INDEX

 Functional foods- INTRODUCTION

1. Definitions of functional foods
2. History of functional foods
3. Classification of functional foods
 SAFETY of functional foods
1. Health claims
2. Sound Criteria for health claims
3. Effectiveness and safety- Safety considerations, Safety limits of nutrients,
dietary reference intake, risk assessment
4. Toxicity and side effects
 Bibliography
 Functional foods- INTRODUCTION
The roles and requirements of six major nutrients viz., carbohydrates, proteins, fats,
vitamins, minerals and water present in foodsare known to us. Besides these
nutrients, there are certain health promoting essential nutritional factors present in
foods whichhave protective and preventive functions for our body. The health
promoting effect of foods beyond their nutritional value is gaining wide popularity.
This extensive vision of nutrition has led to the concept of “functionality”.

Definitions of Functional foods

Functional foods are found in many fruits, vegetables, grains, herbs and spices to
provide a health benefit, lower the risk of certain diseases or affect a particular
body process. There are different terminologies used for functional foods such as:
Nutraceuticals, designer foods, vita foods, pharma foods, medicinal foods,
prescriptive foods, therapeutic foods, super foods, foodiceuticals and medifoods.
One could easily argue that functional foods include everything from natural foods,
such as fruits and vegetables endowed with antioxidants and fiber, to fortified and
enriched foods, such as orange juice with added calcium or additional carotenoids,
to formulated ready-to-drink beverages containing antioxidants and immune-
supporting factors.

The following health oriented professional organizations have defined functional

foods and nutraceuticals.

• The International Food Information Council (IFIC),USA- According to the

International Food Information Council (IFIC), functional foods are “foods or dietary
components that may provide a health benefit beyond basic nutrition.”

• The International Life Sciences Institute of North America (ILSI)- The International
Life Sciences Institute of North America (ILSI) has defined functional foods as “foods
that by virtue of physiologically active food components provide health benefits
beyond basic nutrition.”

• Health Canada- Health Canada defines functional foods as “similar in appearance

to a conventional food, consumed as part of the usual diet, with demonstrated
physiological benefits, and/or to reduce the risk of chronic disease beyond basic
nutritional functions.”

• Nutrition Business Journal (US)- The Nutrition Business Journal classified functional
food as “food fortified with added or concentrated ingredients to functional levels,
which improves health or performance.Functional foods include enriched cereals,
breads, sport drinks, bars, fortified snack foods, baby foods, prepared meals, and
more.”
• The American Dietetic Association (ADA)- As noted by the American Dietetics
Association in a position paper dedicated to functional foods, the term “functional”
implies that the food has some identified value leading to health benefits, including
reduced risk of disease, for the person consuming it.

• The American Council on Science and Health- The American Council on Science
and Health states that functional foods are “whole, fortified, enriched, or enhanced
foods that provide health benefits beyond the provision of essential nutrients, when
they are consumed at efficacious levels as part of a varied diet on a regular basis.”

• The Institute of Medicine of the National Academy of Sciences (IOM)- The National
Academy of Medicine (NAM), formerly called the Institute of Medicine (IoM), states
that functional foods are “those in which the concentrations of one or more
ingredients have been manipulated or modified to enhance their contribution to a
healthful diet”.

• According to the International Food Information Council (IFIC), functional foods are
“foods or dietary components that may provide a health benefit beyond basic
nutrition.”

• European Commission Concerted Action on Functional Food Science in Europe

considers foods to be functional if they have a beneficial effect on one or more
functions of the body and are still in the form of food, not a dietary supplement.

• In Japan, the FOSHU organization states that functional foods are “processed
foods containing ingredients that aid specific body functions in addition to being
nutritious”.

• The Functional Food Center/Functional Food Institute (FFC), Dallas, USA (2017)
defines “functional foods” as: “Natural or processed foods that contain biologically
active compounds; which, in defined, effective, and non-toxic amounts, provide a
clinically proven and documented health benefit utilizing specific biomarkers for the
prevention, management, or treatment of chronic disease or its symptoms”
History of Functional Foods
During the last 2000 years, from the time of Hippocrates (460–377 BC) to the
beginning of modern medicine, there was little distinction made between food and
drugs. Hippocrates, the father of medicine, clearly recognized the essential
relationship between food and health and emphasized that ‘‘...differences of
diseases depend on nutriment’’. The concept of “Medicine and food are
isogonics”originated in ancient China and transported to Japan long ago” similarly
the doctrine of Hippocrates, “Let food be thy medicine and medicine be thy food,”
has had a rebirth. In 1984, the first national project on functional foods was initiated
by a research team headed by Professor Soichi Arai at the University of Tokyo. The
project entitled “Systematic analysis and development of food functions’was
sponsoredby Japan’s Ministry of Education, Science and Culture (MESC). The food
value criteria were defined by three categories:

