §201(s).
and exposure (consumption) data, manufacturing infor-
mation and specifications. Once found to be GRAS, a
substance may be added to only those food categories at
levels for which it was approved.14 While not a require-
ment, some manufacturers choose to undergo the GRAS
Notification process to determine if FDA is in agree-
ment with the GRAS determination. To date, over 3000
ingredients have been approved by this method and rep-
resents a model of industry and regulator cooperation15
(Burdock and Carabin, 2004).
2.1. National Labeling and Education Act and the
Food and Drug Modernization Act—Health Claims
The NLEA (1990), which permitted health claims
(HC) for food, had long been resisted by the FDA, with
the idea that any health claim would render the product
an unapproved drug. However, the safety of substances
for which health claims would be permitted was never
a debated concept, because these substances would be
added to food and by default, must meet the food safety
standard, reasonable certainty of no harm, embodied in
the concept of generally recognized as safe (GRAS) or
that of a food additive petition.
Debate has centered on the ‘proof of efficacy,’
required for a health claim to meet the standard of Sig-
nificant Scientific Agreement (SSA)16 ; importantly and
like drugs, only a government agency could determine
if the standard was met. Further, a health claim required
promulgation of a regulation by FDA (including a pro-
posed rule, comment period and a final rule). In January
of 1993, FDA adopted final regulations implementing
NLEA health claims, but never established specific crite-
ria for SSA, stating only that it would make case-by-case
determinations. It also indicated that it would not per-
mit disease (i.e., health) claims for which a difference
of scientific opinion exists.17 Because this standard was
simply set too high, Congress passed the 1997 Food and
Drug Modernization Act, as an attempt to liberalize the
interpretation FDA had required for health claims, by
14 The specific nature of a GRAS determination was reinforced by
FDA in 1974 with the following Federal Register announcement: “It
has been too often assumed that the GRAS substance may be used
in any food, at any level for any purpose. As a result, the uses of
some GRAS food ingredients have proliferated to the point where the
GRAS status was brought into serious question.” (Federal Register
39:34194–5, 1974).
15 Since the inauguration of the notification program in 1997, as of
30 December 2005, 184 substances have been submitted to FDA for
review. The greatest source of GRAS determinations, the Flavor and
Extract Manufacturers Association, does not submit Notifications.
16 The precise definition of which was not included in the law.
17 Federal Register 58:2501–02, 1993.
 G.A. Burdock et al. / Toxicology 221 (2006) 17–27
Fig. 2. Schematic for assessing strength and consistency of scientific evidence leading to significant scientific agreement
(http://vm.cfsan.fda.gov/∼dms/ssaguide.html).
allowing the claims to be based on “authoritative state-
ments” of (other) qualified government scientific bodies.
In response, FDA simply incorporated the “authoritative
statements” into the rubric of SSA.18
In December of 1999, FDA made the pivotal decision
that there must be significant scientific agreement about
the substance/disease relationship rather than the actual
claim being made.19 While this decision pushed beyond
18 Guidance for Industry: Notification of a Health Claim or Nutrient
Content Claim Based on an Authoritative Statement of a Scientific
Body (11 June 1998) (http://vm.cfsan.fda.gov/∼dms/ssaguide.html)
(site visited 27 December 2005).
19 Guidance for Industry: Significant Scientific Agreement in the
Review of Health Claims for Conventional Foods and Dietary Supple-
ments (http://vm.cfsan.fda.gov/∼dms/ssaguide.html) (site visited 27
December 2005).
