Evaluation of vitamin A toxicity.

Review Evaluation

of vitamin

John N Hat hcock, David P Ramnathan Sundaresan, ABSTRACI’

A toxicity1’2

G Hattan, Mamie YJenkins, and Virginia L Wilkening

Janet

Toxicity

A supplements

Background

.

KEY

WORDS

effects,

humans,

Vitamin

animals,

A,

toxicity,

metabolism,

carotene,

birth

adverse

defects

Introduction This report addresses the established health effects resulting from high vitamin to vitamin A from both diet and vitamin sidered.

In most

cases

of vitamin

and potential adverse A intakes. Exposures supplements are con-

A toxicity

in humans,

how-

ever, the absence or questionable quality ofdietary recall information restricts interpretation of the dose-response relationship for adverse reactions to that associated with the supplemental use of vitamin A. The report is focused on human or clinical evidence ofadverse effects from excess vitamin A consumption, but reports ofvitamin A toxicity and metabolism in animal species are included to give additional evidence of the toxicokinetic (ie, relating to rate and pattern of toxicant metabolism) or toxicodynamic (ie, relating to the adverse effects of the toxicant on the exposed individual) relationships that are ofsignificance in the safety assessment ofvitamin A. It is not assumed, however, that results from experimental animals treated with excess vitamin A can be definitively extrapoIated to humans, but the assumption is made that its toxic effects occurrence

The jected

reports Am iC/in

in animals

should

of similar

medical

be taken

effects

and

of human Nutr

literature

search;

vitamin

1990;52:

ofthe

possible

in humans.

scientific

to computer-based

as indicators

183-202.

since

selected

intoxications Printed

earlier

1976

was

sub-

reviews

are included.

and

A 1980

in USA. © 1990 American

Downloaded from https://academic.oup.com/ajcn/article-abstract/52/2/183/4651378 by University of Durham user on 07 March 2018

TMcDonald,

report for the Food and Drug Administration (FDA) by the Life Sciences Research Office of the Federation of American Societies for Experimental Biology was used for review and summary of much of the earlier work on vitamin A toxicity in animals (1).

has been associated with abuse of viand with diets extremely high in preformed vitamin A. Consumption of 25 000-50 000 IU/d for periods of several months or more can produce multiple adverse effects. The lowest reported intakes causing toxicity have occurred in persons with liver function compromised by drugs, viral hepatitis, or protein-energy malnutrition. Certain drugs or other chemicals may markedly potentiate vitamin A toxicity in animals. Especially vulnerable groups include children, with adverse effects occurring with intakes as low as 1500 IU kg. d, and pregnant women, with birth defects being associated with maternal intakes as low as “.-25 #{216}#{216}#{216} IU/d. The maternal dose threshold for birth defects cannot be identified from present data. An identifiable fraction of the population surveyed consumes vitamin A supplements at 25 000 IU/d and a few individuals consume much more. /3-Carotene is much less toxic than vitamin A. Am J Clin Nutr 1990;52: 183-202. tamin

Artide

Society

In response to continuing reports ofpotential adverse effects oflarge amounts ofvitamin A, this evaluation was undertaken to determine a minimum toxic threshold dose for vitamin A to the extent supported by the available literature and to identify the factors that alter that threshold. From a public health viewpoint it is desirable to identify a maximum safe vitamin A intake, and identification of that intake is inherently linked to identification of the minimum toxic intake. However, limitations in the data do not permit direct, experimental determination in humans of the maximum safe vitamin A intake. It is possible, however, to provide evaluation through extrapolation downward from the reports oftoxic doses identified from published clinical cases. An important question to be considered when attempting to define toxic thresholds is whether there are individuals or groups ofindividuals who, because ofother factors such as disease processes or concomitant exposure to other substances such as drugs or alcohol, might be more susceptible to vitamin A toxicity than is the general population. On the basis of earlier experimental work with vitamin A in animals (1-3) and more recent clinical reports of severe fetal toxicity of certain synthetic analogs of vitamin A, eg, isotretinoin and etretinate (2, 4), high maternal intakes of vitamin A should also be considered potentially harmful to human infants exposed prenatally. The dose required for such effects, however, is unknown. Predisposing conditions such as viral hepatitis, cirrhosis, and other liver diseases may greatly increase susceptibility and thus lower the amount of vitamin A necessary to produce adverse effects to an amount well below the toxic threshold for normal persons. The degrees of susceptibility probably form a continuum, and thus the persons with predisposing conditions may I From the Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC, and the District Office, Food and Drug Administration, San Francisco. 2 Address reprint requests to JN Hathcock, Food and Drug Administration, HFF-268, 200 C Street, SW, Washington, DC 20204.

Received

March

Accepted

for publication

for Clinical

31, 1989.

Nutrition

October

17, 1989.

183

184

HATHCOCK

TABLE

I

Vitamin

A recommended

dietary

allowances*

Agegroup

AL

TABLE

3

Vitamin

A intakes

RE

RE

Infants, 1-3 mo Children, 1-3 y Females,adult

300 300 520

Females, Females,

620 870

375 375 400 500 700 1000 1000 1000 1000 1000 800 800 800 800 800 800

19-24 y

S

Reference

5. RE, retinol

1300 1200

the variability in the whole data on the shape ofthe fre-

quency-degree

distribution

susceptibility

7.

to retinol

equivalents

with equal biological vitamin A as described

equivalents.

be considered to simply increase population. Accurate and reliable of

curve

are

1 RE

from

any

risk

whatever

of vitamin

A toxicity?

Should

entific

plausibility

and

with

little

supporting

evidence,

be con-

(RE),

activity,

the

depends

below

micrograms

of retinol

on the chemical

form

of

(5):

retinol

6 ig fl-carotene

=

not

any putative beneficial effects of intakes higher than recommended dietary allowances (RDAs), even ones with weak sci-

1

=

available. The decision on what proportion of the population should be considered in setting acceptable safe intakes is essentially a policy matter, not a scientific one. Should a recommended safe intake limit be set that would protect a person with severe cirrhosis

pregnant lactating

A Consultative Group (IVACG) recommended daily intakes ofvitamin A, as listed in Table 3 (7). On the basis ofresearch on requirements and of concern about possible human toxicity, recommended dietary intakes (RDI) for vitamin A (Table 4) were suggested by Olson (8). These different recommendations, all intended to support good nutrition status with an appropriate margin of safety, do not define the thresholds above these intakes at which there should be concern about an unacceptable risk ofadverse effects. Conversion of the international units (IU) of vitamin A activity

Reference

by IVACG5

Agegroup

Males, 25-50 y Males,Sly Females, ll-14y Females, 15- 18 y Females, I 9-24 y Females, 25-50 y Females. 51y Females, pregnant Females, lactating First6mo Second6mo S

recommended

RDA

Infants, 0-0.5 y Infants, 0.5- 1.0 y Children, l-3y Children, 4-6 y Children,7-l0y Males,ll-l4y Males,l5-l8y

Males,

ET

=

12 zg other

provitamin

=

3.33 IU vitamin

=

10 IU vitamin

A carotenoids

A activity A activity

as retinol as fl-carotene

Thus, calculation ofthe RE supplied by a diet requires knowledge of the proportions of preformed vitamin A, fl-carotene, and other vitamin A precursors. The RE cannot be calculated from only the total dietary vitamin A activity in IU.

sidered?

Human

intakes

Recommended

of vitamin

A

TABLE

intakes

are listed

dietary

in Table

2 (6). The

International

Infants

(mo) 375

15-17.9

6-11.9

375

Agegroup

375 400 500

Males (y) 10-11.9

IU

12-17.9

l2mo)

Children (< 4 y) Adults and children

aReference

or lactating

4 y women

I 8-24.9 25-49.9 50-69.9 70

1500 2500 5000 8000

6.


S

Reference

8.

(y) 600 600 600 600 600 600

18-24.9 25-49.9

(y)

6-9.9

Pregnant

A in RE per day, by

Females 10-14.9

1-1.9

daily allowances

Infants(

for vitamin

375

Children

Vitamin

2

US recommended

(RDI)

0-2.9 3-5.9

2-5.9

TABLE

intakes

age group5

For vitamin A the RDAs, defined by the Food and Nutrition Board of the National Research Council, are listed in Table 1 (5). These recommendations were set in relation to nutrition adequacy plus a margin ofsafety; toxicity issues associated with high intakes were not used directly in setting the RDA. The US Recommended Daily Allowances (US RDA) for vitamin A set by the FDA

4

Recommended

600 700 700 700 700 700

50-69.9 70

Pregnancy 0-2.9 3-5.9

(mo) +0

6-9 Lactation 0-5.9 6

+200

(mo) +400 +320

VITAMIN Dietary

sources

In all major nutrition surveys conducted during the past 20 y, mean dietary vitamin age groups examined have been found to the standard employed (9- 1 5). However, individual

day-to-day

variations

in the United States A intakes ofall sexapproach or exceed there are wide intra-

in dietary

vitamin

A intake

that complicate interpretation of survey data. The reporting of only mean intakes tends to conceal the wide variation. This variation is seen in the large difference between mean and median

values

of RDA tamin

(1 32%

vs 79%

for women A intakes

of RDA

for mean for

for men

and median,

elderly

persons

and

137%

respectively)

in the

National

Health and Nutrition Examination Survey (NHANES ducted by the Department of Health and Human (DHHS) (14). As a result ofthe wide daily variation intake

of vitamin

A, the

intake

on any

given

day

vs 84%

for vi-

second

II) conServices of dietary

is poorly

re-

lated to the average intake over a longer period. This must be considered in interpreting results ofshort-term food consumption surveys. According to the results ofthe 1977-1978 Nationwide Food Consumption Survey (NFCS) conducted by the US Department ofAgriculture (USDA), and NHANES II, the groups with the lowest mean dietary intakes appear to be adolescents and young adults, particularly females (1 3, 14). However, the more recent Continuing Survey of Food Intakes by Individuals (CSFil) conducted by USDA reported higher mean intakes for females aged 19-34 y ( 1 33% ofthe RDA) (16). Mean intakes among infants and young children tend to substantially

exceed

the

RDA

(16,

17).

