Reference Intakes of Vitamins

Notwithstanding the problems involved in determining requirements for vitamins, most national authorities (as well as the United Nations FAO/WHO and the European Commission) publish, and periodically revise, tables of recommended intakes of nutrients or dietary reference values.

As shown in Tables 1.5-1.8, reference intakes published by different authorities show considerable differences. Some of the reasons for this are apparent from the discussion above; different criteria of adequacy may be applied by the members of different expert committees, and the estimation of average requirements and, hence, reference intakes requires a considerable exercise of judgment to interpret the relatively small body of scientific literature. Historically, tables of reference intakes were based on requirements to prevent deficiency disease, or subclinical signs of inadequacy; increasingly, as evidence accumulates, the emphasis is on requirements to promote optimum health rather than to prevent deficiency.

As shown in Table 1.9, a number of terms are used: Recommended Daily (or Dietary) Intake (RDI), Recommended Dietary (or Daily) Amount (RDA), Reference or Recommended Nutrient Intake (RNI), and Population Reference Intake (PRI). All have the same statistical basis, and all are defined as an intake of the nutrient that is adequate to ensure that the requirements of essentially all healthy people in the specified population group are met. The 2001 FAO/WHO report introduced the term protective nutrient intake - an amount greater than the reference intake that may be protective against specified health risks of public health importance.

There is considerable individual variation in nutrient requirements. It is generally assumed that requirements follow a more or less statistically normal (Gaussian) distribution, as shown in the upper curve in Figure 1.1. This means that 95% of the population has a requirement for a given nutrient within the range of ±2 SD about the observed mean requirement. Therefore, an intake at the level of the observed (or estimated) mean requirement plus 2 x SD will be more than enough to meet the requirements of 97.5% of the population. This is the level that is generally called the RDI, RDA, RNI, or PRI.

There is, in fact, little evidence that requirements do follow a Gaussian distribution; theU.S./Canadian tables (Institute of Medicine, 1997,1998,2000,2001) note this, and state that when the distribution is skewed the 97.5th percentile can be estimated by transforming the data to a normal distribution. Where the standard deviations from different studies are inconsistent, the U.S./Canadian tables determine the RDA on the basis of 1.2 x average requirement. This assumes a coefficient of variation of 10%, which is based on the known variance in basal metabolic rate.

It is apparent from this discussion that reference intake figures are intended for use in populations and communities, and do not apply to individuals. An individual might have a requirement anywhere within the range, and therefore

Table

1.9 Terms that Have Been Used to Describe Reference Intakes of Nutrients

RDA

Recommended Dietary Allowances

U.S., 1941

The name was deliberately chosen to allow the possibility of future modification of the values and was not intended to carry any connotation of minimum or optimal requirements.

RDI

Recommended Dietary Intakes

U.K., 1969

... to emphasize that the recommendations related to foodstuffs as actually eaten

RDA

Recommended Daily Amounts

U.K., 1979

... to make it clear that the amounts referred to averages for a group of people and not to amounts that individuals must meet, as implied by the term "allowances"

Safe levels of

UN agencies

Means safe and adequate, but

intake

does not imply that higher intakes are unsafe

RNI

Reference Nutrient Intakes

U.K., 1991

By parallel with clinical chemistry reference ranges, which encompass 95% of normal values; to emphasize that they are not recommendations for individuals, nor are they amounts to be consumed daily; see Table 1.5

RNI

Recommended Nutrient Intake

FAO, 2001

PRI

Population Reference Intakes

EU, 1993

By parallel with RNI, but emphasizing that these are population ranges, and not applicable to individuals; see Table 1.6

U.S.-RDA

U.S., 1973

Reference intakes for labeling

purposes, the highest RDA

value for any population group;

see Table 1.11

RDI

Reference Daily Intakes

U.S., 1990

Reference intakes for labeling purposes, numerically equal to U.S.-RDA; see Table 1.11

DRV

Daily Reference Values

U.S., 1990

Reference values for fat, carbohydrate, sodium, potassium, and protein; for labeling purposes

AI

Adequate Intake

U.S./Canada, 1997

UL

Tolerable Upper Intake Level

U.S./Canada, 1997

EU, European Union; FAO, Food and Agriculture Organization; UN, United Nations.

intake to meet criterion of adequacy

intake to meet criterion of adequacy

Figure 1.1. Derivation of reference intakes of nutrients from the distribution around the observed mean requirement; plotted below as a cumulative distribution curve, permitting estimation of the probability that a given level of intake is adequate to meet an individual's requirement.