1. Primary function identified as functions of nutrients.

2. Secondary function referring to sensation.

3. Tertiary function as body modulating function of non –nutrients

Year Event
1984 Dr Arai et al. launched project on “Systematic analysis and development
of food functions’ sponsored by Japan’s Ministry of Education, Science
and Culture.
1988 Arai et al. took up second project on ‘analysis of body modulating
(ie.,Tertiary) functions of foods’.
1989 Stephen L. DeFelice, M.D.,Founder and Chairman of Foundation for
Innovation in Medicine New York, US coinedthe term nutraceutical
fromnutrition and pharmaceutical
1991 The Ministry of Health and Welfare, Japan, launched the world’s first
policy “Foods for Specified Health Uses” (FOSHU) for legally permitting
the commercialization of some functional foods
1992 Third project by Arai et al. on “Analysis and molecular design of
functional foods”.
1993 “ Hypoallergenic rice” was the first FOSHU product approved, developed
after the immunological studies.
1994 The structure/function claims were expressed in the Dietary Supplement
Health Education Act (DSHEA) in United States.
1996 Functional food science in Europe (FUFOSE) establish a science-based
approach for concepts in functional food science.
1997 Codex adopted the guidelines in which the nutrient function claim was
included.
2010 In India, the nutraceutical regulation was implemented under The Food
Safety and Standard Authority of India (FSSAI) Act.
2014 Dr. Stephen L. DeFelice, M.D., confessed that nutraceuticals do not work,
and ‘the quest to demonstrate whether … long-term supplementation
[with nutraceuticals] can prevent serious diseases … has come to an
end’
Classification of Functional Foods
Functional foods may be classified in various ways and can be identified/selected on
the basis of their properties, clinical significance or composition. Some of the
important criteria used for classifying functional foods are:

1. Food Source

2. Nutrient and Non Nutrient Source

3. Organ/Organ System

4. Modifications in foods

5. Specific Foods

6. Mechanism of actions

7. Chemical Nature

A. Classification based on Food Source

According to origin or food source, the Functional foods may be classified into plant,
animal and microbial groups.

a. Plant-derived functional foods

Plant-derived functional foods are separated into primary and secondary

metabolites; primary metabolites are plant compounds necessary for growth and
include plant proteins, beta- glucansand omega-3 fatty acids. The secondary
metabolites are not essential for growth, but are used for plant survival
mechanisms and include phytoestrogens, antioxidants, vitamins, tocopherols,
steroids and gamma-linolenic acid (GLA)

b. Animal-derived functional foods

Zoochemicals, which are animal-derived functional foods, include omega-3 and

omega-6 fatty acids, conjugated linolenic acid (CLA), small peptides, whey and
casein, and glucosamine.Omega-3 fatty acids include alpha-linolenic,
docosahexaenoic (DHA), and eicosapentaenoic (EPA) fatty acids whereas Omega-6
include linoleic, gamma-linoleic, and arachidonic fatty acids.

c. Microbial functional foods

Microbial-derived functional foods include four groups of foods viz., Probiotics,

Prebiotics, Symbiotic, and Synbiotics. Recently, a new food has been included and
that is Postbitics.
i. Probiotics: Probiotics are the mono or mixed culture of living microorganisms,
which when ingested in certain amounts, has a positive impact on host
health, beyond conventional nutritional effects.These stimulate the growth of
certain other bacteria in the colon, thus improve health.Bacteria most often
used as probiotics are Lactobacilli and Bifidobacteria which can be given
along with the fermented foods e.g. youghrt, fermented vegetables/ meat.
ii. Prebiotics: Prebiotics are ingredients/ compounds that have a beneficial
effect on microflora in the large intestine of the host e.g. fibre, fructo
oligosaccherides, lactulose, sugar alcohols. Generally they are carbohydrate
that may be fermented in the large bowel and stimulate growth of
potentiality beneficial Bifidobacteria. The most prevalent forms of prebiotics
are nutritionally classed as soluble fiber.
iii. Sybiotics and Synbiotics: Symbiotics contain probiotics and prebiotics
combined randomly while synbiotics contain specific probiotics and prebiotics
mixed together to benefit one another.Because the word alludes to
synergism, this term should be reserved for products in which the prebiotic
compound selectively favors the probiotic compound. For e.g., a product
containing oligofructose and probiotic bifidobacteria would fulfill the
definition.
iv. Postbiotics: Postbiotics are the non-viable bacterial products or metabolic
byproducts from probiotic microorganisms that have biologic activity in the
host. General, postbiotics include bacterial metabolic byproducts, such as
bacteriocins, organic acids, ethanol, diacetyl, acetaldehydes and hydrogen
peroxide, but it is also found that certain heat-killed probiotics can also retain
important bacterial structures that may exert biological activity in the host.