Elderly

individuals

also

tend to consume adequate amounts of vitamin A despite the fact that they are considered to be a particularly vulnerable group for nutrition deficiencies. Actually, the vitamin A density of the diet has been found to increase with advancing age after age 35 (1 3). This increase does not exceed an average intake of4770 IU/l000 kcal, however, an amount that does not give concern about toxicity. The 90th percentile values for vitamin A intake of both males and females (all ages, races, and incomes) for NHANES II ( I 976- 1 980) were 220% for males and 228% for females (14). The 95th percentile values for vitamin A intake rose to 310% for males and 333% for females. Other findings of the major national surveys conducted by USDA and DHHS are as follows: 1) there is little difference in vitamin A intake when other variables are considered, eg, region, urbanization, educational level, and household size; 2) vitamin

A intake

usually

is slightly

higher

in summer

and

fall

than in winter and spring; and 3) vitamin A intake usually is higher in vegetarians than in nonvegetarians (10, 12-14, 18). Usual diets in the United States have been estimated to provide

about

halfofthe

and halffrom data needed enoids, National

the

total

preformed to clarify vitamin

Nutrient

vitamin

vitamin the ratio

A precursors Data

Bank

A activity

from

185

A TOXICITY

carotenoids

,30% ofthe children’s total vitamin A intake and 44% of the women’s and men’s intakes were derived from carotenoids. Estimates ofthe nutrient content ofthe US food supply mdicate that the availability of vitamin A to the consumer was about the same in 1982 (7800 IU .d’ .capita’)as at the beginning ofthe century but was below peak levels in the l940s (18, 2 1). The

US

food

supply

has

exceeded

23).

However,

data

for certain

subgroups

(1 3) to 27%

food

composition data, in terms of retinol equivalents, for provitamm A carotenoids. This new database has been used to evaluate the food intake of women aged 19-50 y and their children aged 1-5 y in the 1985 and 1986 CSFII surveys and men aged 19-50 y in the 1985 CSFII survey (15, 20). Results indicate that


ofthe

population,

eg,

in lactoovovegetarians(24).

A more

likely

estimate,

however, is that ‘-4-6% of users in mixed sample populations take products with vitamin A alone (28, 32). Although numerous reports have been published in recent years

on prevalence

reports provide consumed from dicate

a median

from

slightly

37).

According

ofuse

ofvarious

types

The

vitamin

greater

range

ofsupplements,

information on actual quantities these supplements. Results ofsome

to the

than FDA

A intake

from

the RDA

to two times

survey,

3% ofall

(38).

USDA’s

year

vegetarians (24), pregnant and lactating women (25), and professional athletes (26), indicate a much higher prevalence of supplement use. With few exceptions the surveys have found use of vitamin and mineral supplements to be more common among females than males in almost every age group, to be higher in whites than in blacks, and to increase with higher education and income (23, 27-30). Age is significantly related to supplement usage; it is also a predictor of intake, ie, older individuals tend to consume larger doses ofnutrients (31, 32). As part of the 1986 National Health Interview Survey (NHIS), the National Center for Health Statistics (NCHS) and FDA found that approximately one-fourth of the US population and two-thirds of users of vitamin and mineral supplements ingest products containing vitamin A (23). Similar findings were reported from other surveys (29, 33-35). Estimates of the number of supplement users who ingest products contaming vitamin A alone have ranged from 2% in NHANES II

in plants.

However,

every

Despite the difficulty in comparing results ofsurveys on supplement usage, primarily because of methodological differences, there is no doubt that prevalence of supplement use is increasing among males and females, among whites and blacks, and in income groups below and above poverty level. Depending on the source ofdata, --35-50% ofadults in this country regularly consume vitamin and/or mineral supplements (22,

and mineral supplements in the adult daily 7.5 times the RDA for vitamin

accumulating

RDA

Supplements

A (5, 19). Food composition have been lacking for carotis currently

the

since records were begun in 1909. Hence, low intakes of vitamm A observed among segments of the population are more likely due to food choices rather than to inadequacies in the food supply although as income declines, food choices tend to become limited. Similarly, food choices may produce intakes that are above the RDA. The frequency of highly elevated intakes from unusual food choices is not known.

of intake

in the

FDA

few

of nutrients surveys in-

supplements

ranging

the RDA users

US population A from these sample

population

50-55 000 IU, and the median and 95th percentile 1 .25 and 4.30 times the RDA, respectively (27).

(36,

of vitamin

consume products was

intakes were Preliminary

results ofthe NHIS survey found that the 95th percentile intake of vitamin A for women was 5.6 times the RDA and for men was 7.5 times the RDA (23). The Gallup survey found that 0.08% of supplement users took > 25 000 IU from a single-

186

HATHCOCK

dose vitamin A product, a figure that does not include vitamin A from multivitamin preparations (the predominant formulation used by consumers) and that must be considered, therefore, an underestimate of total intake (39). In the survey of adults in seven Western states, 2.3% of supplement users ingested vitamin A in amounts greater than five times the RDA, and eight individuals (0.33% of the sample population) consumed 200 000-275 000 IU/d (40). The percent of supplement users ingesting 25 000 IU was more than three times as high (7.3%;

3.2%

of the

total

sample)

in a survey

southern California retirement community Western states (31). In the survey ofelderly California readers azine,

which

indicated

that

96%

and

98%

of residents

as that

ofPrevention of the

males

and

The

widespread

consumption

ofvitamin

Children

Adults

Anorexia

Abdominal

Bulging fontanelles

Anorexia

Drowsiness Increased intracranial

pressure

Irritability Vomiting

and

mineral supplements is likely to continue and probably even increase with the popular interest in self-care and concern about dietary adequacy in combination with advertising pressure and an increase in lay publications on nutrition, health, and disease prevention. The likelihood ofan increase in supplemental consumption is even greater for certain nutrients, including vitamin A, which some studies have indicated may help to reduce the rate of certain cancers. Although the Na-


pain

Blurred vision Drowsiness Headache Hypercalcemia Irritability

Muscle weakness Nausea,

vomiting

Peripheral neuritis Skin desquamation

fe-

35, 38, 46).

50).

A toxicity5

mag-

Survey data indicate that people use supplements for reasons that vary widely. The most commonly stated reasons are 1) to supplement the diet (ie, nutrition insurance), 2) to improve general health, and 3) to increase energy and vitality (24, 28, 30, 34, 47). Whereas “light” and “moderate” users are more likely to perceive either general health benefits or no benefits at all, “heavy” users tend to cite specific health benefits as the rcason for taking specific supplements (48). Finally, only a small proportion ofusers(most notably the light and moderate users) report any physician involvement in starting a supplement regimen (48, 49), although this proportion is increased in elderly (34,

of acute vitamin

in seven

respectively, used supplements, 25% ofthe sample popingested 20 000 IU (41). A recent survey of elderly persons in the Boston area found that 5% of males and 6% of females had intakes of vitamin A from supplements 7.5 times the RDA, and 1% ofboth males and females had intakes from supplements 10 times the RDA (29). These intakes cause concern about possible toxicity, especially for elderly persons, because the physiological changes accompanying aging could lower the threshold of toxicity and increase the risk of megadose supplement use (29, 42). As part of an epidemiological study conducted by the New York State Department ofHealth, it was found that 81% of 492 women interviewed took supplements containing vitamin A during pregnancy. Of these, 2.6% had taken supplements containing 15 000-24 999 IU and 0.6% had taken 25 000 IU (25). There are no data in the literature to show total daily intake ofnutrients from both diet and supplements in a representative sample ofthe entire US population, and there are few for select population groups (I 1, 26, 29, 32, 36, 43-45). However, the reports available indicate that total intake can be substantial. In the studies that have provided data on both dietary intake and supplement use, there generally has been no significant difference in diet quality between supplement users and nonusers; if anything, supplement users have, on average, slightly higher nutrient intakes from the diet alone than do nonusers

persons

AL

TABLE 5 Signs and symptoms

of a

males, ulation

(29,

ET

S

References

tional

3, 53, and 55.

Academy

(5 1) specifically

ofSciences’ states

as sources of nutrients vidual nutrients, many

Human

that

Diet, Nutrition, the recommendations

and Cancer apply

report to foods

and not to dietary supplements of mdiconsumers may not heed the warning.

toxicity

Expression of the toxicity of any substance depends on the concentration of the toxic form at the target site. Occurrence ofa threshold or greater concentration depends on dose indices and toxicokinetic processes. For substances such as vitamin A that tend to bioaccumulate (ie, increase in concentration at each step in a food chain), the chronicity ofexposure is crucial because of the slow metabolic clearance and the large storage capacity in certain tissues (52).

