A link to this article Vitamin D and Milk
Prepared by Professor Anthony W. Norman;
Department of Biochemistry & Biomedical Sciences
University of California, Riverside CA 92521
(December 12, 2000)

Purpose of this statement:

The objective of this brief statement isto provide some biological and nutritional background on vitamin D, whichis a precursor of a steroid hormone [1a,25(OH)2D3] in higher animals, includinghumans. This will be followed by brief descriptions of vitamin D's chemistry,nutritional importance, sources, production and presence in milk.

What is a vitamin?

A vitamin is a substance (organic molecule)whose presence is crucial to the normal every day life function of animals.However vitamins can not be directly produced by the animal's body. Accordinglythe daily requirements for the vitamin must be met through regular dietaryintake of appropriate quantities of the vitamin(s). There are two generalchemical categories of vitamins based on their solubility: water solublevitamins (the B vitamins and others) and fat soluble vitamins (A, D, Eand K).

What is a hormone?

A hormone is a chemicalmessenger that is produced and secreted by specific glands and cells withinthe body of animals. After secretion of the hormone, it is transportedthrough the bloodstream to designated target organs where the hormone bybinding to its specific receptor delivers its "message" to that set ofcells. These cells then promptly produce biological responses specificfor that hormone.

What is vitamin D and why is it important:

Chemistry: There are two chemical formsof vitamin D, namely vitamin D2 (sometimes referred to as ergocalciferol)and vitamin D3 (sometimes referred to a cholecalciferol). The natural formof vitamin D for animals and man is vitamin D3 that is produced in theirbodies from cholesterol and 7-dehydrocholesterol. An alternative vitaminD2 is derived from the yeast sterol ergosterol by chemical procedures.

The molecular structure of vitamin D isclosely allied to that of the classical steroid hormones, e.g. cortisol,estradiol, progesterone, aldosterone, and testosterone (1). All steroidhormones and vitamin D3 are chemically related to the well known sterolcholesterol. Cholesterol in animals and man is a precursor substance forall steroid hormones and as well vitamin D3.

Technically the molecule called vitaminD3 is not really a vitamin because it can be produced by exposure of theskin (higher animals and humans) to ultraviolet light or sunlight. Theskin of many animals and man has a high concentration of the sterol cholesterolwhich is converted by enzymes in the skin to the sterol 7-dehydrocholesterol.Exposure of skin (including human skin) to sunlight for regular intervalsresults in the photochemical conversion of 7-dehydrocholesterol into vitaminD3. This sunlight- generated vitamin D3 is a precursor of the steroid hormone1a,25(OH)2D3. Under these circumstances vitamin D3 is not a vitamin becauseit has been produced by the body (with the assistance of sunlight). However,if the animal or man lives in the absence of sunlight (e.g., Alaska inthe winter) or exclusively indoors, then there is indeed an absolute regularrequirement for the fat soluble vitamin D, that must be met through properdietary intake.

Therefore for nutritional and public healthreasons, vitamin D3 continues to be
classified even today in 2000 officially as a vitamin. Thus manyvitamin capsules and food sources including cows milk are supplementedwith vitamin D3 to improve their nutritional value. In the 1940's thismilk supplementation process reduced the incidence rate of juvenile ricketsby 85% in the United States.

Importance: Vitamin D3 is essential forlife in higher animals. Classically vitamin D3 has been shown to be oneof the most important biological regulators of calcium metabolism throughstimulating the absorption of calcium from food across the intestine andparticipating in the incorporation of the absorbed calcium in to the skeleton(2). These important biological effects are only achieved as a consequenceof the metabolism of vitamin D into a family of daughter metabolites, including 1a,25(OH)2-vitamin D3 [1a,25(OH)2D3]. 1a,25(OH)2D3, is consideredto be a steroid hormone because the general mechanism by which it producesthe biological responses attributed to vitamin D is similar to those ofsteroid hormones (3;4).

It has become increasingly apparent sincethe 1980s that 1a,25(OH)2D3 also plays an important multidisciplinary rolein tissues not primarily related to mineral metabolism, e.g. the hematopoieticor blood system, effects on cell differentiation and proliferation includingimportant interactions with keratinocytes and cancer cells, and participationin the processes of parathyroid hormone and insulin secretion (3)

Vitamin D Deficiency: The classic deficiencystate resulting from a dietary absence of vitamin D3 or lack of ultraviolet(sunlight) exposure is the bone disease called rickets in children or osteomalaciain adults. The clinical features of rickets and osteomalacia depend uponthe age of onset. The classical skeletal disorder of rickets includes deformityof the bones, especially in the knees, wrists, and ankles, as well as associatedchanges in the rib joint functions, which have been termed by some as therachitic rosary (1).

A regular access to vitamin D3 throughoutlife is important to facilitate the normal absorption into the body ofdietary calcium which, in turn, is essential for normal bone health andmay diminish or prevent the onset in the elderly of the bone disease osteoporosis.