Non Food Sources:

Apart from plant,animal and microbial sources there are non food sources of
nutraceuticals. Using modern fermentation methods, few nutraceuticals can also be
produced. For example, amino acids and their derivatives have been produced by
bacteria . Eicosapentaenioc acid produced by some algae and bacteria. But now
using recombinant – genetic techniques , this EPA can also be produced by non –
EPA producing bacteria.

B. Classification based on Nutrient and Non Nutrient Components

From the nutritional viewpoint, they can be categorized as nutrients and non
nutrients.

NUTRIENTS NON- NUTRIENTS

Lipids Fibre: insoluble and soluble fibre
N3 fatty acids Phenolic Compounds: Phenolic acids,
Conjugated fatty acids Flavonoids, catechins and Tannins
Vitamins Non digestible oligosaccherides:
Folates Fructans, Galacto oligosaccharides,
 Vitamin E isomaltos oligosaccharides, Xylo
Carotenoids: b-carotene and alpha oligosaccharides
carotene Phytosterols
Vitamin c Glucosinolates
Minerals Carotenoids: Lutein, cryptoxanthine
Selenium Lycopene
Organosulphur Compounds

C. Classification based on Organ/Organ System

Another classification is by the target organ/system benefitted. This is of clinical

significance especially with respect to treatment and management of various
diseases.

Classification of functional foods according to organ/organ system-

Organ/organ system Food Component

Gastrointestinal tract Prebiotics, soluble and insoluble fibres,
Probiotics, Polyphenols, Phytate
Cardiovascular system N-3 fatty acids, Polyphenols,
Micronutrients, Soluble fibre
Kidney Fructans
Immune System Prebiotics, Probiotics, Nutrients, n-3 fatty
acids, polyphenols
Skeletal system Fructans

D. Classification According to Modifications in Foods

Some foods are naturally functional and do not require much modification whereas
others do. Foods may be made functional by:

1. Elimination of components e.g. toxins or allergenic proteins

2. Increasing the concentration of natural component e.g. fortification
3. Addition of components with beneficial effects e.g. non vitamin antioxidants.
4. Addition of beneficial microbes e.g. some yeasts, bacteria.
5. Replacement of a component, usually a macronutrient e.g. fat replaced with
modified or emulsified carbohydrates. And
6. Enhancement of bioavailability of components.

According to modifications done the foods are classified as:

1. Fortified foods- Fortified foods are foods fortified with additional nutrients e.g.
vitamin fortified milk and Calcium-fortified orange juice. These nutrients which are
fortified are present in foods but are not in appreciable amounts.
2. Enriched foods- Enriched foods are foods with added new nutrients or
components not normally found in a particular food e.g. folic acid enriched breads,
butter with phytochemicals, probiotics etc.

3. Enhanced foods- Enhanced commodities are foods in which one of the

components has been naturally enhanced through special growing conditions, new
feed composition, genetic manipulation or otherwise. Examples are eggs with
increased omega 3 fatty acids content achieved by altered chicken feed,
Conjugated linoleic acid enriched milk achieved by feed manipulation etc.

4. Altered foods- Altered products are foods from which harmful components has
been removed, reduced or replaced with another substance with beneficial
effects.E.g. fibers as fat replacers in high fat products.

E. Classification based on Nutraceutical Factors in Specific Foods

This classifiction is more appropriate when there is interest in a particular

nutraceutical compound or related compounds. There are several nutraceutical
substances that are found in higher amounts in specific foods or food families such
as capsaicinoids are found primarily in pepper fruit, and allyl sulfur (organosulfur)
compounds are chiefly concentrated in onions and garlic.

F. Classification based on Mechanism of Action

This system groups nutraceutical factors together, irrespective of food source,

based upon their proven or assumed physiological properties. Among the classes
are anticarcinogenic, antioxidant, anti-inflammatory, antibacterial, osteoprotective,
and so on. This classification would be helpful to an individual who is genetically
predisposed to a particular medical condition , researchers are trying to develop
potent functional foods for such persons or planning diet and product developer to
develop a new functional food.

