Hazards associated with food fortification Omar Obeid, PhD Department of Nutrition & Food Science American University of Beirut.

Hazards associated with food fortification

Omar Obeid, PhDOmar Obeid, PhDDepartment of Nutrition & Food ScienceDepartment of Nutrition & Food Science

American University of BeirutAmerican University of Beirut

Micronutrient malnutrition: widespread problem throughout the world.

Groups such as:– Children– Women of childbearing age– Elderly

Three approaches currently employed to address micronutrient deficiencies:

Dietary Diversification

Supplementation

Food Fortification

Bell I., Fletcher R., and Lambert J. (2004) Proceedings of the Nutrition Society, 63, 605-614Bell I., Fletcher R., and Lambert J. (2004) Proceedings of the Nutrition Society, 63, 605-614

Background

Continuous risk of deficiencies from one or

more nutrients

Continuous risk of deficiencies from one or

more nutrients

StrategyDietary

Diversification Supplementation Food Fortification

AdvantagesThe best long-term solution.

Targets specific risk groups very quickly with larger micronutrients doses.

Provides rapid solutions to address low micronutrient intakes at a population level while maintaining traditional dietary patterns.

DisadvantagesFactors affecting food choices are complex.

It often fails to supply all necessary nutrients.

Risk of over-consumption in individuals outside the at-risk groups or those who consume high amounts of fortified foods.

Individuals in non targeted groups are usually neglected. May not reach the most needy population groups.

compliance is poor.Substantial technical barriers to fortification:

The right dose of fortificant should be found so that it is effective but not toxic. Adverse effects on the sensory qualities of foods.Nutrient-nutrient interaction.Poor bioavailability of some fortificants.Difficulty of fortifying some foods such as rice.

Increased risk of overnutrition with consumption of large doses of micronutrients.

Bell I., Fletcher R., and Lambert J. (2004). Proceedings of the Nutrition Society, 63, 605-614Allen L. (2003) J. Nutr. 133: 3875S-3878S

Advantages & Disadvantages of interventions

Continues to be one of the main strategies employed to tackle

micronutrient deficiencies

Food Fortification

Allen L. (2003) J. Nutr. 133: 3875S-3878S.Allen L. (2003) J. Nutr. 133: 3875S-3878S.

Cost-effective & relatively easy to deliver

Concerns about the risk of over-consumption in individuals outside the

at-risk groups.

However

Bell I., Fletcher R., and Lambert J. (2004) Proceedings of the Nutrition Society, 63, 605-614

Definitions

Food Fortification

Estimating the prevalence of inadequate nutrient intakes Tolerable upper intake levels (UL)Bioavailability of nutrients from food vehiclesEfficacy trialsEffectiveness trials

Allen, L. H. (2006) J. Nutr. 136: 1055–1058Allen, L. H. (2006) J. Nutr. 136: 1055–1058

Observed Level of intakeObserved Level of intake

00

5050

100100 100100

5050

00

Risk

of adverse effects

Risk

of adverse effects

(%)

(%)

Ris

k o

f in

adeq

uac

y (%

)R

isk

of

inad

equ

acy

(%)

EAREAR RDA RDA ULUL

+2SD-2SD

Dual curves of the dose-response relations between intake &risk of adverse effects

Kraemer K et al. (2008). Nutrition Reviews, 66(9): 517–525Kraemer K et al. (2008). Nutrition Reviews, 66(9): 517–525

Supplements

Safe range of intake

Intake from food Fortified

Observed Level of intakeObserved Level of intake

00

5050

100100 100100

5050

00

Risk

of adverse effects

Risk

of adverse effects

(%)

(%)

Ris

k o

f in

adeq

uac

y (%

)R

isk

of

inad

equ

acy

(%)

EAREAR RDA RDA ULUL

0 +2SD-2SD 0 25 50 75

B6Vit C

Vit E

x RDA x RDA

Vit.A

Dual curves of the dose-response relations between intake &risk of adverse effects

Introduction of Fortification

The cumulative effects of supplementation & fortification have raised safety concerns about exceeding the tolerable upper intake levels (ULs).

Actual amount of folic acid being added to food is ≥50% more than the FDA regulations.

Individuals at greatest risk:– Those who consume large amounts of fortified foods & take dietary

supplements.

Risk of micronutrient over-consumption

Bell I., Fletcher R., and Lambert J. (2004) Proceedings of the Nutrition Society, 63, 605-614

NIH State-of-the-Science Conference statement on Multivitamin/Mineral Supplements and Chronic Disease Prevention (2006). NIH Consensus and State-of-the-Science Statements. Volume 23, Number 2.

Conley M., et al. (2003). Am J Clin Nutr; 77:1474-7

Bell I., Fletcher R., and Lambert J. (2004) Proceedings of the Nutrition Society, 63, 605-614

NIH State-of-the-Science Conference statement on Multivitamin/Mineral Supplements and Chronic Disease Prevention (2006). NIH Consensus and State-of-the-Science Statements. Volume 23, Number 2.