Dose and lime indices Vitamin A has along biological half-life and bioaccumulates. The combination ofrelatively rapid absorption with slow clearance can produce acute toxicity after a sufficiently high dose and chronic toxicity after prolonged intake of substantially smaller doses. Vitamin A toxicities in humans may be generally categorized as either acute or chronic. Acute toxicities occur within hours or at most a day or two after a very large intake. Chronic toxicities occur after several weeks, months, or years of consumption oflesser amounts that are not acutely toxic. Numerous cases ofacute hypervitaminosis A have been documented after ingestion ofvery large quantities ofthis vitamin (3, 53). From these reports and from results of experiments with animals, the high toxicodynamic potency of vitamin A is well established. The tendency of vitamin A to bioaccumulate suggests that chronic exposure to excess amounts would be hazardous. This expectation of increased vitamin A toxicity with chronic excess intake has been confirmed: the daily dose needed to produce chronic toxicity is considerably lower than that required to produce acute toxicity (2, 3, 53, 54).

Symptoms

of toxicity

Hypervitaminosis A has been observed in both children and adults. The actual presentation of adverse symptoms varies with the dose and the duration of exposure as well as with the age of the individual exposed. Listed in Tables 5 and 6 are the

VITAMIN TABLE

methodology is available (58, 59), the data on interactions are not sufficient to allow distinction between additive, synergistic, and potentiative effects. The important consideration, however, is that any of these types of interactions may enhance toxic potency, and consequently adverse effects may occur at doses that would be safe otherwise. Alcohol. Synergism oftoxicity resulting from the interactions between alcohol and high vitamin A intakes may be expected on the basis ofmetabolic and toxicologic relationships in experimental animals, but at present evidence ofsuch a relationship

6

Signs and symptoms

ofchronic

vitamin

A toxicity5

Children Alopecia,

anorexia,

bone

fissuring

craniotabes,

pain and tenderness,

at lip corners,

bulging

of fontanelles,

hepatomegaly,

premature epiphyseal closure, photophobia, cerebri, skin desquamation, skin erythema

hyperostosis,

pruritis,

pseudotumor

Adults

in humans

Alopecia,

anemia,

anorexia,

ataxia,

bone

brittle nails, cheilitis,

conjunctivitis,

mucous epistaxis,

dysuria, edema, facial dermatitis,

membranes, exanthema,

hepatomegaly, menstrual

hepatotoxicity,

abnormalities,

negative petechiae,

skin

vomiting,

55,

Reference

and 56).

bone

abnormalities,

diplopia,

dryness

of

elevated CSF pressure, fatigue, fever, headache,

hyperostosis,

insomnia,

stiffness

and

pain,

irritability, nausea,

nitrogen balance, nervous abnormalities, papilledema, polydypsia, pruritis, pseudotumor cerebri, skin

splenomegaly,

signs

pain,

diarrhea,

muscular

desquamation,

S

erythema,

skin

rash,

skin

scaliness,

weight loss

56.

symptoms

of vitamin

A subpopulation

A toxicity

of individuals

in humans with

latent

(3, 53, hypervita-

minosis A may be defined as those persons who had extremely elevated amounts ofvitamin A stored in their livers but whose peripheral tissue concentrations, including serum values, were not elevated above normal. Such cases were reported when the individuals

developed

some

hepatotoxicity (eg, chronic function (eg, severe protein Modulation

coexisting

alcoholism) deficiency)

disease

that

or impaired (57).

resulted

in

hepatic

chronic

expressions

must

of toxicity

(eg,

cirrhosis

and

neo-

plasia). Interactions resulting from chronic exposure may differ from those occurring after acute exposure to the same substances. In assessment of the safety of higher-than-normal intakes of vitamin A, interactions that produce enhanced toxic potency may be important. Although adequate statistical


be categorized

as strongly

suggestive

rather

than conclusive. Alcohol produces hepatic cirrhosis after prolonged, heavy consumption in some individuals, but hepatotoxicity from excess vitamin A is not readily distinguishable from alcoholic cirrhosis (60). In experimental animals, chronic vitamin A toxicity produces certain lesions in the liver that are not caused by alcohol (61). The quantitative measures of toxic potency that have been made with animals do not allow a clear determination of whether the alcohol-vitamin A interaction is additive or synergistic; the inhibition of oxygen consumption and respiratory control ofisolated rat-liver mitochondria by using palmitate as substrate appear to be additive toxic effects of high vitamin A and alcohol intakes (62). Evidence with humans is not sufficient to determine the quantitative character ofthis toxic interaction. Nevertheless, the prudent interpretation is that alcohol and excess vitamin A consumption will result in substantial enhancement ofthe respective toxic effects ofeach ofthese substances.

Protein. Excess vitamin A stimulates gluconeogenesis and protein turnover and, accordingly, low-protein intakes may enhance this aspect ofvitamin A-induced hepatotoxicity (56). In a 6-y-old boy the combination of vitamin A at 20 000 IU/d associated

of toxic potency

The likelihood that humans will be exposed simultaneously to numerous substances, including environmental chemicals, drugs, food substances, and dietary supplements, necessitates consideration ofpossible potency modulation through interactions with these substances. Considerable evidence has accumulated from acute studies with animals and accidental acute exposure of humans that simultaneous exposure to two or more substances may produce results not predictable from the independent actions of the chemicals. Well-known examples include the alcohol-barbiturate and alcohol-carbon tetrachloride combinations. Quantitative assessment of toxicological interactions has usually focused on the acute toxicity of simple (two-component) mixtures of chemically similar substances (58). Often these studies have utilized relatively insensitive endpoints, such as mortality, which result from exposure to high doses, and therefore have limited relevance to predictions of interactions that may follow chronic exposure to low doses of chemicals. There are insufficient data concerning quantitative assessment of interactions resulting from chronic exposures and involving

187

A TOXICITY

with

inadequate-to-marginal

protein

intake

caused

vitamin A toxicity at a vitamin A intake lower described as toxic in older children, suggesting role in vitamin A metabolism was circumvented,

than previously that the liver’s so that vita-

mm

now

A amounts

that

pervitaminosis

were

A (63).

previously

Conversely,

nontoxic ifliver

caused

dysfunction

hy-

were

se-

vere, the peripheral manifestations of hypervitaminosis might be masked by protein-energy malnutrition (PEM). In a 63-yold male, both retinol-binding protein (RBP) and vitamin A secretion were reduced although liver biopsy showed histologic and biochemical evidence of hypervitaminosis A (64). Children with PEM synthesize less RBP and have depressed plasma vitamin A concentrations, which are partially due to depressed carrier

synthesis

Tocopherol, toid

cells

(65).

taurine,

exposed

and zinc. Cultured

for

short

times

human

to retinol

and

lymphoblasretinoic

acid

have a time- and dose-dependent decrease in viability, accompanied by cell swelling. Tocopherol or taurine and zinc together completely protect cells from retinol-induced injury. A membrane-stabilizing action was proposed as the mechanism underlying

the

protective

effect

ofthese

substances

(66).

How-

ever, reports of vitamin E protecting against hypervitaminosis A must be cautiously evaluated. Although some investigators indicate vitamin

enhance 30 000 vitamin

that vitamin A toxicity,

tissue

uptake

E provided others found

ofvitamin

IU vitamin A/d, 200 IU A values while maintaining

a degree ofprotection that vitamin E may

A (67). vitamin normal

against actually

In humans ingesting E/d reduced serum concentrations

of

188

HATHCOCK

ET

AL

plasma RBP and prealbumin (68). It was proposed that zinc could be used not only to treat patients with depressed plasma

that

vitamin

dermatological complaints. Some ofthese reports give only the supplemental intake of vitamin A; most reports give an estimated total daily intake of vitamin A from diet plus supplements of 50 000 IU. Estimates of dietary intakes of vitamin A by these individuals ranged from typical amounts up to %4#{216} 000_SO 000 IU. Probably, prior dietary intake is an important determinant of the tolerance of excess vitamin A because it has a major influence on the degree ofprior saturation of liver storage capacity and because dietary intake can substantially exceed supplemental intake (76). Other conditions such as liver disease of other origin (PEM, alcohol abuse, or viral hepatitis) may enhance susceptibility to vitamin A toxicity. Latent hypervitaminosis A was precipitated

A but also

to treat

hepatic

toxicity

from

hypervitamin-

osis A (69). These data from experimental animals suggested that zinc may be specifically involved in mobilizing vitamin A from the liver to the circulation within a short period. The mechanism by which zinc mobilizes vitamin A is not yet understood.

Tetracycline. Tetracycline (70) and acute or long-term overdosage of vitamin A (7 1 ) were reported to each cause benign intracranial hypertension. Cases of benign intracranial hypertension were reported in persons taking tetracycline plus vitamm A in amounts ranging from 40 000 to 150 000 IU/d (70, 72, 73). It was suggested that patients given tetracycline and vitamin A in combination for acne may be at greater risk for benign intracranial hypertension than patients given either drug alone (70). The combination may also increase the severity ofthe

syndrome.

Vitamin D. An antagonistic and D was suggested. Studies mins

A and

D diminish

interaction in animals

the

toxic

effects

between indicated

vitamins A that vita-

of each

other

(74).