G. Classification of nutraceuticals based on chemical nature

This classification permits nutraceuticals to be categorized under

molecular/elemental groups. This preliminary model includes several large groups,
which then provide a bases for subclassification or subgroups, and so on. One way
to group nutraceuticals grossly is as follows:

• Isoprenoid derivatives

• Phenolic substances

• Fatty acids and structural lipids

• Carbohydrates and derivatives

• Amino acid-based substances

• Microbes

• Minerals
 SAFETY OF FUNCTIONAL FOODS
Health Claims
The principal reasons for the growth of the functional food market are aging
population, health trends and public education. Due to increase in life expectancy,
the number of elderly continues to rise, to the total population. Obesity, heart
disease, cancer, osteoporosis and arthritis continue to climb in countries throughout
the world.

Functional foods offer great potential to improve health and to some extent helps
prevent certain diseases when taken as part of a balanced diet and healthy lifestyle.
Functional foods are one of the fastest-growing segments of the food industry. In
some countries, functional foods have already become part of the dietary
landscape. Functional food constituents may be perceived to enhance short-term
well-being, the benefits are generally related to the long-term mitigation of certain
diseases. Functional foods perform through its bioactive compounds. Bioactive
compounds are diverse types of chemicals present in small amounts in plants and
animal sources (which include fruits, greens, nuts, oils, and whole grains fatty fish
to name few). These have been studied for the prevention of cancer, heart disease,
and different diseases. Examples of some of the bioactive compounds are lycopene,
resveratrol, lignan, tannins, and indoles.

The advent of the internet has opened the doors for a wealth of information. People
have become more nutrition savy than ever before. Their curiosity regarding health
care information can be met by just a single click which can give them vast
information about the etiology, prevention, and treatment of various diseases.
Similarly, the consumers are becoming more alert to health claims and are eager to
know advanced information about food products than before.

Researches in functional foods are fruitless if not used for human health and hence
comes the role of regulations. The health claim for each functional food were
defined by the three different phrases viz., nutrient function claims, other function
claims, and reduction of disease risk claims.

Japan was the first country to legalise health claims under Foods for Specified health
uses (FOSHU) in 1991. Since 1991 about 1271 products have been given green
signal under FOSHU. Recently about 400 foods have been approved under Japan’s
2015 “Foods with Function Claims”(FFC) regulation.

In the United Statesthe structure/function claims were expressed in the Dietary

Supplement Health Education Act (DSHEA) in 1994. European Union established a
science-based approach for concepts in functional food science as “Functional food
Science in Europe” (FUFOSE), in 1996. Codex adopted the guidelines in which the
nutrient function claim was included in 1997.

In India, the nutraceutical regulation was implemented in 2010 under The Food
Safety and Standard Authority of India (FSSAI) Act.

Categories Health Claims

Category 1 Modulation of gastrointestinal conditions
Category 2 Modulation of serum cholesterol level
Category 3 Modulation of serum cholesterol level and gastrointestinal
conditions
Category 4 Modulation of blood pressure
Category 5 Acceleration of mineral absorption
Category 6 Acceleration of mineral absorption and modulation of
gastrointestinal conditions
Category 7 Promotion of bone health
Category 8 Maintenance of healthy teeth
Category 9 Modulation of blood sugar level
Category 10 Modulation of serum triacylglycerol level and blood fat
percentage
Criteria for sound science
According to the Department of Health and Human Services, diet plays a role in 5
of 10 of the leading causes of death, including coronary heart disease (CHD),
certain types of cancer, stroke, diabetes (noninsulin dependent or type 2) and
atherosclerosis. The dietary pattern that has been linked with these major causes of
death in the United States and other developed countries is characterized as
relatively high in total and saturated fat, cholesterol, sodium and refined sugars and
relatively low in unsaturated fat, grains, legumes, fruits and vegetables. An
accumulating body of research now suggests that consumption of certain foods or
their associated physiologically active components may be linked to disease risk
reduction. The great majority of these components derive from plants; however,
there are several classes of physiologically active functional food ingredients of
animal or microbial origin.

Claims linking the consumption of functional foods or food ingredients with health
outcomes require sound scientific evidence and significant scientific agreement.
The Food and Drug Administration (FDA) outlined the criteria for “significant
scientific agreement” in a guidance document released on December 22, 1999.
There is a clear discrepancy between “emerging evidence” (characterized by in
vitro or animal studies, uncontrolled human studies, and inconsistent
epidemiological evidence) and “significant scientific agreement.” To reach such
agreement requires the support of a body of consistent, relevant evidence from
well-designed clinical, epidemiologic and laboratory studies, and expert opinions
from a body of independent scientists. Claims about the health benefits of
functional foods should be based on sound scientific evidence, but too often only so-
called “emerging evidence” is the basis for marketing some functional foods or their
components.

