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OCR for page 3
Vitamin A
Vitamin A was the first fat-soluble vitamin to be dis-
covered and characterized. It has essential roles in vi-
sion, bone and muscle growth, reproduction, and
maintenance of healthy epithelial tissue. Either vitamin
A or a precursor must be provided in the diet. However,
it is among the most highly variable nutrients in feeds.
Plants do not contain vitamin A, and most grains other
than yellow corn are almost devoid of the carotenoid
precursors that provide plant sources of vitamin A activ-
ity. The concentrations of carotenoids in the vegetative
portions of plants vary widely according to geographic
location, maturity, method of harvest, amount and type
of processing, length and conditions of storage, and ex-
posure to high temperature, sunlight, and air. Eggs and
selected poultry, fish, animal products (especially liver,
milk, and milk products), and fats may contain high
levels of vitamin A or carotene, but these levels reflect
vitamin A or carotenoids present in the diets of those
animals. Consequently, vitamin A is a frequent nutri-
tional concern, which has been extensively reviewed
(Moore, 1957; Mitchell, 1967; Eaton, 1969; Olson, 1969,
1984; Ullrey, 1972; Bauernfeind et al., 1974; Goodman,
1980).
Most workers rank vitamin A deficiency next to pro-
tein and calorie deficiency as a worldwide health prob-
lem. It is the most important vitamin in ruminant animal
diets and is almost universally added to commercial di-
ets for nonruminant animals. Vitamin A toxicity due to
the consumption of rich natural sources such as polar
bear's liver and fish oils is well documented (Pitt, 1985)
in humans and laboratory animals but is apparently rare
in domestic animals. The potential for nutritional abuse
leading to toxicity has been increased by the availability
of economical sources of synthetic vitamin A, however.
Pharmacological use of retinoids to treat skin disease
(Moore, 1957) and cancer (Ong and Chytil, 1983) re-
quires levels that make toxicity a major hazard.
NUTRITIONAL ROLE
Dietary Requirements of Various Species
Vitamin A is an essential nutrient for all species of
mammals, birds, and fishes studied and is also essential
in many lower forms of life. The dietary requirements
for most adequately studied species are between 1,500
and 4,000 IU/kg of diet. (One IU provides the vitamin A
activity of 0.3 fig all-trans-retinol.) Based on limited
data, requirements for Japanese quail have been set at
5,000 IU/kg of diet (National Research Council, 1984b)
and those for cats (National Research Council, 1978a),
nonhuman primates (National Research Council,
1978d), and some warmwater fishes (National Research
Council, 1983) at 10,000 IU/kg of diet. Inadequate vita-
min A intake may result in reduced feed intake, edema,
lacrimation, xeropthalmia, nyctalopia (night blindness),
slow growth, low conception rates, abortion, stillbirths,
blindness at birth, abnormal semen, reduced libido, sus-
ceptibility to respiratory and other infections, and
death. Only nyctalopia has been proven unique to vita-
min A deficiency. When several of these other signs are
present, vitamin A deficiency should be suspected. It
may be verified by ophthalmoscopic examination, liver
biopsy and assay for near absence of vitamin A (retinal
esters), blood assay for vitamin A (concentrations of
retinal below 20,ug/100 ml are considered below normal
in most species), spinal fluid pressure testing for an
above-normal elevation, conjunctival smear examina-
tion for epithelial keratinization, and response to vita-
min A therapy.
Biochemical Functions
The classic work of Wald (1968) has defined the bio-
chemical role of vitamin A in night vision. Key steps in
3
OCR for page 4
4 Vitamin Tolerance of Animals
this process are oxidation of retinol to retinal and isom-
erization of the bans form to 11-cis-retinal, which com-
bines with the protein opsin to form rhodopsin, which is
known as visual purple. The 11-cis-3-dehydroretinal
form of naturally occurring vitamin A2 is active in fish
but not in mammals or birds. The molecular bases for
the roles of vitamin A in growth, reproduction, and epi-
thelial health have been studied extensively but remain
incompletely understood. The most widely accepted hy-
potheses propose a role in synthesis of glycoproteins
that may control cell differentiation and involvement in
the control of gene expression (Olson, 1984~.