Requirements for vitamin D:

Since vitamin D3 is produced in the skinafter exposure of 7-dehydrocholesterol to sunlight, the human does nothave a requirement for vitamin D when sufficient sunlight is available.Man's tendency to wear clothes, to live in cities where tall buildingsblock adequate sunlight from reaching the ground, to live indoors, to usesynthetic sunscreens that block ultraviolet rays, and to live in geographicalregions of the world that do not receive adequate sunlight, all contributeto the inability of the skin to biosynthesize sufficient amounts of vitaminD3 (5). Thus, vitamin D3 does become an important nutritional factor inthe absence of sunlight. It is known that a substantial proportion of theU.S. population is exposed to suboptimal levels of sunlight. This is particularlytrue during winter months (6;7). Under these conditions, vitamin D becomesa true vitamin which dictates that it must be supplied in the diet on aregular basis.

Since vitamin D3 can be produced by thebody and since it is retained for long periods of time by animal tissues,it has been difficult to determine with precision the minimum daily requirementsfor this fat soluble vitamin. The requirement for vitamin D3 is also knownto be dependent on the age, sex, degree of exposure to the sun, season,and the amount of pigmentation in the skin (8).

The current "adequate intake" allowanceof vitamin D recommended in 1998 by the Food and Nutrition Board of USInstitute of Medicine is 200 IU/day (5 mgrams/day) for infants, childrenand adult males and females up to age 51 (9). For females ages >51 or malesages > 70, the adequate indicated level is set at 400 IU/day (10 mg/day)or 600 IU (15 ug/day), respectively. The adequate allowance for pregnancyand lactation is set at 200 IU/day (5 mg/day). These recommendations areall summarized in a 1998 publication from the Food and NutritionBoard ofthe Institute of Medicine (9).

In the United States adequate amounts ofvitamin D3 can readily be obtained from the diet and/or from casual exposureto sunlight. The ultraviolet exposure can be as little as 3 X per weekexposure of the face and hands to ambient sunlight for 20 minutes (10).However, in some parts of the world where food is not routinely fortifiedand sunlight is often limited during some periods of the year, obtainingadequate amounts of vitamin D becomes more of a problem. As a result, theincidence of rickets in these countries is higher than in the United States.

What are the sources of vitamin D for humans?

Animal products constitute the bulk sourceof vitamin D that occurs naturally in unfortified foods. Salt water fishsuch as herring, salmon, sardines, and fish liver oils are good sourcesof vitamin D3. Small quantities of vitamin D3 are also found in eggs, veal,beef, butter, and vegetable oils while plants, fruits, and nuts are extremelypoor sources of vitamin D. In the United States, fortification of foodssuch as milk (both fresh and evaporated), margarine and butter, cereals,and chocolate mixes help in meeting the adequate intake (RDA) recommendations(11). Because only fluid milk is fortified with vitamin D, other dairyproducts (cheese, yogurt, etc.) only provide the vitamin that was producedby the animal itself.

How is vitamin D produced commercially for food supplementation?

When the critical importance to human healthof a regular dietary access to vitamin D3 was understood (in the 1930's),milk suppliers realized it would be advantageous to their customers' healthto market milk which had been supplemented with vitamin D3. Thus theredeveloped in the 1940's, and continues to the present, a large businessof industrial production of vitamin D3 used for the supplementation offoods for human consumption: milk (both homogenized and evaporated), somemargarine and breads. Since the 1960's vitamin D3 has been used also forthe supplementation of farm animal and poultry food. In 1973 in the UnitedStates some 290 trillion (290 x 1012) International Units of vitamin D3was manufactured and sold for over 3 million dollars. This vitamin D3 isthe equivalent of approximately 8 tons; [see page 62 of reference (2)].

The commercial production of vitamin D3is completely dependent on the availability of either 7-dehydrocholesterolor cholesterol. 7-Dehydrocholesterol can be obtained via organic solventextraction of animal skins (cow, pig or sheep) followed by an extensivepurification. Cholesterol typically is extracted from the lanolin of sheepwool and after thorough purification and crystallization can be convertedvia a laborious chemical synthesis into 7-dehydrocholesterol. It shouldbe appreciated that once chemically pure, crystalline 7-dehydrocholesterolhas been obtained, it is impossible to use any chemical or biological testsor procedures to determine the original source (sheep lanolin, pig skin,cow skin, etc.) of the cholesterol or 7-dehydrocholesterol.

Next the crystalline 7-dehydrocholesterolis dissolved in an organic solvent and irradiated with ultraviolet lightto carry out the transformation (similar to that which occurs in humanand animal skin) to produce vitamin D3. This vitamin D3 is then purifiedand crystallized further before it is formulated for use in dairy milkand animal feed supplementation. The exact details of the chemical conversionof cholesterol to 7-dehydrocholesterol and the method of large-scale ultravioletlight conversion into vitamin D3 and subsequent purification are closelyheld topics for which there have been many patents issued (2).

