Setting NRVs for Bioactive Compounds

in South Korea:

Current Situation and Future Challenges

Schlosshotel

Kornberg am Taunus

Germany

November 1, 2013

Bioactives: Qualitative NRVs for Lifestage Groups?

CRN-International 4th Scientific Symposium

Namsoo Chang Dept. of Nutritional Science & Food Management

Ewha Womans University

Seoul, Korea

Health benefits of bioactive

compounds

• Stems from knowledge and experience that

humans have accumulated over time in many

culture

• Korean people have been utilizing over ~0000

vegetables, fruits, nuts, legumes, mushrooms,

grains, and foods of marine sources such as fish

and seaweeds

Characteristics of the Korean Diet

• Philosophy: Food = Medicine

• Plenty of vegetables: Variety, amount

• Foods of marine sources: fish & shellfish,

seaweeds

• Fermented food

• Colorful: 5 different color (red, yellow, blue,

white, black)

Adapted from Trujillo, JADA 2006

Health Benefits of Bioactive Food Components

Cell Oxidation

Hemostasis/thrombosis

Epigenetics

Growing consensus in the scientific

community on setting NRVs for

bioactive compounds

• Heber D & Shao A. Bioactive food components: Changing the

scientific basis for intake recommendations. IADSA, 2011

• Bieselski, et al., Nutrient reference values for bioactives: new

approaches needed? A conference report. Eur J Nutr, 2013 (2012

CRN-I conference on NRV, Kronberg im Taunus, Germany)

• Gaine PC, et al. Are dietary bioactives ready for recommended

intakes? Adv Nutr 4:539-41, 2013 (ASN meeting symposium

summary, May, 2013, Boston, USA)

• 11th china Nutrition Science Conference & 2013 China & Korea

Joint International Phytonutrient Symposium on the essential and

non-essential nutrients present and future. (May 2013, Hangzhou,

China)

• CRN-I scientific symposium on Bioactive: qualitative NRVs for life-

stage groups (Nov., 2013, Kronberg im Taunus, Germany)

To set NRVs for nutrients, we need

to have or decide the following:

• DRIs (EAR, RDA, AI, UL)

• What DRI values to use – RDA

– EAR

• Data needed – Intake assessment

– Health benefits

– Risk assessment

• One value for all general population or multiple values to accommodate specific age or physiological stage groups

Procedures for setting NRVs for

nutrients in South Korea (2011)

• Based on RDA

• Nutrients – protein, total fat, saturated fatty acids, carbohydrates,

dietary fiber, cholesterol, sodium

– vitamins & minerals

• Determination of population adjust means (PAMs) – Population groups by age and gender (Using the

population statistical data from the National Statistics Office)

– ∑ (number of population by age & gender x RDA by age & gender)/total number of population