The FDA does not provide a specific definition for functional foods, and thus a
formal regulatory category and framework does not exist. The only regulation for
functional foods is related to its intended use, which is determined by the
manufacturer and is often determined for marketing purposes. Fortunately, current
legislation in the United States is designed to protect consumers from misleading
and false information that may appear on these food products. Functional foods can
be categorized as either conventional foods, foods for special dietary use, food
additives, dietary supplements, or medical foods – all of which are dependent on the
intended use and type of claim made by the manufacturer. The FDA regulates all
claims associated with food products, including that found on the product label,
website, or any other form of advertisement. There are four types of FDA-regulated
claims that can be used on the labels of functional food products:

 Nutrient content claims

characterize the level of a nutrient in food and are limited to nutrients that have
an FDA-established Daily Value. Nutrient content claims are most familiar to
consumers as they relate to the “Nutrient Facts Label” box on all packaged
foods and are typically placed on the front of the package. Examples include
“low sodium”, “fat-free”, “high fiber”, “contain 1200 mg of calcium”, or
“excellent source of vitamin C”. All of these nutrient content claims have
specific definitions and requirements mandated by the FDA.
 Authorized health claims
characterize the relationship of the food or substance to a disease or health-
related condition and is supported by substantial scientific evidence,
demonstrating clinical effectiveness, and/or “significant scientific agreement”
among qualified experts from accredited scientific bodies.
 An example of an authorized health claim for dietary fiber and some
types of cancer is as follows: “Low-fat diets rich in fiber-containing grain
products, fruits, and vegetables may reduce the risk of some types of
cancer, a disease associated with many factors.”
 Qualified health claims
characterize the relationship of any food or substance to a disease or health-
related condition, and are based on the totality of available scientific evidence.
The available scientific evidence does not have to be as strong or well-
established as that required for authorized health claims.
 An example of a qualified health claim for walnuts and heart disease is
as follows: “Supportive but not conclusive research shows that eating 1.5
ounces per day of walnuts, as part of a low saturated fat and low
cholesterol diet and not resulting in increased caloric intake, may reduce
the risk of coronary heart disease. See nutrition information for fat [and
calorie] content.”
 Structure-function claims
characterize the mechanism by which a nutrient affects a structure or function
in the body or an individual’s well-being, provided that such statements are not
disease claims. A key requirement of a structure-function claim is that it cannot
purport to act as a drug or, in other words, it cannot claim to treat, cure, or
diagnose a disease. For example, general claims such as “calcium builds strong
 bones” or “protein helps build strong muscles” are generally accepted by the
FDA as appropriate structure-function claims and do not require post-market
FDA review. In addition, these types of claims may characterize the means by
which a nutrient or dietary ingredient acts to maintain such structure of
function, for example, “fiber maintains bowel integrity”.
Effectiveness and safety
Safety considerations
Although there is evidence that certain functional foods or food ingredients can
play a role in disease prevention and health promotion, safety considerations should
be paramount. Safety concerns have recently been raised, particularly with regard
to the seemingly indiscriminate addition of botanicals to foods. A plethora of
“functional” bars, beverages, cereals and soups are being enhanced with
botanicals, some of which may pose a risk to certain consumers.

The safety issues related to herbs are complex and the issue of herb-drug
interaction has received increasing attention. One example is St John’s wort, a
popular herb utilized for treating mild depression. Hypericum extract from St. John’s
wort significantly increases the metabolic activity of liver cytochrome P450. This
enzyme inactivates several drugs, and thus would be expected to decrease their
levels and activities in the body. Consuming St. John’s wort has been shown to
cause concomitant decreases in plasma concentrations of theophylline,
cyclosporine, warfarin and ethinylestradiol/desogestrel (oral contraceptives). Such
data prompted the FDA to issue a Public Health Advisory about St. John’s wort in
February of 2000, as have Canadian authorities. In the United States, some
consumer groups have lobbied the FDA to halt the sale of 75 functional foods
enhanced with St. John’s wort as well as the following additional herbs: guarana,
gotu kola, ginseng, ginkgo biloba, echinacea, kava kava and spirulina.