It was also shown that the toxicity associated with excessive parenteral administration of vitamin A is markedly reduced when it is administered in combination with vitamins D and E. In long-term vitamin A intoxication, the pathological changes caused by the direct action ofvitamin A on skeletal tissue may be modified by secondary changes in calcium metabolism and in the metabolism ofcalcium-regulating hormones (75). In children hypervitaminosis A, particularly of the chronic type, is frequently confounded by high vitamin D intakes, a fact to be considered when describing manifestations and evaluating critical intakes. In adults the simultaneous intake of high doses of vitamins A and D has been reported much less frequently than in children and infants. Because toxic amounts of vitamin D are often given together with excess amounts of vitamin A in the cases ofchronic hypervitaminosis in children, the effects of excessive vitamin D intakes are difficult to separate from those ofexcessive vitamin A. In reports of birth defects temporally associated with high maternal vitamin A (retinol) intakes, some of the exposures have been in combination with high doses of other vitamins (2). For example, in a physician’s report to the FDA regarding a case ofleft-ventricular hypertrophy, the mother was exposed to 50 000 IU vitamin D and 100 000 IU vitamin A daily before and throughout pregnancy until abortion was induced in the 18th week. Intake

thresholdfor

vitamin

A toxicity

Reports of vitamin A toxicity from consumption tively low amounts of vitamin A have been evaluated of toxic effect and other conditions or factors associated the toxicities. Because of both theoretical and practical on use ofthe data, no attempt has been made to predict mal vitamin A intake that could produce toxicity in an ual or in the population. Instead, reports of vitamin A were evaluated for validity and presence of confounding tors. The several lowest dosages reported to produce

of relafor type with limits a miniindividtoxicity factoxicity

were

such

identified

age, sex, Adults.

in adults

diet,

and disease,

interpreted and

drug

in relation

to factors

use.

Some lower-dose cases of chronic vitamin A toxicity are summarized and referenced in Table 7. Symptoms


as

occurred

cranial

in most

hypertension

by viral

hepatitis

of the patients

included

(pseudotumor

that

had

cerebri),

its onset

after

benign

intra-

headache,

and

10 y of consumption

ofa 25 000 IU vitamin A supplement (79). The diet may have contained another 25 000-50 000 IU. It cannot be known whether the vitamin A toxicity would have occurred without the supplemental intake. Because intracranial hypertension can result independently from excess vitamin A consumption (7 1 ) and from tetracycline use

(70),

reports

of intracranial

hypertension

and

headache

may be confounded in patients treated for acne with both substances. The possibility of an additive or synergistic effect should be taken into account for acne patients in deciding a prudent maximal limit for vitamin A intake. As indicated in Table 7, reports of vitamin A toxicity in adults with supplemental intakes < 50 000 IU/d mainly involve persons with unusually high dietary intakes or with confounding medical conditions, such as liver disease, malnutrition, or use ofdrugs or alcohol. Elderly persons may have quite variable tolerances for high vitamin A intakes. One man aged 79 y who died of a cerebral vascular

accident

had

been

taking

50 000

IU

vitamin

A as

a

supplement along with an unremarkable dietary intake without signs oftoxicity for a reported period of 17 y (83). The liver, which showed no gross or microscopic evidence ofdisease, had an extremely elevated amount of vitamin A ( 1 8.9 mmol vitamm A in the liver). Other elderly persons, however, have much lower tolerance for high vitamin A intakes. Five of 562 healthy elderly subjects taking from 5000 to 10 000 IU/d of supplemental vitamin A had slightly elevated serum retinyl ester concentrations and serum transaminase values, indicating the possibility of marginal liver damage (42). Although these abnormal clinical indices may have resulted from vitamin A toxicity, the possibility that preexisting liver damage led to the elevated serum retinyl ester concentrations is equally plausible. The possible teratogenic effects from high intakes of vitamin A by pregnant women are discussed under Prenatal effects. Children and infants. Children can be intoxicated by total daily intakes of vitamin A lower than those necessary to cause adverse effects in adults. Part if not all of this difference seems to be due to the smaller body size ofchildren. There is little or no scientific information available on age-related differences in sensitivity to elevated tissue concentrations of vitamin A. In terms oftotal intake per day per person, children are more susceptible than adults to vitamin A toxicity (Table 7 and Table 8).

takes

Most

reports

of

in the multiple

a substantial

number

vitamin

hundreds

A toxicity

in

ofthousands

of intoxications

have

children

oflU occurred

involve

in-

per day,

but

with

much

VITAMIN TABLE 7 Some cases ofchronic, Daily

low-dose

vitamin

dose

A toxicity

in adults

Age and sex

It!

Time

y

Symptoms

Other

conditions

Reference

y

5000 + diet = 40 000-50 000 20 000 45 000 50 000 25 000 + diet = 50 000-75 000 20 000 + diet 50 000 50 000 30 000 10 000-20 000

29, 42, 30, 16, 42, 62, 18, 5 1, 18,

50 000

54, M

-

189

A TOXICITY

M F M M M M F F M

? ? 12 2.5 10 7 0.5 20 2

Fatigue Intracranial hypertension Cirrhosis Liver enlargement, headache, etc Headache, desquamation, hypercalcemia Pedal edema Intracranial hypertension Dermatitis, alopecia, liver enlargement Intracranial hypertension

Bilirubinemia, anorexia None reported Ichthyosis, psoriasis Acne (no tetracycline) Viral hepatitis Wasting, PEM Acne (with tetracycline) Alcohol use? Acne (tetracycline

Weakness,

Alcohol abuse earlier

76 71 77 78 79 64 72 80 81

not mentioned)

lower intakes weight as IU verted to lU (National

data

(Table . kg

‘

. kg

Center

3

.d

8). Some of the reports give the dose by ‘ . For the others, the IU/d data were con-

.d

‘

for

by using standard Health Statistics,

weight-for-age unpublished).

headache,

anorexia

compounds in experimental pregnant female experimental

tables These

of vitamin A or one acid or 1 3-cis-retinoic

indicate

7 y

82

animals (2, 55, 96). Treatment of animals with excessive amounts

of its congeners, acid, resulted

such as all-trans-retinoic in dramatically increased

toxicity in a few children beginning at intakes ‘ .d ‘. There are numerous other reports, not included in Table 8, of hypervitaminosis A in children, but they involved much higher doses (89-93) and are not useful with respect to lowest-

rates of fetal resorptions, stillbirths, and birth ofoffspring one or more characteristic defects. Evidence that excessive mm A is a human teratogen falls into the following three gories: 1) Extrapolation of the unequivocal data from several

adverse-effect

cies

< 2000

IU . kg

Accuracy

intake

for excess

of patient

(and

dosage

after

tiously

evaluated. A first

minosis

vitamin parental)

hypervitaminosis

supplemental

The insisted vitamin

reporting

of vitamin

A is diagnosed

parents

that

A in children.

of a 9-y-old

her diet

A intake

was

must

girl

with

A

that

10 000

(94).

Further

high

very amounts

strongly would

suggests

that

vitamin

have

teratogenic

spe-

A at suffieffects

in

hu-

mans. 2) There is temporal A by pregnant women

hypervita-

and

IU/d

ciently

be cau-

was average

of animals

with vitacate-

her

teristic

ofeffects

association of high intakes of vitamin with birth ofbabies with defects charac-

ofexcessive

vitamin

A in animals.

This

tempo-

clinical history, however, revealed that for the previous year the patient had actually been getting 300 000 IU vitamin A/d plus desiccated liver and carrotjuice. A variable tolerance of infants to excess vitamin A has been hypothesized to have a genetic basis (95). Two boys developed apparent hypervitaminosis A by age 2 y for one and by age 6 mo. for the other. They were given chicken liver that supplied ‘--2300 IU vitamin A/d and various supplements that supplied another 450-2500 IU/d. An older sister who had been treated

ral association together with the unequivocal evidence from animals leaves little doubt that a sufficiently high intake of vitamm A by a woman at a critical stage of pregnancy could have teratogenic effects. There is much uncertainty about the dose ofvitamin A needed to produce such effects. 3) The teratogenicity of 1 3-cis-retinoic acid, a derivative of vitamin A used as a drug to treat recalcitrant cystic acne, has been established in epidemiological studies (4) as well as in animal experiments. This compound occurs naturally in very

similarly

small erties

remained

Prenatal togenic

potential

TABLE Some

effects.

completely Numerous ofexcessive

healthy. reports clearly intakes

ofvitamin

establish A and

the terarelated

amounts and it shares with all-trans-retinoic

many acid,

metabolic and a direct product

binding propofvitamin A

metabolism.

8 cases ofchronic,

Daily

dose

lU/kg 6338

low-dose

vitamin

A toxicity

Age and sex

Time

mo

mo

3 1, M

5

in children Symptoms

Xerosis,

cortical

thickening

phosphatase, dermatitis, photophobia,

Other

in femur,

2361 2700-3300

26, M 29, F

6 28

alkaline Irritability, Irritability,

1689 3247 4085

48, F 12, F 30, M

24 9 12

seborrheic plaques Pain in feet and ankles, papilledema, Irritability, vomiting Anorexia, ataxia, lethargy


high

irritability some alopecia pseudoparesis,

conditions

None

84

Pica ofpaint None dermatitis

None None Health

Reference

chips

85 86 87 88

food use

88

190

HATHCOCK

TABLE Some

defects

Maternal

Reports

associated

with high maternal

intake

of individual

Single dose, month

25 000 IU 50 000 IU

0-13 wk I 4 wk to term

of multiple 000 IU

-2 to

Before and throughout

consumed

liver

amounts) was reported the mother had a flu-like medications.

known,

comparison

dose

cases

causative

argues factor;

Table 9. The lowest in humans

of the

in

97

Fetus aborted at 20 wk because ofspinal abnormality and polycystic kidney

98

Abnormalities

Cases reported

illness

with the

99

RT Davis, N Teresi, unpublished

that

vegetables

etiology

vitamin

A intake

reason,

against this

ofvitamin

A that

be estimated

from

in modest

fourth month, hyperpyrexia not treated

of vitamin

head,

jaws,

in the

reports

ofthe

face, ears, eyes, mouth, heart, and urinary system; other defects

orange

However,

very strongly for

intake cannot

and

( 101).