intake to meet criterion of adequacy

Figure 1.1. Derivation of reference intakes of nutrients from the distribution around the observed mean requirement; plotted below as a cumulative distribution curve, permitting estimation of the probability that a given level of intake is adequate to meet an individual's requirement.

might satisfy requirements with an intake considerably below the reference intake. In the United Kingdom, the RNI is regarded as a goal for planning and evaluating the intake of population groups and communities, rather than applying to an individual (Department of Health, 1991); in contrast, in the United States and Canada, the RDA is regarded as a goal for individuals to achieve (Institute of Medicine, 1997,1998, 2000, 2001).

The lower curve in Figure 1.1 shows the population distribution of nutrient requirements plotted as a cumulative percentage. This can then be reinterpreted as indicating the statistical probability that a given level of intake will be adequate for an individual.

1. At an intake equal to the mean requirement minus twice the standard deviation, only 2.5% of the population have been included. Therefore, there is only a 2.5% probability that this intake is adequate for an individual.

2. At an intake equal to the mean observed requirement, 50% of the population have been included, and there is thus a 50% probability that this level of intake will be adequate for an individual.

3. At an intake equal to the observed mean requirement plus twice the standard deviation (RDA or RNI), 97.5% of the population have been included, and there is thus a 97.5% probability that this intake will be adequate for an individual.

1.2.4.1 Adequate Intake Forsome vitamins, notably biotin (Section 11.5) and pantothenic acid (Section 12.6), dietary deficiency is more-or-less unknown, and there are no data from which to estimate average requirements or derive reference intakes. In such cases, the observed range of intakes is obviously more than adequate to meet requirements, and the average intake is used to calculate an adequate intake figure.

1.2.4.2 Reference Intakes for Infants and Children For obvious ethical reasons, there have been almost no experimental studies of the vitamin requirements of infants and children. For infants, it is conventional to use the nutrient yield of breast milk and assume that this is equal to or greater than requirements. Although this is termed an RNI in U.K. tables (Table 1.5), in the U.S./Canadian tables (Table 1.7), it is more correctly referred to as an acceptable intake.

Most authorities have estimated reference intakes for children by linear interpolation between the experimental data for young adults and the nutrient yield of breast milk (Figure 1.2). The EU expert group (Table 1.6; Scientific Committee for Food, 1993) took a different approach and extrapolated backward from the experimentally determined reference intakes for young adults on the basis of energy requirement (for which there are good experimental data), with the possibly unjustified assumption that the nutrient density of adequate diets should be essentially constant through childhood. The advantage of this approach was that it takes into account the higher nutrient requirements at times of rapid growth (because energy requirement increases in growth). This backward extrapolation gave figures for vitamin requirements in infancy that were the same as those based on the composition of breast milk.

age (years)

Figure 1.2. Derivation of requirements or reference intakes for children. Dotted line shows linear interpolation between the assumed acceptable intake at age 3 months (based on breast milk composition) and the experimentally derived reference intake at age 17 to 18 years. Solid line shows extrapolation backward from the experimentally derived reference intake at age 17 to 18 years on the basis of energy requirements.

age (years)

Figure 1.2. Derivation of requirements or reference intakes for children. Dotted line shows linear interpolation between the assumed acceptable intake at age 3 months (based on breast milk composition) and the experimentally derived reference intake at age 17 to 18 years. Solid line shows extrapolation backward from the experimentally derived reference intake at age 17 to 18 years on the basis of energy requirements.

1.2.4.3 Tolerable Upper Levels of Intake A number of the vitamins are known to be toxic in excess. For most, there is a considerable difference between reference intakes that are more than adequate to meet requirements and the intake at which there may be adverse effects, although for vitamins A (Section 2.5.1) and D (Section 3.6.1) there is only a relatively small margin of safety.