21
what was required in the law (FFDCA 403(r)(3)(B)(i)
(which only required significant scientific agreement
about the claim), it had the effect of forcing petition-
ers perilously close to the edge of a drug claim, leaving
only a narrow gap for claims for reduced incidence
of disease in otherwise healthy populations. For exam-
ple, because a claim based on reducing the symptoms
of arthritis in arthritis-sufferers became a drug claim,
manufacturers were forced to test the ability of the sub-
stance to decrease the incidence of arthritis in the gen-
eral population—significantly, the population could not
already have arthritis. This requirement to test in a gen-
eral population resulted in a quantum leap in the cost of
proving the claim, because it required a very large sample
size, a much longer study duration and complex subject
exclusion criteria (Carabin, 2004a, 2004b). Further, FDA
22 G.A. Burdock et al. / Toxicology 221 (2006) 17–27

Table 3 for approvals of the very claims it had resisted making

Significant scientific agreementa before NLEA was passed. The bar for SSA status was
21 CFR Substance and disease or health-related condition simply set too high and in response, a series of lawsuits
101.72 Calcium and osteoporosis were launched against FDA (i.e., Pearson vs. Shalala
101.73 Dietary lipids and cancer and others) asserting the right of commercial free speech
101.74 Sodium and hypertension
101.75 Dietary saturated fat and cholesterol and risk of
on food labels. As the result of decisions by the Court,
coronary heart disease FDA was forced to provide a mechanism accommodat-
101.76 Fiber-containing grain products, fruits and ing free speech. In response, FDA launched “Task Force
vegetables and cancer Final Report: Consumer Health Information for Better
101.77 Fruits, vegetables, and grain products that contain Nutrition Initiative” in July 2003, allowing for Qualified
fiber, particularly soluble fiber, and risk of coronary
heart disease
Health Claims (QHC), which was theoretically some-
101.78 Fruits and vegetables and cancer thing less than an (unqualified) health claim under the
101.79 Folate and neural tube defects rubric of SSA. For QHC, FDA has chosen not to officially
101.80 Dietary non-cariogenic carbohydrate sweeteners and approve any claims, but instead “exercise enforcement
dental caries discretion” relative to claims FDA has mandated using
101.81 Soluble fiber from certain foods and risk of coronary
heart disease
it’s qualifications.
101.82 Soy protein and risk of coronary heart disease At present, there are six categories for which the
101.83 Plant sterol/stanol esters and risk of coronary heart Agency has allowed claims, but the claims permitted
disease have been worded by FDA to accommodate FDA’s esti-
Proposedb Whole grain foods and risk of heart disease and mate of the strength of the scientific evidence supporting
certain cancers
Proposedc Potassium and the risk of high blood pressure and
the claim (Table 5). Needless to say, in an Agency as con-
stroke servative as FDA, the claims are sometimes only those
a
from which a competitor could benefit, as exemplified
http://www.cfsan.fda.gov/∼dms/flg-6c.html (site visited 24
November 2005).
by the claims for green tea and cancer:
b Docket No. 99P-2209.
c Docket No. 00Q-1582.
Based on FDA’s review of the strength of the total
body of publicly available scientific evidence for a
claim about green tea and reduced risk of breast can-
continues to cling to the weight of evidence concept, con-
cer, FDA ranks this evidence as the lowest level for
trary to the urging from the Courts that credible evidence
a qualified health claim. For the reasons given above,
be permitted as the basis of a claim. As illustrated above,
FDA concludes that it is highly unlikely that green
the chances are slim for achieving SSA based on any-
tea reduces the risk of breast cancer.21
thing other than the “gold standard” of an interventional,
randomized, controlled, clinical trial20 (Fig. 2). Based on FDA’s review of the strength of the total
Although there are now twelve SSA claims, claims body of publicly available scientific evidence for a
languished at the Agency until 1993, when the first claim claim about green tea and reduced risk of prostate
(calcium and osteoporosis) was approved (Table 3). It cancer, FDA ranks this evidence as the lowest level
would be fair to say that none of these claims were for a qualified health claim. For the reasons given
“tough calls,” and for many, the claims were obviously above, FDA concludes that it is highly unlikely that
valid even before new supporting data were generated in green tea reduces the risk of prostate cancer.22
response to the requirement for SSA.
Permission from the FDA to use claims, such as
In comparison, the Japanese FOSHU list of foods or
above, does not provide much encouragement to man-
ingredients that affect the structure/function of the body
ufacturers to generate the quality and quantity of data
is lengthy (Table 4).
apparently required to convince the Agency of the valid-
2.2. Qualified Health Claims ity of a claim. At this point, the standard will continue
to be set by SSA.