Also in 2000, the General Accounting Office (GAO) released a report that raised
concerns about the safety of certain functional foods. The GAO report stated that
the FDA “has not developed regulations or provided guidance to companies on the
type of safetyrelated information that should be included on their labels for
functional foods and dietary supplements. The absence of such safety information
poses a significant safety risk to some consumers.” In June of 2001, the FDA issued
warning letters to the food industry concerning the use of “novel ingredients” such
as St. John’s wort in conventional food. The GAO has made the following
recommendations regarding the safety of functional foods:

● Develop and promulgate regulations or other guidance for industry on the

evidence needed to document the safety of new dietary ingredients in dietary
supplements
● Develop and promulgate regulations or other guidance for industry on the safety-
related information required on labels for dietary supplements and functional foods

● Develop an enhanced system to record and analyze reports of health problems

associated with functional foods and dietary supplements

Safety depends on the following factors-

1. Regulation

Unlike pharmaceutical drugs, nutraceutical products are widely available and

minimally monitored. Companies are not obligated to back claims about the
function and effectiveness of their product, but many companies attempt to provide
scientific backing of their products to increase credibility.

2. International sources

In the global market, there are significant product quality issues Nutraceuticals from
the international market may claim to use organic or exotic ingredients, yet the lack
of regulation may compromise the safety and effectiveness of products. Companies
looking to create a wide profit margin may create unregulated products overseas
with low-quality or ineffective ingredients.

3. Bioavailability

Bioavailability, which can be thought of as the the "absorption rate" of a

supplement product, is one of the main challenges in finding effective nutraceutical
products. The bioavailability of nutrients is higher in food eaten in its natural state.
Even among unprocessed foods, not all foods are broken down and digested as
effectively. Nutraceuticals with poor absorption rates results in nutrients being
disposed from the body without providing any nutritional or medicinal benefit.

4. Impact of placebo effect

Part of the effectiveness of nutraceuticals may be attributed to the placebo effect.

Consumers using nutraceuticals may inaccurately credit their use of nutraceuticals
for healing illness, when the body is often able to recover on its own.

SAFETY OF FUNCTIONAL FOODS

Needs to be assessed according to established regulations-

 Clinical – Randomised Clinical Trials

 Biomarkers
 ADI / Safe upper limits
 Pharmacokinetics
 Preclinical test – Efficacy and safety
  Proof of Concept

Safe Limits for Nutrients

There is no evidence that essential micronutrients should be regarded as inherently
safe at high doses and much evidence, that excessive intakes can cause harm.
Dietary Reference Intakes
Estimated Average Requirement (EAR): the average daily nutrient intake level
estimated to meet the requirement of half the healthy individuals in a particular life
stage and gender group.

Recommended Dietary Allowance (RDA): The average daily dietary nutrient intake
level sufficient to meet the nutrient requirement of nearly all (97 to 98 percent)
healthy individuals in a particular life stage and gender group.

Adequate Intake (AI): The recommended average daily intake level based on
observed or experimentally determined approximations or estimates of nutrient
intake by a group (or groups) of apparently healthy people that are assumed to be
adequate. Used when an RDA cannot be determined.

Tolerable Upper Intake Level (UL): The highest average daily intake level that is
likely to pose no risk of adverse health effects to almost all individuals in the
general population. As intake increases above the UL, the potential risk of adverse
effects may increase. 

Safe Upper Levels (SULs) an intake that can be consumed daily over a lifetime
without significant risk to health on the basis of available evidence
 Guidance Levels an approximate indication of levels that would not be expected to
cause adverse effects, but have been derived from limited data and are less secure
than SULs.

SULs or Guidance Levels are the doses of vitamins and minerals that susceptible
individuals could take daily on a life-long basis, without medical supervision.

Supplemental intake + Dietary and other known exposures = Estimated SUL (total)

Risk assessments
 Risk assessments
 Hazard identification ( Adverse effects)
 Hazard characterisation (including dose-response assessment);
 Exposure assessment
 Risk characterisation.
 Risk-benefit analysis
TOXICITY and SIDE EFFECTS OF
FUNCTIONAL FOODS- Dietary
supplements
1. Vitamin and mineral supplements

Although adequate intake of these micronutrients is required to maintain optimal

health, the possibility of toxicity increases with increasing dose. Since dietary
micronutrient deficiency is increasingly rare in developed counties, most
supplement consumers actually have excess vitamin and mineral intake. Despite
widespread belief that vitamin and mineral supplements are health beneficial,
recent reviews of vitamin and mineral supplement trials in community-dwelling
adults with no nutritional deficiencies have concluded that there is no clear
evidence of beneficial health effects.