Although

if the mother’s

rect,

Reference

Dose caused acute toxicity the pregnant woman

Various reports ofbirth defects in temporal association with maternal exposure to moderately elevated intakes of vitamin A are summarized in Table 9. The occurrence of birth defects after maternal exposure to an acutely toxic but unquantified single dose early in pregnancy has provided the most convincing direct evidence for human teratogenicity ofvitamin A (97). This single dose was estimated to be 500 000 IU (in the second month) (2). Less massive doses (eg, 1 50 000 IU/d) taken daily for several weeks or longer can produce similar defects (98, 100). There are reports of related characteristic birth defects temporally associated with maternal intakes of ‘-25 000 IU/d during pregnancy (2, 99, HL Vallet et al, unpublished observations, 1985). A cause-and-effect relationship in this range or at even lower intakes is equivocal. Caution must be exercised not to assign a cause-and-effect relationship solely on the basis of occurrence of characteristic defects. A case of multiple congenital anomalies associated with apparently normal maternal intake of vitamin A (ie, the mother took a multivitamin supplement containing 2000 IU

with

conditions

cases

HL Vallet, AD Stark, K Costas, S Thompson,

A and

Other

Preauricular appendices, epibulbar dermatoid (eye malformations similar to Goldenhar’s syndrome) Facial dysmorphism, pterygium colli, distended abdomen, absence of external genitalia and of anal and urethral openings, polycystic kidneys, dysmorphism of lumbar spine Unilateral ureteral duplication with one ureter ending in the vagina, hydronephrosis, hydroureters

pregnancy

vitamin

A Symptoms

second

Periconceptual +3 mo

18 000-100

ofvitamin

cases

000 IU

Reports

intake

Duration

150 000 lU

S

AL

9 cases ofbirth

-‘-500

ET

of this

A intake with

excess case

the

is not

were

cor-

next-lowest

vitamin A as the is not included in

has teratogenic present

case

data.

potential If the

birth

defect or pattern of defects is strongly suggestive of vitamin A toxicity and the maternal dose is very high, the argument for a causal relationship is strong, as in the case with the single dose


by physicians

to

2

FDA; cases reported to NY State Birth Defect Registry

lips,

observations,

1985.

of ‘-500 000 IU (97). Even if the birth defects are similar to those produced by excess vitamin A in animals, the causal relationship remains questionable ifthe maternal dose is not in the toxic range, as was probably the situation in several ofthe cases cited by Rosa et al (2). Several ofthese cases cited by Rosa et al (2)were reported by the New York State Birth Defects Registry; the maternal intakes of vitamin A ranged from 18 000 to ‘-25 000 IU/d. The relative risk ratios for high maternal exposure

to vitamin

A were

not

significantly

different

for the

group

with birth defects compared with case controls (H Lawrence Vallet, personal communication, 1986). From the data available, it is impossible to determine whether the numbers of cases were too small to establish statistical significance or whether vitamin A is not teratogenic at the observed exposures. The relative

risk

ratios

were

2-3

for all categories

ofbirth

defects.

Ifthere is a teratogenic risk ofthis small magnitude, a very large study would have to be conducted to identify it. Ifthe maternal diet plus the supplemental intake is well within the usual range (101), excess vitamin A is almost certainly not the etiologic factor. Other cases cited by Rosa et al (2) include physician reports sent directly to the FDA. The maternal doses associated with birth defects in these cases were higher and ranged from 25 000 to 100 000 IU/d on a chronic basis. Part ofthe uncertainty in estimating the amount of elevated maternal vitamin A intake that might cause birth defects relates to the unknown rates of normal outcomes of pregnancy with elevated maternal intakes of vitamin A. Rosa indicated (personal communication, 1986) that he knows ofno cases of normal outcome when maternal intake was I 00 000 IU/d on a protracted basis just before or during early pregnancy. Certainly, the exact opposite is true for supplemental intakes of 8000

IU vitamin

A, because

many

prenatal

vitamin

formu-

1

VITAMIN las contain

8000

therefore,

the

lU,

number

the

US

RDA

for

of exposures

pregnant

in this

women

dose

range

equivalent

and, is very

studies

on toxicity

and overdose

The

rats

subchronic retinol

was was

toxicity that

extensively

produced

in animals

appeared

in the

reviewed by retinol

(102). doses

of vitamin literature

A preparaup to the

Hypervitaminosis

of 3 mg (10 000

early A in

IU)/d;

the

duration of treatment varied from a few days to several weeks. Route of administration, species, age of the animal, treatment duration, the specific toxic manifestation in question, and the size of the dose all affect the time to first appearance of toxic signs. Hypervitaminosis A has produced anorexia, weight loss, anemia, cachexia, and finally death. Spontaneous fractures appearing as hind-leg paralysis have frequently been observed in rodents. Extensive subcutaneous and/or intramuscular hemorrhages commonly occurred and are signs of hypoprothrombinemia. Internal hemorrhage and inflammation ofthe nasal pasthe amount of substance in a single dose required to kill 50% of a population ofanimals. An LD50, expressed in mg/kg, is calculated from a dose-response curve and is dependent on various factors such as route ofadministration, species, strain, sex, age, nutrition status, and environmental conditions. The LD50 may not relate closely to chronic toxic potency, the toxicity time range more relevant to most human exposures. For lack of a better short-term alternative, however, the LD50 is widely used as a first approximation ofthe potential ofa substance for causing toxicity. LD50 values for retinol, all-trans-retinoic acid (RA), 1 3-cisRA, and etretinate given orally to mice are 2570 (8.6 X 106 IU), 1 100-4000, 3389-26 000, and > 4000 mg/kg, respectively; in rats the LD50 values for retinyl palmitate, all-trans-RA, 13-cisRA, and etretinate given by oral intubation are 79 10 (14.4 x 106 IU), 2000, > 4000, and > 4000 mg/kg, respec(103).

Young monkeys given a single water-miscible intramuscular dose the equivalent of300 mg(l X 106 IU) retinol/kg as retinyl acetate became progressively weak, had difficulty in breathing, lapsed into coma, and then died; in some cases death was preceded by convulsions ( 104). No animals receiving the equivalent of 100 mg (0.33 x 106 IU) retinol/kg died. The LD50 was estimated

to be 168 mg(0.56

X 106 IU)

retinol/kg.

Chronic toxicity. Studies ofsubchronic toxicity in laboratory animals often involve periods ranging from 2 wk to 3 mo. Doses selected have ranged from low amounts with no observed toxic effects to amounts sufficiently high to produce well-defined toxic effects ofhypervitaminosis A, as follows: 1) Skin effects. Hair loss, localized erythema, and thickened epithelium were observed (103). 2) Internal organ effects. Fatty infiltration of the liver and fatty changes in the heart and kidney have been observed. Testicular hypertrophy has been found in adult rats. Degenerative testicular changes occurred in weanling rats but not in adults after prolonged treatment. Extensive foci ofdegenerative myocardial

.d

of serum

triglycerides.

Hypertriglycendemia

was

ob-

fibers

were

reported

in

rats

treated

with

vitamin


in rats fed 33 mg ( 1 10 000 IU) retinol/d ( 106, 107), or 550-1 100 mg ( 1-2 X 106 IU) retinyl palmitate/d ( 108). In the latter report, the effect on serum lipids was reversed upon discontinuation of treatment. However, other studies reported that retinyl palmitate at 185 mg (336 000 IU)/ 100 g body wt did not affect serum triglyceride concentrations (109). 4) Skeletal-system effects. At a daily dose of 10 000 times the amount required to maintain growth, a limping gait was observed in rats and mice (1 10). Rats were fed 8.5-1 3.6 mg (28 300-45 300 IU) retinol/d as retinyl acetate, a dosage range that proved to be toxic but not lethal. A limping gait was observed after 1 wk; x-ray examination showed fractures. Bone mineralization was normal as indicated by bone-ash determinations and, hence, toxicity was associated with the formation or destruction ofbone matrix. ‘

Histopathological

sage, gut, and conjunctivas have been often observed. Acute toxicity. This index is often expressed as an LD50,

tively

kg

served

and

l950s

000 or 20 000 lU) retinol.

mo(l05). 3) Blood effects.

vation Retinoltoxicity

tions

to 3 or 6 mg(lO

for3

Decreased hemoglobin concentration and transient increases in total circulating lipids and serum cholesterol were reported (103). Many subchronic-toxicity studies found that treatment with retinoids was associated with an ele-

large.

Animal

191

A TOXICITY

A

changes

in bone

were

elicited

by excess

retinol (102). Either there was increased activity of osteoclasts or decreased activity ofosteoblasts with no change in osteoclast activity (1 1 1). In either case, the bone growth longitudinally was greater than circumferential bone growth, resulting in a thin fragile cortex that ultimately fractured. The effects of hypervitaminosis A on bones has also been demonstrated in dogs (1 12) and

other

species.