The goal of a SSA/health claim regulation was rarely,
or at best, slowly obtained by petitioners. This was
because the very Agency that had resisted passage of the 21 Letter Responding to Health Claim Petition dated 27 January 2004:
NLEA health claim process, was made the gate-keeper Green Tea and Reduced Risk of Cancer Health Claim (Docket number
2004Q-0083) (http://www.cfsan.fda.gov/∼dms/qhc-gtea.html) (Site
visited 25 December 2005).
20 See footnote 19. 22 See footnote 21.
 G.A. Burdock et al. / Toxicology 221 (2006) 17–27
Table 4
FOSHU (foods for specialized health uses)
Health Claim Functional ingredients
Food that improves gastrointestinal conditions
Prebiotics: oligosaccharides, raffinose, lactulose, arabinose
Probiotics: lactobacillus, bifidobacterium
Dietary fiber
Foods for those with high serum cholesterol
Soy protein and peptide, alginate, chitosan, sitosterol ester
Foods for those with high blood pressure
Peptides
Foods for those with high serum triacylglycerol
Diacylglycerol and sitosterol
Foods related to mineral absorption and transport
Casein, calcium citrate, isoflavone
Non-cariogenic foods
Mannitol, xylitol, paltinose
Foods for hyperglycemics
Wheat albumin, globulin digest, polyphenols
Consumers are, as well, disappointed by the qualified
health claims allowed by the Agency. Consumer sur-
vey information (IFIC, 2005) has demonstrated that the
use of a letter grade for claims, embedded disclaimers
or point-counterpoint statements are often interpreted
wrongly. Three categories of problems emerged: (1)
some consumers felt that the claim reflected the quality
of the product, rather than the strength of the evidence
supporting the claim; (2) anything less than a “B” grade
was unacceptable and; (3) the statements had the para-
doxical effect such that structure–function claims were
looked upon more favorably than QHCs, presumably
because of fewer “weasel-words.”
2.3. Dietary Supplement Health and Education
Act—Structure Function Claims and a new standard
for safety
On a similar front, in the early 1980’s, the use
of dietary supplements began to proliferate, quickly
followed by FDA’s attempts to curtail them through
several measures, including a challenge that dietary
supplements were actually unapproved food additives
(Burdock, 2000). Congress responded again to public
demand, by passage of DSHEA, which declared dietary
23
Number of Type of products in the market
products approved
336 Soft drinks, yogurt, cookies, table sugar, soy
bean curd, vinegar, chocolate, powdered
soup, fermented milk, miso soup, cereal
28 Soft drinks, meat balls, sausage, soy milk,
soup, cookies, margarine
42 Soft drinks, soup, drinkable products
containing probiotic bacteria, soybean
products
9 Cooking oil
17 Soft drinks, fermented soybean (natto), jelly
6 Chocolate, chewing gum
4 Candy, soup, soft drinks
supplements not to be food additives, but foods, for
which structure/function claims (SFC) could be made.
The rationale by which dietary supplements were actu-
ally foods is evident from the list of examples provided
by Congress (Table 6). Clearly this list is one of sub-
stances that either should be or could be a legitimate
addition to the diet. Particularly insightful is the phrase
“a dietary substance for use by man to supplement the
diet by increasing the total dietary intake”—this con-
firms that Congress viewed supplements as substances
that should or could have been part of the diet in the
first place, but importantly, did not require the sub-
stances to have nutritive value. Implied by its omission,
is that the dietary supplement must be extracted from
a food; that is, the supplement could be produced by
synthetic means, just so it mimics the dietary supple-
ment identified in food. The closeness of the mimicry
has not generally been addressed in any guidelines pro-
mulgated by FDA, but persuasive logic would include
an argument that if a substance were made more stable
or more effective or without possible toxic ligands, this
“improvement” would be acceptable. Lastly, the suppo-
sition that the dietary supplement should or could have
been part of the diet is reflected in the claims allowed.