FORMS OF THE VITAMIN
Vitamin A activity is a generic term for ,B-ionone de-
rivatives having the biological activity of all-trans-
retinol. In plants this activity is present only in the form
of carotenoid precursors of all-trans-retinol. The most
active of these precursors is 3-carotene, which can be
cleaved by intestinal enzymes to yield two moles of all-
trans-retinol per mole of 9-carotene. Foodstuffs of ani-
mal origin may contain either carotenoids or retinoids.
The most significant retinoids in animal metabolism are
the alcohol (all-trans-retinol), the aldehyde (11-cis
FIGURE 1 Major compounds of the vitamin
A group.
retinal and 11-cis-3-dehydroretinal), and the acid (all-
trans-retinoic acid) forms, as well as retinyl esters
(especially retinyl palmitate) and retinyl 3-glucuronide.
Structural formulas for most of these are given in
Figure 1.
ABSORPTION AND METABOLISM
Various forms of vitamin A and carotenoids are ab-
sorbed mainly in conjunction with lipids. (See Table 1
for the relative vitamin A activity of carotenoids.) Carot-
enoids are normally converted to retinol in the intestinal
mucosa but may also be converted in the liver and other
organs, especially in yellow fat species such as cattle
and poultry. Either dietary retinol or retinol resulting
from conversion of carotenoids is then esterified with a
long-chain fatty acid, usually palmitate. Dietary retinyl
esters are hydrolyzed to retinol in the intestine; they are
absorbed as the free alcohol and then re-esterified in the
mucosa. In mammals, the retinyl esters are transported
mainly in association with lymph chylomicrons to the
liver where they are hydrolyzed to retinol and re-
esterified for storage. Hydrolysis of the ester storage
form mobilizes vitamin A from the liver as free retinol.
Reti-nol is released from the hepatocyte as a complex
~ CH'OH
All-tra,?s-retinol
~C-<'~'
Il-Ci.~-retinal
CElO
:~,~,,t,,,~1~ COOH
All-tra~ls-retinoic acid
X~,
Il-Cis-3-dehydroretinal
~·: ~ ~
3-Ca rotene
, ~H2`o ~ OH
Ii0 0~]
,~ c00~!
~,
All-trans-retinyl ~plucllror~idt~
CHO
OCR for page 5
Vitamin A 5
TABLE 1 Relative Vitamin A Activity of Carotenoids
Relative
Biological
Activitya
100
100
100
23-75
10-100
30
50
26
21
28
To
Compound
Retinol (all-trans)
Natural or artificial esters of all-trans-retinol
Retinal (all-trans)
Cis-isomers of retinal
Phenyl or methyl esters of retinal
Vitamin A2
in-Carotene
cY-Carotene
v-Carotene
Cryptoxanthin
Zeaxanthin
aIn reference to all-trans-retinol set at 100. Comparisons are on a
molar basis for retinoids but on a weight basis for comparisons of
carotenoids with retinal.
SOURCE: Derived from Moore (1957) and Olson and
Lakshmanan (1969) from data for chicks and rats. Vitamin A2 data is
based on liver storage by fish.
with retinol-binding protein; it is transported in this
form to the tissues. The main excretory pathway is by
elimination as glucuronide conjugates in the bile. Glu-
curonide formation may follow irreversible oxidation to
retinoic acid. Retinoic acid supports growth and cell
differentiation but not the functions of vitamin A in vi-
sion and reproduction. The enterohepatic circulation
may provide an important means of conserving vitamin
A prior to fecal excretion. Small amounts of glucuronide
and chain-shortened metabolites may be excreted in the
urine.