• Comparison of population adjust means and RDAs

• Compared NRVs with ULs

Current (2013) NRVs for nutrients in

South Korea

Nutrients Amount Nutrients Amount Nutrients Amount

Carbohydrates (g) 330 Iron (㎎) 12 Pantothenic acid (㎎) 5

Dietary fiber (g) 25 Vitamin D (㎍) 5 Phosphorus (㎎) 700

Proteins (g) 55 Vitamin E (㎎α-TE) 11 Iodine (㎍) 150

Fats (g) 51 Vitamin K (㎍) 70 Magnesium (㎎) 315

Saturated fats (g) 15 Vitamin B1 (㎎) 1.2 Zinc (㎎) 8.5

Cholesterol (㎎) 300 Vitamin B2 (㎎) 1.4 Selenium (㎍) 55

Sodium (㎎) 2,000 Niacin (㎎ NE) 15 Copper (㎎) 0.8

Potassium (㎎) 3,500 Vitamin B6(㎎) 1.5 Manganese (㎎) 3.0

Vitamin A (㎍ RE) 700 Folate (㎍) 400 Chromium (㎍) 50

Vitamin C (㎎) 100 Vitamin B12(㎍) 2.4 Molybdenum (㎍) 25

Calcium (㎎) 700 Biotin (㎍) 30

Revised, June 5, 2013

NRVs for bioactive

substances

• Lack of a scientific framework on which to

base recommendations

– Not chemically well-defined except a very few,

often mixtures

– Not essential, but provide health benefits

– No/unclear deficiency symptoms

Bioactive food components

• Are frequently used in the health/functional

foods (HFF) or as ingredients for HFF in

South Korea

The Health Functional Food (HFF) Act

• Enacted in 2004 to ensure the safety of health functional foods with certain

health claims for consumer information.

• Definition: A product (form: tablets, capsules, powders, granules, pastes,

gels, jellies, bars) intended for use to enhance and preserve the human

health with one or more functional ingredients or constituents

• In 2008 the scope was extended to include conventional foods and other

diet supplements

Functional ingredients listed in the

Health/Functional Food Code (Generic type)

Nutrients Non-nutrients

Vitamin A

Vitamin D

Vitamin E

Vitamin K

Beta-carotene

Vitamin B1

Vitamin B2

Vitamin B6

Vitamin B12

Niacin

Vitamin C

Pantothenic

acid

Folic acid

Biotin

Calcium

Magnesium

Potassium

Zinc

Copper

Selenium

Manganese

Iron

Iodine

Molybdenum

Chrome

Dietary fiber

Essential fatty

acids

Protein

Alkoxyglycerol

Aloe gel

Aloe whole leaf

Chitosan/chitooligosaccharide

Chlorella

CLA

Coenzyme Q10

Fructooligosaccharide

Gamma-linolenic acid

Ginseng

Glucosamine

L-theanine

Lecithin

Lutein

MSM

Mucopolysaccharide

N-acetylglucosamine

Octacosanol

Omega-3 fatty acids

Phosphatidylserine

Phytosterol/-ester

Plants containing chlorophyll

Probiotics

Red ginseng

Red yeast rice

Soy isoflavone

Soyprotein

Spirulina

Squalene

Banaba leaf extact

Evening primrose seed

extract

Ganodermalucidun fruit

body extracts

Garciniacambogia

extract

Ginko leaf extract

Green tea extracts

Guava leaf extract

Haematococcus extract

Japanese apricot extract

Milk thistle extract

Propolis extracts

Saw palmetto extract

Functional fiber:

Gua gum/hydrolyzates

Glucomannan

Indigestible

maltodextrin

Oat fiber

Soy fiber

Tree ear

Wheat fiber

Barley fiber

Arabic gum

Corn bran

Inulin

Psyllium husk

Polydextrose

Fenugreek seed

(28) (55)

Regulation on approval of functional

ingredient for HFF (Product-specific type)

functional ingredients other than what is listed in the HFF Code need to

be approved for health claims individually

Data needed to apply for a product to be

considered as HFF (Product-specific type)

• Hx of safe use

• Manufacturing processes

• Recommended intake

• Toxicological data

• Clinical data

• Nutritional evaluation data

• Bioavailability data

Soy Isoflavone (Generic type)

• Health claims: Help to maintain bone health

• Recommended intake: 24 ~ 27 mg/d as aglycone

soybean isoflavone

• Caution

– Infants, children, pregnant and lactating women

– Individuals who has an allergy to soybean

– Individuals who are sensitive to the estrogen

Isoflavone contents of common

soybean products in Korea

Korean J F&N, 2000

Isoflavone intake assessment in

South Korea

• Adolescents: 28.1mg/d

• Female college students: 33.8mg/d

• Middle-aged women: 24.4mg/d

– Pre-/post-menopausal women: 16.0mg/34.9mg/d

– Postmenopausal women: vegans/omnivores (33.9mg/

23.9mg/d)

• Intake level very close to that of Japanese

(25mg/d)