That is, DSHEA allows three types of “statements of
24 G.A. Burdock et al. / Toxicology 221 (2006) 17–27
Table 5
Qualified health claims subject to enforcement discretion
Cancer risk
Tomatoes and/or tomato sauce and prostate, ovarian,
gastric and pancreatic cancers
Calcium and colon/rectal cancer and calcium and
recurrent colon/rectal polyps
Green tea and cancer
Selenium and cancer
Antioxidant vitamins and cancer
Cardiovascular disease risk
Nuts and heart disease
Walnuts and heart disease
Omega-3 fatty acids and coronary heart disease
B vitamins and vascular disease
Monounsaturated fatty acids from olive oil and coronary
heart disease
Cognitive function
Phosphatidylserine and cognitive dysfunction and
dementia
Diabetes
Chromium picolinate and diabetes
Hypertension
Calcium and hypertension, pregnancy-induced
hypertension and preeclampsia
Neural tube birth defects
0.8 mg folic acid and neutral tube birth defects
Table 6
Definition of a dietary supplement (Federal Food Drug and Cosmetic
Act (FFDCA)
CHAPTER II—DEFINITIONS
SEC. 201 For the purposes of this chapter
(ff) The term ”dietary supplement”
(1) means a product (other than tobacco) intended to supplement
the diet that bears or contains one or more of the following
dietary ingredients
(A) a vitamin; (B) a mineral; (C) an herb or other botanical;
(D) an amino acid; (E) a dietary substance for use by man to
supplement the diet by increasing the total dietary intake; or
(F) a concentrate, metabolite, constituent, extract, or
combination of any ingredient described in clause (A); (B);
(C); (D); or (E)
nutritional support” on labels without obtaining FDA
approval (Table 7), with the caveats; however, that (1)
the statement is truthful, not misleading and can be doc-
umented; (2) a statement follows relating to the fact that
FDA does not endorse the claim and; (3) that the sub-
stance is not a drug (according to the definition of a
drug).23 That is, only structure/function claims may be
23 This statement avoids the conundrum of ‘when is a food a drug’
(e.g., cure disease (such as starvation), mitigate or prevent a disease
Table 7
Supplement claims
SEC. 403. [343] (r)(6) For purposes of paragraph (r)(1)(B), a
statement for a dietary supplement may be made if:
“the statement claims a benefit related to a classical nutrient
deficiency disease and discloses the prevalence of such disease in
the United States, describes the role of a nutrient or dietary
ingredient intended to affect the structure or function in humans,
[the statement] characterizes the documented mechanism by which
a nutrient or dietary ingredient acts to maintain such structure or
function [of the body], or
[the statement] describes general well-being from consumption of a
nutrient or dietary ingredient.”
[However, these claims are allowed only if]
“(B) the manufacturer of the dietary supplement has substantiation
that such statement is truthful and not misleading, and
(C) the statement contains, prominently displayed and in boldface
type, the following: ”This statement has not been evaluated by
the Food and Drug Administration. This product is not intended
to diagnose, treat, cure, or prevent any disease.”
“. . . the manufacturer shall notify the Secretary no later than 30
days after the first marketing of the dietary supplement with such
statement that such a statement is being made.”
made. These claims relate only to the maintenance of
a physiologic function or structure (e.g., healthy bones
or healthy urinary tract function), which falls short of a
nutrient claim. DSHEA also requires that “the statement
be truthful and not misleading.”
Foods per se are also permitted to bear struc-
ture/function claims, but such claims must be made on
the basis of the nutrients they contain and for which a
daily requirement (e.g., an RDA) has been established
(CAST, 2003); for example, calcium in milk or potas-
sium in orange juice.