HYPERVITAMINOSIS
A voluminous amount of literature clearly indicates
that vitamin A has the potential to act as a cumulative
toxicant in most species that have been studied (Nieman
and Obbink, 1954; Moore, 1957; Hayes and Hegsted,
1973; Bauernfeind, 1980; Agricultural Research Coun-
cil, 19~(), 1981; Ong and Chytil, 1983; Olson, 1984~.
Table 2 summarizes many of the published reports.
Acute single dose toxicity has been well-documented in
humans (Nieman and Obbink, 1954; Hayes and
Hegsted, 1973~. Massive doses elicit responses within
hours. Reactions may include general malaise, ano-
rexia, nausea, hyperirritability, peeling skin, muscular
weakness, twitching, convulsions, paralysis, and death.
If death is avoided, recovery from these signs of toxicity
is usually prompt upon removal of vitamin A from the
diet.
Chronic toxicity typically results from intakes 100 to
1 ())) times nutritional requirements for a prolonged
period but has been observed at intakes of approxi-
mately 10 times the specific requirement (Olson, 1984~.
The most characteristic signs of hypervitaminosis A are
skeletal malformation, spontaneous fractures, and in-
ternal hemorrhage. Other signs include loss of appetite,
slow growth, loss of weight, skin thickening, sup-
pressed keratinization, increased blood clotting time,
reduced erythrocyte count, enteritis, congenital abnor-
malities, and conjunctivitis. Degenerative atrophy, fatty
infiltration, and reduced function of liver and kidneys
are typical. Endocrine effects related to the pituitary,
thyroid, pancreas, and ovary have been reported in labo-
ratory animals. Because the availability of natural di-
etary sources of vitamin A and its precursor carotenoids
is seasonal, periods of dietary excess accompanied by
accumulation of body stores are critical to the health and
survival of most animals under natural conditions of
feeding.
Normal vitamin A metabolism provides protection
from toxicity. The conversion of diverse sources of di-
etary vitamin A activity to the more stable and less toxic
ester form (usually retinyl palmitate) is one such means
of protection. Transport to the liver in a lipoprotein com-
plex continues this protection. The tremendous storage
capacity of the liver affords great protection against
toxicity as well as dietary deficiency. It is not uncommon
to find concentrations of 500 to 1,000 IU/g in the livers
of most species (Kirk, 19621; however, 13,000 to 18,000
IU/g is common in fish livers (Moore, 1957) and 20,000
IU/g has been observed in human livers (Weber et al.,
19821. Storage in the ester form affords protection to
liver tissue. Controlled release of the alcohol from the
liver by hydrolysis of the ester and subsequent complex-
ing with retinol-binding proteins continue to control re-
activity and protect against toxicity. Vitamin A toxicity
may be viewed as resulting from intakes that over-
whelm one or more of these steps or from malfunctions
in this protective system in the presence of intakes that
are high but would not normally be toxic. Toxic re-
sponses are likely when tissues are exposed to free reti-
nol not bound to retinol-binding protein (Smith and
Goodman, 1976~. In addition to its role as a storage or-
gan, the liver is the site of glucuronide formation, which
facilitates the biliary excretion of vitamin A. The liver is
also active in the synthesis of the major vitamin A trans-
port protein, retinol-binding protein.
Although the pathways described above have been
studied intensively in only a limited number of species,
the available data suggest that most, if not all, species
share these routes of metabolism. The apparently
greater tolerance for vitamin A of ruminants (see Table
3) than for nonruminant animals is supported by the
well-documented ability of ruminal microorganisms to
destroy large quantities of vitamin A (Mitchell, 1967~.