These include primary or secondary prevention of chronic diseases including

cardiovascular disease, cancer, cognitive decline and effects on overall
mortality. Indeed, on the contrary, there is evidence for possible harm based on
consumption of individual vitamins and mineral in excess.

Toxicity following consumption of water-soluble vitamins is rare. However,

photosensitivity and neurotoxicity have been reported at doses higher than 500
mg/d of pyridoxine (vitamin B6) and cases of pyridoxine-associated chronic
sensory polyneuropathy have been reported in elderly patients consuming
multivitamin supplements.

Reports of toxicity associated with overconsumption of supplemental antioxidant

fat-soluble vitamins are more prevalent. Vitamin E is a family of 8 related
tocopherols and tocotrienols of which α-tocopherol is the form generally used in
supplements. Doses of 800–1200 mg/d can result in bleeding associated with
antiplatelet action and doses above 1200 mg/d can result in diarrhea, weakness,
blurred vision and gonadal dysfunction. Moreover, vitamin E supplementation
following radiation therapy in a randomized trial of head and neck cancer
patients was associated with increased cancer recurrence in the first 3.5 years of
follow-up and meta-analysis has suggested an increase in all-cause mortality
after high dose vitamin E supplementation.

Toxicity has also been associated with consumption of supplemental vitamin A

and its provitamin carotenoid precursors. In two large clinical trials, the Retinol
Efficacy Trial and the ATBC study, male smokers receiving β-carotene
supplements had significantly increased risk of lung cancer. The ABTC study
further showed that prostate cancer incidence and mortality were increased in
male alcohol users consuming the supplement. An additional two studies have
suggested increased mortality in smokers consuming β-carotene supplements.
Excess vitamin A supplementation has been suggested to be associated with
adverse effects on bone health including low bone mineral density and increased
fracture risk. In addition, women consuming large amounts of vitamin A
supplements during pregnancy have been reported to have increased incidence
of congenital abnormalities. There is also a case report of intra-hepatic
cholestasis in a patient with chronic hypervitaminosis A after 12 years of
supplement consumption which resolved after supplements were ceased. In
addition to toxicity from excess vitamin consumption, toxicity can arise from
excess consumption of minerals. In particular, there is an increasing risk of
hyperchromatosis, an iron storage disease associated with liver injury after
excess consumption of iron or multimineral supplements. This can be
exacerbated by alcohol consumption 

2. Fish Oil and Omega-3 Fatty Acids

Fish oil and omega-3 fatty acids are well tolerated even at doses of 1–2,000
mg/d and there is little evidence of toxicity. However, simultaneous consumption
of fish liver oils which also contain vitamin A and multivitamin supplements could
result in hypervitaminosis A. Furthermore, fish oils and omega-3 fatty acid
supplements may exacerbate anticoagulation and promote bleeding in patients
taking anticoagulant medications such as warfarin.