Of particular interest to dietary supplement manu-
facturers should be the exclusionary clause of DHSEA
(Table 8). This clause simply indicates that a dietary sup-
plement cannot have had prior use as a drug or have been
under investigation as a drug with clinical studies hav-
ing been instituted. This provision theoretically prohibits
the re-direction of substances once intended for use as
drugs to the dietary supplement market or the dietary
supplement version of a drug to be marketed. A case in
point was the marketing of red yeast rice (Cholestin® ),
which although having been used as a food in China for
centuries and in the US for decades, was known to con-
tain HMG-CoA reductase inhibitors (which lower blood
(such as a vitamin deficiency) and further; that, “[a] food, dietary ingre-
dient, or dietary supplement for which a truthful and not misleading
statement is made in accordance with section 403(r)(6) of this title is
not a drug . . . solely because the label or the labeling contains such a
statement.”
 G.A. Burdock et al. / Toxicology 221 (2006) 17–27
Table 8
Exclusionary clause
“[The definition of a dietary supplement does] not include
(i) an article that is approved as a new drug, . . . certified as an
antibiotic . . . or licensed as a biologic . . . or (ii) an article
authorized for investigation as a new drug, antibiotic, or
biological for which substantial clinical investigations have
been instituted and for which the existence of such
investigations has been made public, which was not before
such approval, certification, licensing, or authorization
marketed as a dietary supplement or as a food . . .”
FFDCA 201(ff)(3)(B).
cholesterol). These inhibitors, although natural to the
food, are indistinguishable from the synthetic lovastatin,
the active ingredient in the prescription drug, Mevacor®
by Merck. Based on this similarity and the fact that the
manufacturer had tweaked the manufacturing process to
maximize the level of HMG-CoA reductase inhibitors,
Cholestin® was determined a “drug” by FDA and could
not be marketed as a dietary supplement (Kracov et al.,
2005). The take home lessons here are three:
1. a manufacturer should not use a process designed to
heighten the concentration of a constituent;
2. there should be no promotion of a particular con-
stituent of a supplement, unless that constituent was
previously marketed as a dietary supplement and;
3. the mere presence of a substance in the food supply
may not be sufficient to meet the standard as having
been previously marketed.
In a case similar to the Cholestin® /lovastatin case, a
citizen petition to FDA by BioStratum Inc., states, among
other things, that it is the manufacturer of Pyridorin®
(pyridoxamine dihydrochloride), which is the subject of
an investigational new drug application (NDA) that was
filed with FDA in July 1999; that Pyridorin was being
tested for use as a potential therapeutic agent to slow
or prevent the progression of diabetic nephropathy in
patients with Type 1 and Type 2 diabetes. The petition
further states that substantial clinical trials have been
conducted for this drug and that the existence of those
studies has been made public. In addition, the petition
states that pyridoxamine was not marketed as a dietary
supplement or as a food prior to Pyridorin’s authoriza-
tion for investigation as a new drug under an IND.24
FDA is awaiting comments regarding the prior use of
this substance as a dietary supplement before it makes
24 Federal Register: 18 November 2005 (Volume 70, Number 222)
page 69976–69977, Request for Comment on the Status of Pyridox-
amine.
25
Table 9
Definition of an adulterated food
SEC. 402. [342] A food shall be deemed to be adulterated
(f)(1) If it is a dietary supplement or contains a dietary ingredient
that
(A) presents a significant or unreasonable riska of illness or
injury under
(i) conditions of use recommended or suggested in labeling, or
(ii) if no conditions of use are suggested or recommended in
the labeling, under ordinary conditions of use
(B) is a new dietary ingredient for which there is inadequate
information to provide reasonable assurance that such
ingredient does not present a significant or unreasonable risk
of illness or injury
(C) the Secretary declares to pose an imminent hazard to public
health or safety . . .
a Importantly, this was changed from “significant and unreasonable
risk” in the original bill.
a final decision. An ironic twist of fate may result if
FDA determines that pyridoxamine is, in fact, covered by
the exclusionary clause, and if BioStratum Inc., decides
not to market Pyridorin, the end result may be a loss to
the consumer because pyridoxamine would be forever
excluded from being marketed as a dietary supplement.
A cause of controversy with DSHEA is the setting of a
different standard for safety than that for food ingredients
and; therefore, substances for which a qualified health
claim can be made. The new standard is the concept of
reasonable expectation of no harm, although articulated
in the FFDCA as [no] “significant or unreasonable risk
of illness or injury”, above (Table 9)25 .