The major producers of vitamin D3 used formilk and other food supplementation are the companies F. Hoffman La Roche,Ltd (Switzerland) and BASF
(Germany).

What is the source of vitamin D in milk?

Milk from all lactating animals, includinghumans, contains vitamin D3 that has been produced photochemically from7-dehydrocholesterol present in the skin. In cow's milk it has been determinedthat the concentration of vitamin D3 in milk provided by the cow is roughly35-70 International Units per quart as determined via biological assay(12) and approximately 50-80 International Units as determined by modernchemical mass spectrometric procedures (13). However these are rather lowlevels of vitamin D3 from the perspective of providing the 200-400 IU perday as recommended by the Food and Nutrition Board of the Institute ofMedicine (9). Accordingly, as discussed above, the business practice ofsupplementing cows milk with chemically synthesized vitamin D3 was initiated.At the present time almost all milk sold commercially in the United Stateshas 400 IU of chemically synthesized vitamin D3 added per quart. Any vendorof milk for human consumption containing added vitamin D3 is required bythe US Food and Drug Administration (FDA) to include a notice on the milkcarton label. Usually this label
states "400 IU of added vitamin D3". However it is not requiredby law to indicate either the manufacturer of the added vitamin D3 or thesources of the cholesterol and 7-dehydrocholesterol used for its production.

It is a fact that most milk sold in theUS will contain vitamin D3 with two origins. (a) That vitamin D3 made bythe cow using sunlight to irradiate 7-dehydrocholesterol present in herskin. (b) That vitamin D3 made by a chemical process and then added tothe cow milk as a nutritional supplement. It is simply not possible todistinguish the origins of the two vitamin D3 preparations by any biologicalor chemical procedure, because they are the same molecular structure. Further,there is no legal requirement for the manufacturer of the vitamin D3 formulatedfor human food supplementation to specify the animal sources of the precursormolecules that were employed in the synthesis of the D vitamin.

If a "food product" is construed to includea chemically pure substance that is the same in all animal species, thenthose individuals with strict religious reasons for avoiding food productsfrom a particular species have, in the instance of milk and vitamin D3,a dilemma.

Selected references:

Also the WEB sites for the VitaminD Workshop and the WEB sites of BASFand Hoffmann-LaRoche, LTD [two of the largest industrial producers of vitamin D3
in the world] provide other general information related to vitaminD.

Reference List

1.Norman,A.W. and Litwack,G.L. Hormones, Academic Press,San Diego, CA.(1997).

2.Norman,A.W. Vitamin D: The calcium homeostatic steroidhormone., Academic Press, New York.(1979).

3.Bouillon,R., Okamura,W.H., and Norman,A.W. Structure-functionrelationships in the vitamin D endocrine system. Endocr.Rev. 16 (1995)200-257.

4.Norman,A.W.: Vitamin D. In Present knowledge in nutrution(PKN7). Ziegler,E.E. and Filer,L.J., Eds., International Life SciencesInstitute, Washington (1996) pp. 120-129 .

5.Holick,M.F. Environmental factors that influence thecutaneous production of vitamin D. Am.J.Clin.Nutr. 61 Suppl. (1995) 638S-645S.

6.Webb,A.R. and Holick,M.F. The role of sunlight inthe cutaneous production of vitamin D3. Ann.Rev.Nutr. 8 (1988) 375-399.

7.Webb,A.R., Pilbeam,C., Hanafin,N., and Holick,M.F.An evaluation of the relative contributions of exposure to sunlight andof diet to the circulating concentrations of
25-hydroxyvitamin D in an elderly nursing home population in Boston.Am.J.Clin.Nutr. 51(6) (1990) 1075-1081.

8.Harris,S.S. and Dawson-Hughes,B. Seasonal changesin plasma 25-hydroxyvitamin D concentrations of young American black andwhite women.
Am.J.Clin.Nutr. 67 (1998) 1232-1236.

9.Food and Nutrition Board. Dietary reference intakes:A risk assessment model for establishing upper intake levels for nutrients.1998) , 1-71. Washington, D.C., National Academy Press, Institute of Medicine.

10.Adams,J.S., Clemens,T.L., Parrish,J.A., and Holick,M.F.Vitamin-D synthesis and metabolism after ultraviolet irradiation of normaland vitamin-D-deficient subjects. New
Engl.J.Med. 306 (1982) 722-725.

11.Collins,E.D. and Norman,A.W.: Vitamin D In Handbookof vitamins. Machlin,L.J., Ed., Marcel Dekker, New York (1990) pp. 59-98.

12.Hollis,B.W., Roos,B.A., and Lambert,P.W.: VitaminD compounds in human and bovine milk In Advances in nutritional research.Draper,H.H., Ed., Plenum Press, New York (1994) pp. 59-75 .

13.Adachi,A. and Kobayashi,T. Identification of vitaminD3 and 7-dehydrocholesterol in cow's milk by gas chromatography-mass spectrometryand their quantitation by
high-performance liquid chromatography. J.Nutr.Sci.Vitaminol. 25(1979) 67-78.

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