OCR for page 6
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OCR for page 8
[3 Vitamin Tolerance of Animals
TABLE 3 Required and Presumed Upper Safe Levels
of Vitamin A (IU/kg diet)
Presumed
Safe Levelb
S.
pecles
Birds
Chickens, growing
Chickens, laying
Ducks
Geese
Quail
Turkeys, growing
Turkeys, breeding
Requirementa
Cats
Cattle, feedlot
Cattle, pregnant,
lactating or
bulls
Dogs
Fish
Catfish
Salmon
Trout
Goats
Horses
Monkeys
Rabbits
Sheep
~ . .
swine, growing
Swine, breeding
1,500
4,000
4,000
1,500-4,000
5,000
4,000
4,000
10,000
2,200
2,800-3,900
3,333
3,333-6,667
2,500
2,500-5,000
1,500
1,600-3,400
10,000
580-1,160
940-3,000
2,000
4,000
15,000
40,000
40,000
15,000
25,000
15,000
24,000
100,000
66,000
66,000
33,330
33,330
25,000
25,000
45,000
16,000
100,000
16,000
45,000
20,000
40,000
aFrom the National Research Council (1977, 1978a, 1978b,1978c,
1978d, 1979, 1981a, 1981b, 1983, 1984a, 1984b, 1985a, 1985b).
bFor chronic dietary administration.
Data on interaction of other dietary components with
potentially toxic intakes of vitamin A are limited. Vita-
min A may be viewed as competing with other fat-
soluble vitamins at the sites of absorption. At normal
intakes of these vitamins, excess vitamin A may cause
them to become deficient as components of the toxicity
syndrome. Consequently, elevated intakes of vitamins
D, E, and K may reduce vitamin A toxicity by restoring
their respective adequacies or by interfering with vita-
min A assimilation, or both (Vedder and Rosenberg,
1938; McCuaig and Motzok, 1970; Combs, 1976; Sklan
and Donoghue, 1982; Stevens et al., 1983~. Protein sta-
tus can have a major influence through the response of
the retinol-binding protein systems (Weber et al., 19821.
Protein malnutrition reduces circulating retinol-binding
protein. Lack of retinol-binding protein may slow re-
moval of vitamin A from the liver and prevent elevation
of blood vitamin A in the presence of potentially toxic
vitamin A stores (Weber et al., 1982; Ong, 19851.
Concentrations in Tissues
In most species, more than 90 percent of the vitamin A
in the body is stored in the liver (Kirk, 1962~. Most of the
remaining stores are found in the kidneys, fat depots,
adrenals, lungs, and blood. Blood contains levels be-
tween 20 and 100 fig of vitamin A/100 ml. In normal
ranges, blood levels are poorly correlated with either
intake or liver stores. Upon depletion of liver stores of
vitamin A, blood concentrations will drop sharply to
levels between 5 and 20 ~g/100 ml. Persistence of con-
centrations above 100 ~g/100 ml is indicative of toxicity
(Eaton, 19691.
PRESUMED UPPER SAFE LEVELS
Experiments have not been conducted with appropri-
ate designs for determining the maximal amounts of
vitamin A that can be administered without adverse
effects. Consequently, the presumed upper safe levels
for orally administered vitamin A are necessarily esti-
mates. The presumed upper safe levels summarized in
Table 3 represent levels between the minimal require-
ments recommended by the National Research Council
(NRC) and those reported to be toxic in the referenced
scientific publications. When administered for long pe-
riods, these levels would be expected to substantially
increase stores in the liver. However, the levels have not
been reported to produce saturation of the storage ca-
pacity of the liver, result in above-normal increases in
vitamin A blood concentrations, or elevate retinyl esters
in the blood above 50 percent.
The levels selected for nonruminants are consistent
with recommendations for humans (Nutrition Founda-
tion,1982; Olson, 1984~. They also agree with Canadian
Feed Regulations for the most part (Blair, 1985~. The
levels are consistent with the ability of mammals to in-
crease concentrations of vitamin A activity in colostrum
several times more than concentrations normally found
in milk (Walker et al., 1949; Branstetter et al., 1973;
Mitchell et al., 1975; Tomlinson et al., 1974, 19761. In
view of the lack of reported toxicity in most functioning
ruminants, the higher safe levels proposed for them are
considered conservative. These levels agree well with
the Agricultural Research Council (1980) recommenda-
tions for ruminants. The values allow for a wide safety
factor in providing requirements or stimulating accu-
mulation of stores.