3. Protien Powders and infant Formula

The dairy proteins appear to have little toxicity except in individuals with
allergies to cow’s milk protein, although excessive consumption may result in
ketosis. In contrast, there is an ongoing debate with regard to the potential
safety of SPI. This is related primarily to the presence of weakly estrogenic
compounds – the isoflavones genistein and daidzein which are among the 100
phytochemicals which remain bound to the protein isolate. These compounds
can reach potentially estrogenic levels after SPI consumption in soy-formula fed
infants and in children, men and post-menopausal women taking soy protein
supplements. Concerns have focused on potential estrogenic effects in early
development resulting in reproductive toxicity, infertility, demasculinization and
increased promotion of estrogen-responsive cancers such as breast and
endometrial cancer. Several clinical studies of SPI and soy formula toxicity have
been conducted. Epigenome-wide DNA methylation analysis of vaginal cells from
cow- and soy-infant formula fed girls indicated differential DNA methylation
associated with decreased expression of the estrogen-responsive proline rich 5-
like (PRR5L) gene. In addition, epidemiological studies have suggested a slightly
earlier age of menarche (12.4 vs. 12.8 years) but less female-typical play in soy
formula-fed girls. In contrast, data from a longitudinal ultrasound study of breast,
cow’s milk formula and soy-formula-fed infants (The Beginnings Study)
demonstrated no significant effects on testis or prostate volumes or structural
characteristics at ages 1 year and 5 years. In addition, a retrospective cross-
sectional study of adults fed soy formula or cow-milk formula as infants did not
find significant differences in responses to questions about health and
reproduction. Moreover, in adult men, a recent meta-analysis showed no
significant effects of soy protein on male reproductive hormones. Animal studies
of SPI and soy formula toxicity have likewise been contradictory. Akingbemi et
al. reported that perinatal exposure to diets made with soy resulted in
suppressed steroidogenesis, decreased testosterone secretion and increased
Leydig cell proliferation in rats. Similarly, Sharpe et al. reported that marmoset
monkeys fed soy infant formula had suppressed serum testosterone
concentrations. Increased testis size, and Leydig cell numbers/testis were also
observed in these monkeys at adulthood consistent with compensated Leydig
cell failure. In adult female ovariectomized mice, feeding SPI was shown to
increase growth of human breast cancer cell xenografts consistent with an
estrogenic effect. These studies, and concerns regarding estrogenicity, led to a
recent review of the safety of soy infant formula by a panel from the Center for
the Evaluation of Risks to Human Reproduction (CERHR) established by the
National Toxicology Program (NTP) and the National Institute for Environmental
Health Sciences (NIEHS). However, the committee was unable to issue a
conclusive recommendation regarding developmental and reproductive toxicity
as a result of limitations in the available human data. In contrast to the small
number of animal studies with SPI suggesting estrogenicity, lifetime feeding
studies in rats fed with soy protein isolate (SPI), the sole protein source in soy
formulas revealed no effects on sex organ weights, no effects on serum sex
steroids concentrations and no effects on fertility. Moreover, chronic feeding
studies with SPI in adult male cynomolgus macaque monkeys also are reported
to have had no effect on testis weight, morphology, serum testosterone or
estradiol concentrations, or sperm counts. In addition, our laboratory has
conducted a series of studies in ovariectomized adult female rats, in prepubertal
male and female rats and in neonatal piglets in which we have utilized genomics
analysis either with Affymetrix chips or using RNAseq to examine head to head
gene expression profiles in the liver, bone, mammary gland, uterus and testis
after treatment with 17β-estradiol (E2) or feeding SPI. These studies revealed
only minor overlap between E2 and SPI-regulated genes (3–10%) representing
specific subsets of E2 regulated pathways, indicative of actions similar to those
of selective estrogen receptor modulators (SERMS), rather than weak estrogens,
and with either no effect or antagonist actions on reproductive and proliferative
pathways.

4. Neutraceuticals

Metabolites of EGCG – the active catechol in green tea extract, typically

considered to be responsible for green tea’s antioxidant properties – are
suspected to enhance oxidative stress and have been associated with liver
injury. It is also far from clear that consumption of these nutraceutical
supplements have true health benefits given a lack of large clinical trials. The
most intensively studied nutraceutical flavonoids are the soy derived isoflavones
genistein and daidzein, and the daidzein metabolite equol. Unlike other
flavonoids, the isoflavones in their purified form have been shown to possess
estrogenic properties in vitro and in animal models, including the ability to
produce uterine hypertrophy or reproductive tract malformations, reduce testis
size, inhibit androgen production, reduce fertility, and stimulate estrogen-
dependent tumor growth. Since evidence emerged demonstrating health risks
following hormone replacement therapy in post-menopausal women,
menopausal women have increasingly turned to use of dietary supplements to
treat symptoms such as hot flashes, depression and bone loss. A recent survey
indicated that as many as 42% of such women were using soy products including
isoflavone extracts and purified isoflavones such as genistein. Since these are
concentrated or purified products, they can achieve far higher plasma levels
than when isoflavones are consumed as part of SPI or soy foods, which are
complex mixtures of bioactive proteins, peptides and over one hundred
phytochemicals. There have been case reports of endometriosis in women
consuming isoflavone supplements and, given the clear evidence of
estrogenicity, there is a likelihood of increased risk of estrogen sensitive cancers
in consumers of these products.
 Bibliography
 Handbook of nutraceuticals and functional foods by ROBERT E. C. WILDMAN;
Chapter 1
 Functional Foods: Benefits, Concerns and Challenges—A Position Paper from the American
Council on Science and Health1 Clare M. Hasler2 (Department of Food Science and Human
Nutrition and Functional Foods for Health Program, University of Illinois, Urbana, IL 61801)
 ADVERSE EFFECTS OF NUTRACEUTICALS AND DIETARY SUPPLEMENTS Journal by Martin J. J.
Ronis, Kim B. Pedersen, and James Watt
 Nutraceutical and functional food as future food: A Review by Rajesh K. Kesharwani, Anil Kumar
Sharma and Narendra Vyas
 Swayam course modules and nutraceuticals and functional foods- M1W1,
M2W1 and M3W1
 Asian food regulation information service website- www.asianfoodreg.com