The basis for this rationale is that consumption of a
dietary supplement is by choice, not involuntary as for
a food (i.e., food must have a presumption of safety);
and because there is choice, there is an assumption of
some risk on the part of the consumer. In many respects,
DSHEA was a safety valve, venting consumer discon-
tent with the high degree of restriction placed upon health
claims. A tacit bargain between Congress and the con-
sumers was struck, whereby Congress granted continued
access by the public to dietary supplements by (1) pro-
viding for a lower threshold of evidence for safety; (2)
changing the role of FDA from gate-keeper to policeman
(i.e., abandoning pre-market approval);26 and (3) allow-
ing a type of claim (i.e., structure function claims, not
health claims). The consumer’s concessions were that (1)
25 Also articulated in the FFDCA (§413) as “reasonably be expected
to be safe”.
26 FFDCA§402(f)(1) “In any proceeding under this subparagraph, the
United States shall bear the burden of proof on each element to show
that a dietary supplement is adulterated.”
26 G.A. Burdock et al. / Toxicology 221 (2006) 17–27
supplements could not be added to food (because of the
lower threshold for safety); (2) consumption will always
remain the product of an overt, voluntary act on the part
of the consumer (a dietary supplement can never be rep-
resented as a food) and; (3) because the recommended
daily dose is presented on the supplement, the consumer
will assume at least some risk27 from consumption (artic-
ulated by the standard of reasonable expectation of no
harm (21 CFR 190.6(a)28 ). Because no system is per-
fect, Congress empowered the Secretary of Health and
Human Services (not the Commissioner of FDA), to take
action through the “imminent hazard” clause of the reg-
ulation.
Therefore, keys to a SFC are (1) the substance must
maintain a physiologic function and (2) the standard of
safety of reasonable expectation of no harm.
The results so far on DSHEA are uneven. One pro-
vision of DSHEA was to allow continuation of sale of
dietary supplements marketed prior to October 1994; for
substances not marketed prior to this date, a new dietary
ingredient notification (NDIN) to FDA was required.
However, the exact criteria for what constitutes a market-
ing of a substance prior to October 1994 is unclear, espe-
cially as it relates to what sort of marketing is claimed
and to whom. What is very clear, is that FDA intends to
use the NDIN provision as a mechanism for pre-market
notification of new dietary supplements. At this point in
time (December 2005), out of 234 substances submitted
since 15 November 1999, 69% have been rejected. FDA
has cited several reasons for objecting to these submis-
sions, including (1) mismatches between the marketed
and tested ingredient; (2) use of therapeutic language,
i.e., ingredient is represented for treatment or mitiga-
tion of a disease state; (3) use of food language, i.e.,
ingredient is represented as a traditional food; (4) clini-
cal studies have been done via non-oral routes, but most
often and; (5) a lack of sufficient safety data and/or that
the substance fails to meet the safety standard.29
FDA does not provide a concise list of sufficient safety
data it would find to be persuasive, it only indicates that
safety must be demonstrated to the ‘reasonable expec-
27 FDA has stated that it would use a “reasonable consumer” stan-
dard in determining whether a claim is misleading. The reasonable
consumer standard replaced the standard of “the ignorant, the unthink-
ing, and the credulous” consumer, used by courts at the request of FDA
in the past (Walsh et al., 2005).
28 Referred in the FFDCA (§402(f)(1)(A)) as “significant or unrea-
sonable risk of illness or injury.”
29 §402 (f)(1) If it is a dietary supplement or contains a dietary ingredi-
ent that—(B) is a new dietary ingredient for which there is inadequate
information to provide reasonable assurance that such ingredient does
not present a significant or unreasonable risk of illness or injury.
tation’ of no harm standard. This is not to say that some
‘objections’ are not well-founded. Some new dietary
ingredient notifications have rightfully been faulted, as
the submitter has the misguided assumption that a lower
safety standard means no safety standard. However, an
inspection of the rationale for rejection would seem to
be an application of a higher standard than the thresh-
old of reasonable expectation. This extraordinarily high
‘objection’ rate of rejection and application of a higher
standard of safety, is essentially a form of paternalism
and abrogates the bargain with the public; namely, a
lower standard of safety for an assumption of risk, espe-
cially in light of the “reasonable consumer” standard
adopted by FDA (Griffiths, 2005).