In addition,

toxicity

is not

restricted

to

the skeletal system as indicated by reduced formation of dentine and atrophy of lingal odontoblasts (1 1 1). The effect of excess retinol on bone in culture has been found to be similar(l 13). Only a few chronic toxicity studies with retinoids have been reported in rats and dogs (103). Doses ofO, 5.5, 13.8, and 27.5 mg (0, 10 000, 25 000, and 50 000 IU) retinyl palmitate.kg. d’ for studies in rats and doses ofO, 0.6, 2.8, and 13.8 mg (0, 1000, 5 100, and 25 100 IU). kg’ . d for dogs were administered. The highest dosage for each species was 250 times higher on a body weight basis than the human RDA for vitamin A, which is -0.06 mg (1 10 IU) retinyl palmitate . kg’ . d ‘ . No adverse effects were found in rats or dogs treated for 10 mo with these doses of vitamin A palmitate. Body growth and hematologic indices were unaffected in both species. Of course, with the difficulties in extrapolation between species, these data should not be construed to indicate that an intake of 250 times the RDA is safe for humans. Modulation

oftoxic

Potentiation humans, fatty liver

injury

from

potency

ofvitamin A toxicity by ethanol. In animals liver has been recognized as a manifestation ethanol.

The

morphological

and

and of

biochemical

changes induced in liver and the modifications in the system of transport for vitamin A in rats consuming ethanol and moderate amounts of vitamin A, compared with those pair-fed vitamm A supplements only, were described (61, 62). In the ethanol-fed, vitamin A-supplemented rats tested at 2-mo intervals, the quantity of vitamin stored in the liver was markedly reduced, although the serum concentrations of vitamin A and RBP were unaffected. After a prolonged intake ofethanol, the

192

HATHCOCK

serum levels of vitamin A and RBP were less than in the pair-fed, vitamin probably

indicating

a decreased

in the ethanol-fed A-supplemented

capacity

ofthe

group group,

liver

line

occurred

ethanol

after

short-term

administration

Potentiation

ethanol

produced

intake,

liver

to synthe-

ofethanol-induced

but

fibrosis

vitamin

long-term

and cirrhosis.

A depletion

by drugs

In addition to ethanol, drugs such as Lmethyldopa, prednisone, and hydrocortisone have been observed to decrease hepatic vitamin A in humans. This type of and

food

effect

additives.

was

also

confirmed

in rats

which

received

methylcholan-

threne and phenobarbital or butylated hydroxytoluene

(1 14). Treatment with phenobarbital (BHT) enhanced the ethanol-induced hepatic vitamin A depletion in rats (1 1 5). The depletion ofhepatic vitamin A was exaggerated by a combined treatment ofethanol with phenobarbital or BHT. Both retinyl esters and retinol

were

depleted.

lung

concentrations

ther

phenobarbital

vitamin

Chronic

ethanol

of retinyl

esters

nor

BHT

consumption and

affected

increased

retinol

lung

whereas

nei-

concentrations

of

A.

The

mechanism

by which

A concentration clearly

and

understood.

occurred

as a result

increase

in the

curred

not

of other

that

some

of increased

enzyme

1 18). This

microsomal

vitamin

tissues

hepatic

mobilization,

resulting

tissues.

This

could

bound

to RBP

increase but

also

is not

depletion

in an have

in the

ocform

with lipoproteins, as observed previously administration (1 16). A second possibility A depletion is enhanced degradation. Me-

of retinoic

dependent

hepatic

that

as retinol

of retinol associated after acute ethanol for hepatic vitamin tabolism

increased

reduced

It is possible peripheral

only

ethanol

acid

proceeds

system

through

in hamster

retinoic

a microsomal

intestine

P450-

and liver

acid-metabolizing

( 1 17,

system

can

be reconstituted

with various forms ofpurified cytochrome P450 (1 14). Furthermore, this system is induced by chronic ethanol consumption (1 19). Thus, the ethanol-induced depletion of hepatic

vitamin

A may

have

been

due,

at least

in

part,

to en-

hanced degradation through this pathway. The marked hepatic vitamin A depletion observed after ethanol consumption, when combined with other drugs or food additives, may have significant implications with respect to vitamin A requirements and/or safety. For those segments ofthe population who chronically

consume

additives nificantly

Toxic

alcohol

such as BHT, elevated and

and

are exposed

the vitamin the toxicity

to certain

A requirement threshold may

drugs

or food

may be sigbe changed.

endpoints

Membrane effects. Excess vitamin A lyses membranes, leases the content oforganelles, and impairs membrane-associated processes in experimental animals. The effect of 1 10 IU vitamin A/d for 2 d on heart phospholipids and on the lecular species of phosphatidylcholine and phosphatidylethanolamine of rats was studied (120). Vitamin A reduced amounts ofheart total phospholipids, phosphatidylcholine its tetraenoic

species,

dylethanolamine. The 32PO4 into the various

and

the

hexaenoic

species

AL and

phosphatidylethanolamine

showed

that

excess

mm A impaired the synthesis of these phospholipids CDP-choline-ethanolamine pathway. In vitro studies

size or release the transport protein. The vitamin A content of the liver was increased to high amounts in the vitamin Asupplemented groups, but inclusion ofethanol in the diet lowered the liver vitamin A content dramatically. It was also demonstrated that a quantity of vitamin A that is not hepatotoxic can enhance liver damage produced by ethanol in rats. Fatty liver

ET

re000 mothe and

bryonic chick ited membrane

mandible showed bone formation

all concentrations 13 300 IU/L)

and

duced


with

em-

that hypervitaminosis A inhibin the isolated mesenchyme at

vitamin

A tested

(1-4

mg or 3300-

chondrogenesis at concentrations 66001 3 300 IU/L ( 12 1). This study suggests that A-induced fetal defects in membrane bones are due to inhibitory effects on their formation. cartilage regression and resorption often result retinol or retinoic acid. This effect may be pro-

of2-4 mg or excess vitamin at least partly Bone and from excess

inhibited

by a detergent

action,

resulting

from

release

of cathep-

sins from lysosomes after membrane destruction by the excess retinol (122). Retinol caused cartilage resorption only when in the free state, whereas the same concentration of retinol when bound to serum RBP had no such effect (123). Studies in rats showed that vitamin A toxicity was associated with increased plasma concentrations of retinol and retinyl esters circulating in association with plasma lipoproteins instead ofbeing bound to RBP. Vitamin A toxicity may be manifested when the capacity of RBP is exceeded and free retinol is presented to cell membranes, leading to nonspecific toxic effects on cell membranes(l24).

The distribution of vitamin E is closely associated with that of vitamin A in fatty tissues. a-Tocopheryl acetate stabilized red blood cells against lysis caused by excess vitamin A (125). The protective effect of vitamin E may have been due to amelioration ofsome biochemical effect at reactive sites. The effect ofvitamin E in hypervitaminosis A may be more complex than an antioxidant reaction involving unsaturated fatty acids of membranes. Aside from acting as an antioxidant of unsaturated fatty acids, vitamin E may stabilize membranes through other mechanisms. Experiments with model systems involving monolayers of unsaturated phospholipids at air-water interfaces have led to the suggestion that tocopherol may facilitate molecular packing ofphospholipids and thus have a structural role in membrane stability (126). Results of in vitro studies suggested that one of vitamin A’s functions may be to destabilize lipid bilayers and thus enhance membrane permeability, whereas vitamin E may counter these effects of vitamm

A (127).

Mutagenicity. The mutagenic potentials of vitamin A, tretinoin, isotretinoin, and etretinate have been evaluated in the Ames test. Except for a weakly positive reaction in Salmonella typhimurium strain TA 100, observed at a relatively high concentration of etretinate, the retinoids were nonmutagenic

(103).

Carcinogenicity. There have been many studies in which natural or synthetic retinoids were administered in pharmacological amounts in animals exposed to known carcinogens. In many of these studies, treatment with certain retinoids other than vitamin A reduced the number oftumors induced by carcinogens ( 128, 1 3 1). In contrast, pharmacologic amounts of vitamin A sometimes potentiated the effects of carcinogens (1 32). Cell-activating properties of retinoids or enhancement oftumorigenic responses to chemicals or ultraviolet irradiation by topically

applied

Teratogenicity.

of phosphati-

results of the incorporation of NaH2 molecular species of phosphatidylcho-

ofexcess

vita-

via the

was

conclusively

retinoids

In animal shown

(Table 10). It produces

were

demonstrated

experiments

to result

malformations

(132).

hypervitaminosis

in congenital

in almost

A

malformations

all organ

sys-

VITAMIN TABLE

193

A TOXICITY

10

Teratogenicity

ofvitamin

A Conditions

Dose

and effects

Hamster All-irans-retinylidene mg/kg) ( 133)

methyl

nitrone

Percentage ofmalformed fetuses and severity ofthe malformations increased as dose was increased. Malformations ofeyelids with exophthalmos were common at 50 mg/kg and caudal regression syndrome characterized by occult spina bifida (sacral rachischisis occulta with myelocele or meningomyelocele), imperforate anus, and aplastic or hypoplastic tail predominated at higher doses.

(50, 75, or 100

Monkey Retinoic acid (7.5-10 mg/kg) by mouth gestation days 20 to 44(134)

All fetuses exhibited

from

complex

craniofacial

were affected;

Abnormal

specimens

abnormalities.

zygomatic

resembled

bone

Nearly all bones of craniofacial

and mandible

Treacher-Collins

were most

syndrome

severely

altered.

in humans.