The biochemical mechanism for vitamin A toxicity is
not known. Efforts to assign toxicity to a portion of the
retinol molecule have also been unsuccessful.
Absorption of intact carotene is genetically controlled
among species. For example, yellow fat species such as
cattle and poultry absorb more carotene than white fat
species such as sheep and swine. Absorption is also ge-
netically controlled within species. Jersey and Guern-
sey cows, for instance, put much more carotene in milk
OCR for page 9
Vitamin A 9
than Holsteins. The varying conversions of carotene to
vitamin A by the intestine and perhaps other organs
cause these differences. High intake of carotenoids
from natural feedstuffs does not produce vitamin A tox-
icity. Carotenosis is not a practical problem in domestic
animals. It produces yellowing of the skin but few other
adverse signs in humans. In poultry, carotenosis is use-
ful in producing desired color in egg yolks.
SUMMARY
1. Vitamin A is required for normal vision, growth,
reproduction, and epithelial tissues in all vertebrates.
2. Excess vitamin A has been demonstrated to have
toxic effects in most species studied. However, the ex-
cess administered has usually been 10 to 1,000 times the
dietary requirements.
3. Presumed upper safe levels are 4 to 10 times the
nutritional requirements for nonruminant animals, in-
cluding birds and fishes, and about 30 times the nutri-
tional requirements for ruminants.
REFERENCES
Agricultural Research Council. 1980. The Nutrient Requirements of
Ruminant Livestock. Farnham Royal, England: Commonwealth
Agricultural Bureaux.
Agricultural Research Council. 1981. The Nutrient Requirements of
Pigs. Farnham Royal, England: Commonwealth Agricultural Bu-
reaux.
Anderson, M. D., V. C. Speer, J. T. McCall, and V. W. Hays. 1966.
Hypervitaminosis A in the young pig. J. Anim. Sci. 25:1123.
Baker, J. R., J. M. Howell, and J. N. Thompson.1967. Hypervitamin-
osis A in the chick. Br. J. Exp. Pathol. 48:407.
Bauernfeind, J.C. 1980. The Safe Uses of Vitamin A. Washington,
D.C.: International Vitamin A Consultative Group. 44 pp.
Bauernfeind, J. C., H. Newmark, and M. Brin.1974. Vitamin A and E
nutrition via intramuscular or oral route. Am. J. Clin. Nutr. 27:234.
Blair, R.1985. Canadian vitamin ranges for poultry, swine examined.
Feedstuffs 57(19):73.
Branstetter, R. F., R. E. Tucker, G. E. Mitchell, Jr., J. A. Boling, and
N. W. Bradley. 1973. Vitamin A transfer from cows to calves. Int.
J. Vit. Nutr. Res. 43:142.
Castano, F. F., R. V. Boucher, and E. W. Callenbach.1951. Utilization
by the chick of vitamin A from different sources. J. Nutr. 45:131.
Combs, G. F., Jr. 1976. Differential effects of high dietary levels of
vitamin A on the vitamin E-selenium nutrition of young and adult
chickens. J. Nutr. 106:967.
Dorr, P., and S. L. Balloun.1976. Effect of dietary vitamin A, ascorbic
acid and their interaction on turkey bone mineralization. Br. Poult.
Sci. 17:581.
Eaton, H. D.1969. Chronic bovine hypo- and hypervitaminosis A and
cerebrospinal fluid pressure. Am. J. Clin. Nutr. 22:1070-1080.
Frier, H. I., E. J. Gorgaez, R. C. Hall, Jr., A. M. Gallina, J. E. Rous-
seau, H. D. Eaton, and S. W. Nielsen. 1974. Formation and ab-
sorption of cerebrospinal fluid in adult goats with hypo- and hypervi-
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Representative terms from entire chapter:
safe levels