Soy isoflavone safety

• No safety data in Korea

• Current safe intake level for isoflavone:

30mg/d (aglycone) • Adopted the Japanese standards for isoflavone in

Special Foods for Health Purposes

• Health claims: helps eye health by maintaining

the density of macular pigments which can be

decreased by aging

• Daily intake amount: 10 ~ 20 mg as lutein

• Caution

– When taken in excessive amounts, it may turn the

skin yellow temporarily

Lutein (Generic type)

Efficacy reevaluation of ingredients

for HFF (generic type)

• 2012 Korea Ministry of Food & Drug

Safety reevaluation

– Recommended intake

• Omega-3 fatty acids: 0.5-2.0g/d

• Glucosamine: 1.5-2.0g/d

• Saw palmetto extracts: 70-115mg/d

• Coenzyme Q10: 90-100mg/d

Korea MFDS

Based on 2008 KNHANES data, Koreans consumed 1549

plant foods.

Collated flavonoid database on 1317 food items covering

85% of plant foods

Development of flavonoid database

for commonly consumed foods by

Koreans

Yang, et al., Korean J Nutr 2012

Flavan-3-ols intake associated with

metabolic syndrome in Korean

adults

• Daily intake: 30.0 mg/d (men) and 22.5 mg/d (women)

Low tea and red wine consumption in Korean adults may

be attributed to their low intakes of flavan-3-ols

• Estimated daily flavan-3-ols intakes of Australia (422

mg/d, black tea), Denmark (148 mg/d, fruits) and the

Netherlands (145mg/d, red wine). U.S. (158 mg/d) and

Spain (32 mg/d)

Yang, et al., Nutr Res Pract. 2012

Tomato extracts (Product-specific type)

• Health claim: Antioxidant (Health claims Grade

II)

• Recommended intake: [(all-trans)-lycopene]

5.7~15 mg/day

• Caution:

– Pregnant and lactating women

– Children

Establishing NRVs for

bioactive substances face

many challenges ahead!!

Challenges to provide intake

recommendations for bioactive

substances

• Bioactives content of plant

foods varies: sun, ripeness,

storage, preparation,

processing

• Bioavailability influenced by

chemical structures, baseline

diet, genetic makeup

• Very limited food database

• Difficult to assess usual

intake

• No solid health

outcomes/endpoints

• Usual intake of general

population << recommended

intake for efficacy

• Difficult enough to give a

recommendation for general

public living within one

country, may be impossible

to apply it to other

populations or those living in

other countries of a different

food culture

Gaine et al., Adv Nutr, 2013

Yeum, et al., APJCN 1999

Serum levels of lutein and

lycopene in South Korea

• Serum levels of healthy Korean adults

– Lutein: higher (30-40 μg/dL) than Western

populations (11-14 μg/dL). We consume a

significant amount of spinach and turnip greens

which are high in lutein content

– Lycopene: lower (7-11 μg/dL; tomato

consumption: 11.8g/person/day) than Spanish

(20-22 μg/dL, tomato consumption: 35.3

g/person/day) or US adults (NHANESIII 26.4 and

23.9 μg/dL for male and female, respectively)

Korean J Nutr 2009 J Geochem Explor 1997

Do we have enough evidence for

setting NRVs for bioactives?

CRN International Symposium Schlosshotel, Kornberg am Taunus, Germany November 1,

2013

• No DRIs established for bioactives

• Do have some data

– Intake assessment

– Health benefits

– Risk assessment

Basic types of data needed to inform

bioactive intake recommendations and

South Korea HFF

Type of data Specific application HFF (S. Korea)