Mouse All-trans-retinol (75 mg/kg) or all-trans retinylidene methyl nitrone (75 mg/kg) administered by gavage on day 7, 8, 9, 10, or 1 1 ofgestation(135) All-trans or I 3-cis retinoic 1 1.5 or I 2.0 ofgestation

acid (100 mg/kg) (136)

Treatment on day 7, 8, or 9 with retinol induced malformations ofhead; treatment on day I I induced bilateral forelimb-reduction defects. Treatment on day 8 with either retinoid produced highest in utero death rate. Malformations induced by administration ofeither retinoid were similar, but retinol was always associated with a higher total percentage ofmalformed offspring. Single oral dose ofall-trans retinoic acid on either day was maximally effective; >

on day

oftreated embryos developed reduction defects oflimb bones and an equally high percentage also had cleft palate. Under identical conditions treatment with 13-cisretinoic acid produced no apparent teratogenic effects. Neural tube defects produced by retinoic acid; females were preferentially affected. With increasing doses proportion ofseverely affected females increased then declined. Most embryos became exencephalic. Changes in neuroepithelial cells were apparent within hours after maternal treatment. Early cellular alterations apparently led to disruption ofarchitecture ofneuroepithelium so that neural folds failed to meet and close. Tissues may survive initial insult but continue to grow in everted manner characteristic of exencephaly.

Retinoic acid (0, 5, 10, 15, 20, 40, 60, or 80 mg/kg) administered to dam on day 8 ofgestation (137) Retinol palmitate (1.65 mg) to pregnant mice during neurulation (138)

Rat Vitamin animal

A palmitate by gavage

(0.55, 5.5, or 22.0 mg) per on days 6-15 ofgestation (139)

Maternal toxicity evidenced by decreased consumption at 22.0 mg. Malformations

exencephaly, Vitamin A (30-45 gestation (140)

mg) orally

on days 8-14

microphthalmia,

of

In lung sections,

Vitamin A (28.5 mg) gastric and 18 of gestation (144)

Offspring

liver

of several

gastrointestinal

on days

17

showed

in adulthood;

and

gallbladder,

types),

tract urinary

heart

(ventricular

(imperforate system

tions),

muscles,

and

situs

inversus

septal

anus, (renal

kidney, hydronephrosis), genitalia, pituitary, skull, vertebrae, ribs, extremities (phocomelia,

brachygnathia,

pinna

expansion

oflung

either did not occur or was not uniform.

Apparently in fetal

Animals dosed on days 8-10 were hyperactive. Animals dosed on days 1 1-13 acquired T-maze skills more slowly than did controls and animals dosed on days 8-10 and 1 113 acquired water maze skills more slowly than did controls. Animals dosed on days

tems. The types and incidence ofmalformations depend on the stage of gestation and dose and to a lesser extent on species and strain. Reported effects on structures in animals that are analogous to some malformations observed in humans include the following: brain (anencephaly), spinal cord (spina bifida), face (cleft lip, cleft palate, micrognathia), eye (microphthalmia), all parts ofthe ear, teeth, salivary glands, aortic arch (mallungs,

hydronephroses,

hypervitaminosis A during fetal period alters normal lung maturation. Incidence ofcleft palate 90%. Increase in DNA and glycoproteins synthesis palate was found.

1 1-13 were significantly

formations

anophthalmia,

anomalies, and great vessel and heart anomalies. Fetuses collected on day 21 had anomalies ofthe eyes, eg, open eyelids, exophthalmia, cataractous lens, microphthalmia and anophthalmia, and degenerative changes in cornea, lens, and retina. Eye malformations were stage dependent and mostly found in groups treated on days 8 and 9 of gestation.

Retinyl acetate (55 mg) during the last third of gestation (141) Retinyl acetate (41.3 mg) final dosage on day 15 of gestation (142) Vitamin A palmitate (44 mg) during gestation days 5-7,8-10, 11-13, l4-l6,and 17-19(143)

intubation

gain, decreased food and water fetuses included cleft palate,

body-weight in surviving

defects),

omphalocele),

agenesis,

polycystic

thyroid, thymus, digit malforma-

(145).


lighter

than

slower rates ofresponse learning

ability

were controls

and all other

than controls

during

test groups.

discrimination

training

was not impaired.

An important issue relative to birth defects, however, is the existence of permanent learning disabilities in animals from doses much lower than those that produce gross teratologic defects. In studies of rats given 90 000 IU vitamin A on days I 7 and 18 ofgestation, vitamin A temporarily interfered with neurogenesis. However, early damage results in permanent behavioral deficits in adulthood despite apparent cytochemical repair (146). Growth inhibition. Depression ofgrowth rate is a very sensitive but nonspecific measure of vitamin A toxicity. Marked growth depression was reported in a number ofspecies (eg, rat, dog, calf, chick, cat, and guinea pig) given large amounts of vitamin A. Weight reductions of 35% and 39% were observed

194

HATHCOCK

for day-

16 and

A (maternal (147).

day-

dose

The

type

19 rat

fetuses

of 40 000

and

extent

exposed

IU/d)

ofabnormality

A may vary with the timing of the toxic rates ofgrowth ofdifferent tissues. High the

dietary

growth

vitamin

( 148) and

chicks

E was

retardation rats

in utero

on days

that

reported is due

to

to vitamin

9-12

of gestation

produced

by vitamin

insult

and the relative

to prevent

or counteract

hypervitaminosis

A in

ET

AL

of retinol,

nyl esters,

(149).

ofbile

salts,

the globules

are broken

into

congregates that are easily digested by pancreatic ester hydrolase, and cholesteryl ester hydrolase mixed micelles containing retinol, carotenoids, pholipids, and cell membranes.

monoand diglycerides Various components

make of the

smaller

lipid

lipase, retinyl (1 50). The sterols, phos-

contact micelles

with the are then

readily absorbed into the mucosal cells. After free retinol is absorbed into the mucosal cell of the intestine, it is reesterified with palmitic acid and transported via the lymph. The newly esterified retinol, together with large amounts of triglyceride, some phospholipid, and protein, is released into the lymph in the form of chylomicrons. The chylomicrons also contain small amounts ofunesterified retinol. fl-Carotene and other provitamins enter the intestinal cell, and varying amounts are cleaved to form retinaldehyde. fl-Carotene can yield two molecules of retinaldehyde whereas many other carotenoids yield only one. This reaction is catalyzed by fl-carotene-l 5, 15’-dioxygenase (1 5 1), and subsequently the retinal

is reduced

to retinol

by retinaldehyde

reductase

(1 52).

The

amount ofconversion is governed by several factors including the amount in the diet, the amount of retinol in the diet, the total stores of retinol, and other factors. At very high intakes large amounts of fl-carotene are absorbed intact and stored in skin

and

Retinal they

are

other

and mainly

tissues

or excreted.

3-dehydroretinal reduced

in the intestinal mucosa oral dose of retinoic acid as rapidly excreted in the uronic acid (154). Transport. The retinyl lacteals

ofthe

intestine

are readily

to retinol

absorbed

by retinaldehyde

although reductase

and esterified before absorption. An is rapidly absorbed by rats (1 53) and bile after its conjugation with gluc-

with

esters

(mainly

chylomicrons

palmitate) and

are then

enter

the

carried

to the general circulation via lymph and the thoracic duct. During the transport ofchylomicrons from the lymph into the gen-

eral circulation, much of the triglyceride is digested and removed, resulting in chylomicron remnants that contain retinyl esters, cholesteryl esters, and some other lipids that are taken upbythe liver(l55). Retinol circulates in the plasma bound to the specific transport protein RBP. In human plasma the RBP forms a complex with transthyretin (prealbumin), a tetramer that also binds thyroid hormones. The formation of transthyretin-RBP complex may be physiologically significant in humans in minimizing the loss of the RBP during its passage through the kidney (156). Retinoic acid, which possesses some of the biological activity


and

but

is carried

in plasma

the total vitamin A is stored in the the adrenal gland serving as minor absorbed retinyl esters are largely by the liver mainly in association remnants. After uptake of reti-

reesterification

A is stored

fat-storing

both

cells.

occur

in the liver.

in parenchymal

However,

the

and

majority

He-

nonparen-

of the

hepatic

159). Parenchymal cells contained --9% of the total retinoids, 98% of the total RBP, 91% ofthe total cellular RBP (CRBP), and 71% of the total cellular retinoic acid-binding protein (CRABP) found in the liver (160). The fat-storing cells accounted for vitamin

Absorption. Dietary preformed vitamin A in animal tissues and the provitamin A carotenoids in vegetables and fruits are released by digestive enzymes in the small intestine. The carotenoids and retinyl esters from animal tissues congregate in fatty globules in the stomach and then enter the duodenum. In the

hydrolysis

vitamin

chymal

Metabolism

by RBP

Storage. About 90% of liver, with the kidney and storage sites (1 50). Newly taken up from circulation with the uptake ofchylomicron patic

presence

is not transported

by albumin.

(79-84%)

‘88%

of the

total

is stored

in the

stellate

retinoids,

0.7%

of the

( 157,

cells

total

RBP,

8% of the

total CRBP, and 21% ofthe CRABP in the liver. The endothehal and Kupffer cell fractions contained low concentrations of all these substances. Biotransformation. The physiological transformation of one vitamin A form to another in situ is a complex process. The reduction

ofretinal

mucosa ence

occurs

produced

from

in the cytoplasm

of NADH;

the

resulting

fl-carotene

of intestinal retinol

is then

by the intestinal

cells

in the pres-

esterified.