Conley M., et al. (2003). Am J Clin Nutr; 77:1474-7

Rothman, K. J., et al. (1995). N.Engl.J.Med.333, 1369-1373

Teratogenic Risk of High Prenatal Exposures to Performed Vitamin A

Retinal intake(µg/day)

Retinal intake(IU/day)

Pregnancies Cranial-neural crest

defects

Total defects

0-1500 0-5,000 6,410 33(0.51%) 86(1.3%)

1,500-3,000 5,001-10,000 12,688 59(0.47%) 196(1.5%)

3,000-4,500 10,001-15,000 3,150 20(0.63%) 42(1.3%)

>4,500 >15,000 500 9(1.80%) 15(3.0%)

Recommended amounts:Adult men 900 µg/day

Adult women 700 µg/day.

Recommended amounts:Adult men 900 µg/day

Adult women 700 µg/day.

Anderson J. Journal of Bone and Mineral Research 2002, 17 (8)

Vitamin A

Tolerable upper limit (UL): 2800–3000 µg/day for adult

women & men.

Tolerable upper limit (UL): 2800–3000 µg/day for adult

women & men.

Standard dose of vitamin A in multi-mineral/vitamin supplement:

1500 µg/day, whether in the retinol form (retinyl palmitate) or combination of retinol & β-carotene.

Standard dose of vitamin A in multi-mineral/vitamin supplement:

1500 µg/day, whether in the retinol form (retinyl palmitate) or combination of retinol & β-carotene.

Feskanich D et al. JAMA. 2002;287(1):47-54.

Vitamin A Intake & Hip FracturesAmong Postmenopausal Women

Long-term consumption of high vitamin A diets may contribute to osteoporosis & hip fracture.

Feskanich D et al. JAMA. 2002;287(1):47-54.

Vitamin A Intake & Hip FracturesAmong Postmenopausal Women

Feskanich D et al. JAMA. 2002;287(1):47-54.

Vitamin A Intake & Hip FracturesAmong Postmenopausal Women

Feskanich D et al. JAMA. 2002;287(1):47-54.

Vitamin A Intake & Hip FracturesAmong Postmenopausal Women

Thus, long-term intake of a diet high in retinol may promote the development of

osteoporotic hip fractures in women

Vitamin A intakes accumulate from

Anderson J. Journal of Bone and Mineral Research 2002, 17 (8)

Food

Fortified food

SupplementsCan easily exceed UL

safety

Vitamin A Fortification

Iron Fortification

Sarker A et al. AJCN. 2004; 80:149-53.

Most cost-effective way to prevent iron deficiency

Non-nutritional Anemia

Infection

Inflammation

H. PyloriNutritional

anemia Folate

Vitamin B12

Fe intake

Iron Fortification

H. Pylori

Anemia

ID

Sarker A et al. AJCN. 2004; 80:149-53.

IDA

Although associated with ID & IDA, H. Pylori eradication does not significantly influence iron absorption.

Infected children with IDA

P = 0.34P = 0.34

Iron overdose

Iron Fortification

Additional exposure to dietary iron places some segments of the population at increased risk of iron excess (Athletic males)

8 mg Males

8 mg Males

18 mg

Females

18 mg

Females

45 mg

UL

45 mg

UL

Supplements Fe-fortified foods

RDARDA

Increased Energy intake

Frequent consumption of red meat

Iron Zinc interaction

Iron & Zinc

Similar absorption & transport mechanisms compete for absorptive pathways

Walker CF et al. Am J Clin Nutr 2005; 82:5–12 Walker CF et al. Am J Clin Nutr 2005; 82:5–12

No firm conclusionson the existence of interactions

between iron and zinc

However However

Basal meal:• Wheat rolls served with margarine and water on 2 mornings.

(iron content of the rolls was adjusted to 4.1 mg by adding ferrous sulfate to the dough).

Hallberg L,Hulthén L. Am J Clin Nutr 2000;71:1147–60.

Effect of calcium on absorption & bioavailability of dietary iron

310 subjects

194 females 116 males

No inhibition when calcium in a meal was < 50 mg

Inhibition maximum when Ca 300-600 mg

Effect of calcium on absorption & bioavailability of dietary iron

1998: FDA made folic acid fortification of all cereal-grain products mandatory in the U.S.

Rationale: reduce the risk of a women having a child with neural tube defect (NTD).

Ganji V. & Wyckoff K. (2007). Am J Clin Nutr: 86:1187-92Conley M., et al (2003). Am J Clin Nutr; 77:1474-7

Folate Fortification

Associated with

Ganji V. & Wyckoff K. (2007). Am J Clin Nutr: 86:1187-92Conley M., et al (2003). Am J Clin Nutr; 77:1474-7

incidence of neural tube defects stroke associated mortality

incidence of colorectal cancer harm to population with low vitamin B-12 statusCognitive decline in older persons

But also withBut also with

Folate Fortification

Folate Fortification

Amount of fortification in the U. S set at 140 µg/100 g of cereal grain product

Expected to the average folic acid intake attributable to fortification by 100 µg/d.