Analytical Methods to characterize bioactive(s) V

Detect and quantify bioactive(s) in human sera and tissues V

Quantify bioactive(s) in the food supply

Quality control V

Preclinical In vivo data suggesting health benefit, bioavailability,

pharmacokinetics, risk assessment

V

In vitro data to establish mode of action, biologic plausibility V

Clinical Population intake patterns

Epidemiologic observation V

Intervention V

Biomarkers of exposure and efficacy V

Risk assessment V

Post-market surveillance V

Heber & Shao. IADSA, 2011

Setting NRVs for bioactives in South Korea

• Regulatory bodies for setting NRVs

– Korea Ministry of Food and Drug Safety

• Establish NRVs for labeling purposes: all processed foods

and Health Functional Foods

• Currently not considering NRVs for bioactives

• Revision of KDRIs is currently undergoing

– The Ministry of Health and Welfare is in charge of the

KDRIs

– Revised version due in 2015

• Establishing KDRIs for bioactives is not yet a subject of major

discussion

• An issue for a potential need for establishing DRIs for

bioactives was raised

Adequate intake

US Institute of Medicine’s Dietary Reference Intakes

AIs and ULS for Bioactives

Establishing Uls for bioactives

• Establishing Uls for bioactives should be

based on risk assessment

– Problems:

• no known NOAEL/LOAEL

– Use of WHO/FAO Highest observed intake

(HOI) approach

• Highest tested dose can be concluded as safe

Establishing Uls for bioactives

• For efficacy, the intake recommendation for

bioactives can be much higher (several fold ~

100 fold) than normally consumed by the

general population

• In some cases, need a more rigorous safety

data

• NRVs for bioactives need to be set at the level

which is not too close to the ULs

South Korea may be able to contribute to

establishing Uls for bioactives

• Postmarket surveillance system

– Adverse events (AE) reporting and signal generating system for

HFF is in operation from 2006 (Korea MFDS)

– On-line system for AE data collection

• Consumers: www.hfcc.or.kr

• Manufacturers: www.hfood.or.kr

• Healthcare professionals: hfoodi.kfda.go.kr

– Korea Integrated System for Signal Manipulation and Evaluation

of HFF:

• Integrated database for HFF Products, AE, Safety data

• WHO scale/Statistical analysis on cause-effect of AE

– Safety Evaluation Advisory Committee for HFF (27 members: MDs, Pharm Ds, epidemiology, statistics, consumer agency,

government officials, etc. )

CODEX NRVs

• Nutrient Reference Values (NRVs) are a set of

numerical values that are based on scientific data for

purposes of nutrition labelling and relevant claims.

• They comprise the following two types of NRVs: – Nutrient Reference Values - Requirements (NRVs-R) refer to NRVs

that are based on levels of nutrients associated with nutrient

requirements.

– Nutrient Reference Values - Noncommunicable Disease (NRVs-

NCD) refer to NRVs that are based on levels of nutrients associated

with the reduction in the risk of diet-related noncommunicable diseases

not including nutrient deficiency diseases or disorders.

GUIDELINES ON NUTRITION LABELLING, revised 2013

NCDS and Health Benefits of Bioactive Food Components

Trujillo, JADA 2006

Epigenetics

Hemostasis/thrombosis

Cell Oxidation

Positioning bioactives in the

Codex NRVs in the future

• Nutrient Reference Values -

Noncommunicable Disease (NRVs-NCD)

– Detrimental (?): macronutrients, sodium

– Beneficial (?): bioactives

The Science of Diet:

challenges in chemical biology

• Two challenges in chemical biology

– Protein chemical engineering studying protein dynamics: structure and function,

deciphering specific contributors of post-translational modifications

– The Science of diet: Disease prevention using natural products and their analogs

• Chemoprevention through dietary adjustments is attractive public

health strategy. But

• Need to move from phenomenological to mechanistic

• Skepticisms surrounding research in this area that lacked rigor and

molecular detail

• To exert a much greater impact on public health, key molecular

pathways need to be defined

Qualitative NRVs for Bioactives

Cole, BMC Biology 2013, 11:87

Thank you very much

for

your kind attention!

CRN International Symposium

Schlosshotel

Kornberg am Taunus

Germany

November 1, 2013