The core of the issue is simply that the regulatory
Agency equates ‘expectation’ to ‘certainty’ thus, negat-
ing or at least diminishing the distinction between the
two standards of safety. The Agency ‘expects’ the NDI
notifier to be ‘certain’ of the safety of the ingredient,
and this mind-set is not likely to change. In many ways,
this attitude by the Agency is understandable, that the
Agency likely feels it must err on the side of conser-
vatism, and recent episodes with legend drugs, such as
Vioxx® and Celebrex® , as well as adverse effects and
publicity on kava kava and ephedra, lessen the chances
that FDA will cede more safety decisions to the general
public.
A predictable response from manufacturers will be
to take control of the decision process, by opting out of
the DSHEA program and review the new dietary ingre-
dient to the level of a food ingredient through a GRAS
determination. This route adds a potential increase in
time and expense to generate safety data and prepare a
safety dossier to the ‘reasonable certainty’ safety stan-
dard. However, this approach has the advantage of taking
the decision of safety off the table for an NDIN, espe-
cially when the GRAS acceptable daily intake includes
consumption from use as a dietary supplement. It would
be essential, however, to indicate in the NDIN, that the
substance had been found GRAS (and undergone Noti-
fication), otherwise an intractable Gordian knot would
be created if FDA decides that the data was insufficient
to meet the reasonably expectation standard.
3. The future
For the immediate future, without a comprehensive
change in the statute, it is likely that (unqualified) Health
Claims will remain as now positioned: approved under
SSA in response to overwhelming evidence of health
benefit and to distinguish a decision by the Agency from
that promulgated by industry.
 G.A. Burdock et al. / Toxicology 221 (2006) 17–27
Qualified Health Claims will likely experience at
least one more round in the Courts, addressing the issue
of freedom of commercial speech with two significant
changes: (1) an abandonment of the various grades of
acceptance, settling on a binary system of “yes” or
“no” for a claim, rather than leaving the public baf-
fled with confusing statements and; (2) abandonment of
the strictly “in-house” review system (which currently
includes various “evidence-based” practice centers), lev-
eling the playing field and including an option for review
by independent panels of experts, much on the model of
the GRAS system and similar to that employed by the
Federal Trade Commission (i.e., “competent and reliable
scientific evidence . . . based on the expertise of profes-
sionals in the relevant area”).
The pressure for this change will come rather soon,
within the next 2 years, in response to new and dif-
ferent types of claims, many of which will be gen-
erated as the result of progress in nutrigenomics and
metabolomics. For example, for substances such as sul-
foranes (as detoxicants, promoting enzymes for type
II detoxication reactions), sulfur compounds in garlic
(which decrease gastric nitrosamine formation), proan-
thocyanins in cranberries and, health claims for spe-
cific subpopulations (e.g., higher amounts of biotin are
required by pregnant women of Mexican descent then
women of Western European heritage, and for which
precedent has been established by setting a standard
for choline intake, a substance not required so much
for women, as it is for men). These changes for QHC
will also be a response to safeguard against a prolifer-
ation of inclusions into the “foods for special dietary
use” and “medical foods” categories, two categories for
which the framework for admission has not been well
established.
It is likely that future QHCs will be directed toward
specific enhancements and specific population subsets,
rather than addressing the general population. This will
require re-thinking how clinical studies will be con-
ducted and the general caveats that a substance will be
safe for anyone to consume (within guidelines) and may
instead have particular benefit for a specific population
subset.
27
All of these new demands on the system for deter-
mination of efficacy and safety can be easily met with a
renewed faith by FDA in the independent judgment of
panels of experts, which have served both industry and
regulators for over 40 years.
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