For food additives and contaminants, an acceptable level of intake is calculated from the highest intake at which there is no detectable adverse effect - the no adverse effect level (NOAEL) - by dividing by a factor of 100, thus ensuring a very wide margin of safety. This approach is not appropriate for compounds that are dietary essentials, and indeed in many cases would result in a (tox-icologically calculated) acceptable intake below the reference intake or even below the requirementformetabolic integrity. TheU.K. (Department of Health, 1991) and EU (Scientific Committee for Food, 1993) tables give "guidance on higher intakes," suggesting upper safe levels of habitual intake from supplements. The U.S./Canadian tables (Institute of Medicine, 1997,1998,2000,2001) give tolerable upper levels of intake derived from the NOAEL divided by appropriate safety factors. The upper level of intake is defined as the maximum level of habitual intake that is unlikely to pose any risk of adverse health effects

Figure 1.3. Derivation of reference intake [Recommended Dietary (or Daily) Amount (RDA)],and tolerable upper level (UL) for a nutrient. Curve shows the probability that a subject will show signs of deficiency (left) or toxicity (right) at any given level of intake.

to almost all individuals in the (stated) population group. It is a level of intake that can (with a high degree of probability) be tolerated biologically, but is not a recommended level. "There is no established benefit for healthy individuals consuming more than the RDA." As shown in Figure 1.3, the RDA is set at the 97.5th percentile of the distribution of requirements, and is thus adequate to meet the requirements of "essentially all" of the population group, whereas the upper tolerable intake is set below the level at which any of the population might be expected to show adverse effects.

Table 1.10 shows the NOAEL for the vitamins, the upper limits for supplements available over the counter proposed by the European Federation of Health Product Manufacturers Associations (Shrimpton, 1997), the U.S./ Canadian tolerable upper levels, and the prudent upper levels of consumption from the EU tables.

The upper levels for over-the-counter supplements shown Table 1.10 are voluntary, but because the report (Shrimpton, 1997) was commissioned by the European Federation of Health Product Manufacturers, it is likely that most manufacturers of nutritional supplements will abide by them. The problem is that in most countries nutritional supplements are covered by food

Table 1.10 Toxicity of Vitamins: Upper Limits of Habitual Consumption and Tolerable Upper Limits of Intake

Vitamin

NOAEL

Upper Limit for Supplements"

Tolerable Upper Levels U.S.6 EU°

A

|g

3,000

3,000

2,800, 3,000d 7,500, 9,000

Carotene

|g

25

D

|g

20

20

50

50

E

mg

800

800

1,000

>2,000

K

mg

30

B1

mg

50

50

>500

b2

mg

200

200

Niacin

mg

500, 250e

Nicotinic acid

mg

500, 250e

35

Nicotinamide

mg

1,500

Be

mg

200

200

100

25f

Folate

lg

1,000

1,000

1,000

1,000

3 B12

lg

3,000

3,000

200g

Biotin

mg

2,500

2,500

Pantothenate

mg

1,000

1,000

C

mg

>1,000

1,000

2,000

10,000

EU, European Union; NOAEL, no adverse effect level, the highest level of intake at which no adverse effects are observed.

Sources: aShrimpton, 1997; "Institute of Medicine, 1997, 1998, 2000, 2001; Scientific Committee for Food, 1993; dwhere two figures are shown for vitamin A, the lower is for women and the higher is for men (Table 2.5). efor niacin and nicotinic acid, the lower values are for sustained release preparations; f the EU upper level of 25 mg of vitamin Be was proposed by the Scientific Committee for Food Opinion, 2000; and ®the EU upper level of 200 |xg of vitamin Bl2 was set because of the possible presence of inactive corrinoids in pharmaceutical preparations, not because of toxicity of the vitamin itself.

legislation rather than regulations covering medicines. A report to the U.S. Food and Drug Administration (FDA; Department of Health and Human Services, 2001) noted the lack of surveillance, and the lack of an adequate system for reporting or investigating adverse effects of nutritional supplements. Indeed, in one-third of cases in which adverse effects were reported, the FDA was unable to discover from the manufacturers precisely what was included in the supplements. In some cases, they could not find the manufacturer of products that were implicated. The report recommended the following:

• a requirement for manufacturers to report serious adverse effects;

• provision of information to health care professionals and consumers about the procedure for reporting adverse effects;

Table 1.11 Labeling Reference Values for Vitamins

U.S.

European Union

Reference

Proposed by Scientific

Daily Intake"

Committee for Food6

Required by Directive0

Vitamin A, |xg

1,500

500

800

Vitamin D, |g

10

5

5

Vitamin E, mg

30

10

Vitamin C, mg

60

30

60

Thiamin, mg

1.5

0.8

1.4

Riboflavin, mg

1.7

1.3

1.6

Niacin, mg

20

15

18

Vitamin B6, mg

2.0

1.3

2.0

Folate, |g

400

140

200

Vitamin Bi2, |g

6.0

1.0

1.0

Biotin, | g

300

150

Pantothenic acid, mg

10

6

Sources: "National Research Council, 1989; bScientific Committee for Food, 1993;

European Commission, 1990.