High folic acid intakes may lead to the correction of hematological abnormalities associated with vit. B12 deficiency. May delay the diagnosis of B12 deficiency irreversible

neurologic damage

Wyckoff K. & Ganji V.(2007). Am J Clin Nutr: 86:1187-92

Kalmbach R D et al. (2008). American Journal of Clinical Nutrition 88 (3): 763-768Kalmbach R D et al. (2008). American Journal of Clinical Nutrition 88 (3): 763-768

Potter J. and Ulrich C. (2006) Epidemiol Biomarkers Prev; 15(2): 189-93

Wyckoff K. & Ganji V. (2007). Am J Clin Nutr: 86:1187-92

B12 necessary for the fxn of MS.

MS responsible for the remethylation of tHcy to methionine.

MS also responsible for the conversion of N5-Methyl THF to THF.

In B12 deficiency, folate is “trapped” as N5-Methyl THF .

Thus N5, N10-methylene THF needed for DNA synthesis is not produced which leads to macrocytosis

MS also responsible for the conversion of N5-Methyl THF to THF.

In B12 deficiency, folate is “trapped” as N5-Methyl THF .

Thus N5, N10-methylene THF needed for DNA synthesis is not produced which leads to macrocytosis

High dietary folic acid intake leads to bypassing the “trap”.

Macrocytosis associated with B12 deficiency is corrected.

High dietary folic acid intake leads to bypassing the “trap”.

Macrocytosis associated with B12 deficiency is corrected.

Mechanism

Mean corpuscular volume of subjects with low serum vit. B12 concentrations stratified by folic acid fortification period

Wyckoff K. & Ganji V. (2007). Am J Clin Nutr: 86:1187-92

Higher proportion of individuals with low serum vit. B12 concentrations without macrocytosis in the postfortification

period than in the prefortification period.

Folic acid fortification may have led to a correction of macrocytosis associated with vitamin B12 insufficiency

Could be appropriate to add vitamin B12 to foods currently fortified with folic acid.

Folic acid fortification

Wyckoff K. & Ganji V. (2007). Am J Clin Nutr: 86:1187-92

Morris MS et al. Am J Clin Nutr. 2007;85:193-200.Morris MS et al. Am J Clin Nutr. 2007;85:193-200.

Odds Ratio (OR)Odds Ratio (OR)

0.10.1 0.50.5 1.01.0 55 1010

1.01.0

0.6 (0.2-2.2)0.6 (0.2-2.2)

2.0 (1.1-3.5)2.0 (1.1-3.5)

5.2 (2.5-10.6)5.2 (2.5-10.6)

Interaction between Vitamin B12 status and serum folate in relation to anemia

Vitamin Status

B-12 Folate

Normal Normal

Normal High

Low Normal

Low High

Morris MS et al. Am J Clin Nutr. 2007;85:193-200.Morris MS et al. Am J Clin Nutr. 2007;85:193-200.

Odds Ratio (OR)Odds Ratio (OR)

0.10.1 0.50.5 1.01.0 55 1010

1.01.0

0.5 (0.2-0.9)0.5 (0.2-0.9)

1.9 (1.1-3.1)1.9 (1.1-3.1)

4.9 (2.6-9.2)4.9 (2.6-9.2)

Interaction between Vitamin B12 status and serum folate in relation to cognitive impairment

Vitamin Status

B-12 Folate

Normal Normal

Normal High

Low Normal

Low High

Important role of folate in nucleotide synthesis– Deficiency affects primarily rapidly dividing tissues.

The administration of folate enhanced the growth of existing tumors.

Folate antagonists (methotrexate) became a basis of cancer chemotherapy.

Poorer clinical response to methotrexate were related to higher blood folate concentrations due to induced multiple drug resistance.

Folic acid fortification & Cancer

Potter J. & Ulrich C. (2006) Cancer Epidemiol Biomarkers Prev; 15(2): 189-93Kim Y. et al (2008) Am J Clin Nutr; 87:517-33Potter J. & Ulrich C. (2006) Cancer Epidemiol Biomarkers Prev; 15(2): 189-93Kim Y. et al (2008) Am J Clin Nutr; 87:517-33

Folate plays a dual role in carcinogenesis

Once established small tumor may grow more rapidly with folate supplementation

Prevention of early lesions.

Prevention of early lesions.

Potential harm once

preneoplastic lesions have developed.

Potential harm once

preneoplastic lesions have developed.

Folic acid fortification & Cancer

Potter J. & Ulrich C. (2006) Cancer Epidemiol Biomarkers Prev; 15(2): 189-93Kim Y. et al (2008) Am J Clin Nutr; 87:517-33Potter J. & Ulrich C. (2006) Cancer Epidemiol Biomarkers Prev; 15(2): 189-93Kim Y. et al (2008) Am J Clin Nutr; 87:517-33

Overconsumption of nutrients– Vitamin A

Competition with other nutrients– Zinc and iron ?– Calcium and Iron

Interaction with metabolism– Folate and B12

Knowledge gap– Causes of anemia

Folic acid fortification & Cancer

Thank You