• a requirement for manufacturers to register themselves and their products with the FDA;

• a requirement for guidance to manufacturers on safety information to be provided.

1.2.4.4 Reference Intake Figures for Food Labeling Tables of reference intakes provide figures for different age groups, separate figures for men and women, and additional figures for pregnancy and lactation. For nutritional labeling of foods, it is obviously desirable to have a single figure that will permit comparison of different foods and pharmaceutical preparations. In the United States, the figure that is used for labeling (the U.S. RDA or RDI) is the highest RDA for any population group for that nutrient (National Research Council, 1989). The EU Scientific Committee for Food (1993) noted that to use the highest reference intake might lead to excess nutrient intake by a substantial proportion of the population and that those unable to achieve this high level might be tempted to take (unnecessary) supplements. It might also lead to a loss of confidence in traditional foods that would appear to be of low nutritional value. They proposed that the labeling reference value should be the average requirement for men (which in many cases equals the reference intake for women). However, at present, the law in the EU requires that the figures shown in column 3 of Table 1.11 be used for labeling.

FURTHER READING

Ames BN (2001) DNA damage from micronutrient deficiencies is likely to be a major cause of cancer. Mutation Research 475, 7-20.

Ames BN, Elson-Schwab I, and Silver EA (2002) High dose vitamin therapy stimulates variant enzymes with decreased coenzyme binding affinity (increased Km): relevance to genetic disease and polymorphisms. American Journal of Clinical Nutrition 75, 616-58.

Anonymous (1997) The development and use of dietary reference intakes. Nutrition Reviews 55, 319-51.

Ball GFM (1998) Bioavailability and Analysis of Vitamins in Foods. London: Chapman and Hall.

Bates C and Heseker H (1994) Human bioavailability of vitamins. Nutrition Research Reviews 7, 93-128.

Beaton G (1988) Nutrient requirements and population data. Proceedings of the Nutrition Society 47, 63-78.

Bhaskaram P (2001) Immunobiology of mild micronutrient deficiencies. British Journal of Nutrition 85(Suppl 2), S75-80.

Brubacher G, Muller-Mulot W, and Southgate DAT (1985) Methods for the Determination of Vitamins in Food: Recommended by COST 91. London: Elsevier Applied Science Publishers.

Crews H, Alink G, Andersen R, Braesco V, Holst B, Maiani G, Ovesen L, Scotter M, Solfrizzo M, van den Berg R, Verhagen H, and Williamson G (2001) A critical assessment of some biomarker approaches linked with dietary intake. British Journal of Nutrition 86(Suppl 1), S5-35.

Donnelly JG (2001) Nutrient requirements in health and disease. In Food and Nutritional Supplements: Their Role in Health and Disease, JKRansley, JK Donnelly, and NW Read (eds.), pp. 29-44. Berlin: Springer.

Fairfield KM and Fletcher RH (2002) Vitamins for chronic disease prevention in adults: scientific review. JAMA 287, 3116-26.

Fenech M (2001) Recommended dietary allowances (RDAs) for genomic stability. Mutation Research 480, 51-4.

Gibson R (1990) Principles of Nutritional Assessment. Oxford: Oxford University Press.

Hathcock JN (1997) Vitamins and minerals: efficacy and safety. American Journal of Clinical Nutrition 66, 427-37.

Powers H (1997) Vitamin requirements for term infants: considerations for infant formula. Nutrition Research Reviews 10, 1-33.

Ransley JK (2001) The rise and rise of food and nutritional supplements: an overview of the market. In Food and Nutritional Supplements: Their Role in Health and Disease, JK Ransley, JK Donnelly, and NW Read (eds.), pp. 1-16. Berlin: Springer.

van den Berg H,van der GaagM, and Hendriks H (2002) Influence of lifestyle on vitamin bioavailability. International Journal of Vitamin and Nutrition Research 72, 53-9. Various authors (1996) New approaches to define nutrient requirements. American Journal of Clinical Nutrition 63,983s-1001s. WalterP, StahelinH, and Brubacher G (1989) Elevated Dosages of Vitamins: Benefits and Hazards. Toronto: Hans Huber Publishers.

References cited in the text are listed in the Bibliography.

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