Retinyl

esters may be hydrolyzed back to retinol. This set of reactions occur in many tissues, including the intestine, liver, and adrenal gland. Retinol may be transformed in liver cells to its figlucuronide, which is secreted into the bile. Retinaldehyde may be further oxidized to retinoic acid, a reaction catalyzed by several

dehydrogenases

acid

is not

undergo

and

stored

in liver

several

derivative,

oxidases

ofthe

or in other

transformations:

oxidation

liver

tissues.

formation

to its 4-hydroxy

and

and

gut.

Retinoic

Retinoic acid

may

of its 5,6-epoxy 4-oxo

derivatives,

and formation ofthe fi-glucuronide (161). Excretion. At normal intakes, -P20% of the vitamin A consumed is not absorbed but is excreted in the feces within 1-2 d as metabolites 80%

that

ofvitamin is absorbed,

or as unconverted ‘-20-50%

is either

carotenoids.

Of the

conjugated

or oxi-

dized to products that are excreted within 1 wk in the feces or urine. The remainder (30-60%) is stored in the body, principally in the liver. Derivatives of vitamin A with an intact carbon chain are generally excreted in the feces whereas acidic chain-shortened products tend to be excreted in urine (150). Pharmacokinetics ofvitamin A. The rate ofmetabolism of a small dose oflabeled preformed vitamin A given to vitamin Adeficient rats maintained with retinoic acid was measured by assaying for radioactive metabolites in urine and feces. The rate showed three distinct phases, apparently representing three pools of vitamin A (162). The first phase is characterized by a rapid metabolism and excretion of metabolites of newly absorbed vitamin A. Newly absorbed vitamin A was found to enter a compartment different from that of stored vitamin A (163).

Phase

two

of metabolism

of vitamin

A is indicated

constant slow (zero-order) rate ofdecrease in urinary of radioactivity from the labeled compound. This been

estimated

to last

for 35 d and

is believed

by a

excretion phase has

to represent

nor-

mal, functional metabolism. Phase three ofvitamin A metabolism begins at about the 43rd day, when liver stores have been depleted and blood concentrations suddenly decrease. It involves rapid metabolism and lasts until about the 70th day. The amount of dietary vitamin A metabolized depends on

VITAMIN the

amount

of liver

was

;zg ( 1780

535

fully

chosen

diet

the rate

(164).

IU) per liver was

the rats constant the experimental mine

stores

In one

study

from the body of the rat was time of 82 d, provided that

depletion rate with a depletion

used

( 165).

the

liver

study

a care-

concentrations

liver

vitamin

A was replaced

in

± I 63 IU)/g mented with retinoic rate (linear) was 3.05 mined

were fed a vitamin A-free diet suppleacid for 100 d ( 167). The liver depletion zg ( 10.2 IU)/d and the half-life was deter-

to be 77 ± 14 d. In an investigation

ofthe

early

phase

of

the three-phase metabolism of vitamin A, the amount of vitamm A that is initially metabolized in phase one directly depended upon the amount ofliver storage (168). In a comparative pharmacokinetic study ofvitamin A in rats and hamsters, the absorption and elimination of all-trans-retinol in the plasma were studied after an oral dose of 45 mg (150

000

IU)/kg.

Plasma

retinol

uptake

and

elimination

were

consistent with a two-compartment open model with first-order kinetics ( I 69). The dynamics of retinol transport and turnover in moderately vitamin A-sufficient rats in short- and long-term studies were described (170). Tracer kinetic analysis, with application of mathematical and computer methods, was employed for data analysis and interpretation. The findings indicated the existence ally,

oftwo

pools

extensive

ofextrahepatic

recycling

of holoRBP

tissue

vitamin

was

A. Addition-

indicated

by the

ki-

netic model. More than half of the secretion from the liver of a retinol-RBP-transthyretin complex (R-RBP-TTR) was from recycled plasma R-RBP-TTR. During vitamin A depletion nonparenchymal retinyl ester as well as parenchymal retinyl ester concentrations were lowered and were significantly correlated with declines in total liver vitamin A. Retinol utilization rate was not decreased and unesterified retinol concentrations in the parenchymal and nonparenchymal cells as well as in plasma were maintained. This suggests that homeostatic control mechanisms were operative to maintain plasma and hepatic unesterified retinol concentrations at a steady state (171). In summary, the utilization of retinol varies with liver vitamm A stores. The utilization is low in animals with low liver vitamin A concentrations and high in animals with marginal or high liver vitamin A concentrations. During vitamin A depletion retinol-utilization rate does not decrease, and declines in liver vitamin A are attributed to decreases in stellate cell as well as parenchymal cell retinyl ester concentrations. Homeostatic control mechanisms effectively maintain plasma and hepatic

retinol

at constant

concentrations

during

darknonthan fi-

even

by vitamin

A from the diet (166). Replacement time in liver was found to be 82 d with a half-life of 57 d. In a third study rats that were dosed with retinol so that their livers contained 5 17 ± 49 g

( 1 720

found in abundance in deep yellow-orange and leafy vegetables. fl-Carotene has been widely considered to be virtually toxic, even at intakes several orders of magnitude greater those likely to be used as food additives(l72). Use ofpurified carotene as a dietary supplement, however, may generate higher intakes.

green

at -400 g (1 330 IU) per liver throughout period. Labeled vitamin A was used to deter-

at which

195

monly

metabolic

5 g ( 16.7 IU)/d the liver storage

In another

to maintain

A TOXICITY

depletion.

Absorption,

metabolism,

and tissue

distribution

Provitamin A carotenoids may be absorbed intact or converted to vitamin A before absorption. Carotenoids in foods are usually associated with membranes and lipoproteins. The proteins are digested partly by pepsin, and limited lipolysis occurs

in the stomach.

lipid

globules

The

and

are

lipids

freed

solubilized

from

by bile

Carotenoids are then absorbed through ofthe mucosal cells lining the intestine into the blood. Carotenoids and retinol by endocytosis

into

the

mucosal

foods salts

aggregate in the

into

intestine.

the plasma membrane and may directly enter may also be transported

cell.

The absorption of carotenoids is increased by the presence of bile salts, lipids, proteins, antioxidants, and zinc. Approximately 25-75% ofthe carotenoids consumed are not absorbed and can be found in the feces unchanged (173-175). fl-Carotene is not excreted in the urine, even after high doses ( I 76). fl-Carotene is stored in human fat and is found in most organs and tissues, including the epidermal and dermal layers of the skin, and in platelets and white blood cells. In rats the uptake and depletion rates offi-carotene in each tissue are unique; there was a dose-response effect between fl-carotene ingested and its concentration in each tissue. Liver had the highest (50 Lg or 167 IU/g) and muscle had the lowest (0.03 g or 0. 10 IU/ g) tissue fl-carotene concentrations (177). One IU of vitamin A activity is defined as 0.3 g retinol (0.344

zg retinyl

matic titative.

maximum is -50% carotene. tion

acetate)

and

as 0.6

g

fl-carotene.

The

enzy-

to retinol is theoretically quanBecause of physiological inefficiency, however, the conversion demonstrated with low doses in animals on a weight basis, ie, 1 mol retinol from I mol fiIn addition to this inefficiency, there is a wide varia-

conversion

offl-carotene

in the efficiency

ofabsorption

offl-carotene

from

different

foods. In humans the average absorption of fl-carotene is assumed to be one-third of the amount ingested whereas retinol is assumed to be completely absorbed under normal circumstances. The overall utilization of fl-carotene is assumed to be one-sixth

of that

of retinol.

Other

carotenoids

tene and cryptoxanthin are only one-half tene; their efficiency as vitamin A sources twelfth ofthat ofretinol (5, 8). Toxicity

offl-carotene

such

as active is assumed

as a-caro-

as fl-caroto be one-

in animals

Carotenoids provide a substantial proportion ofthe total vitamin A activity in foods. There are > 400 different natural carotenoids, 50 of which have provitamin A activity. Among these provitamin A carotenoids, fl-carotene has the highest pro-

fl-Carotene administration at a dietary level of 1 mg/g diet to four successive generations of rats had no deleterious effects on growth, food consumption, white blood cell counts or other blood components, or reproduction. No gross or histopathological tissue changes attributable to feeding this carotenoid were detected in these animals. Microscopically, the Kupffer cells of the liver were filled with material that was positive to Sudan staining and also gave an intense green-yellow fluorescence when exposed to ultraviolet light (178). In embryotoxic-

vitamin

ity studies

Metabolism

in humans

and adverse and animals

biological

activity.

effects

Provitamin

of fl-carotene

A carotenoids

are corn-


palm

oil was

the source

offl-carotene;

it was

admin-

HATHCOCK

196 istered

daily

through Increases

by gavage

palm-oil

Several

toxicological mice,

and

administered No

maternal There

toxicity were

‘

day

of

from

mg.

investigated form

study

fl-carotene

fl-carotene studies

occurred

in a young

failed

to demonstrate

any

evaluations, test on bone

to have in both

and

mice

abnor-

included

marrow

no mutagenic

rats

reproductive

which

cells

properties. gave

eccentric was

often

Although

in

was

in cows,

(1 8 1). In addition, A was

fruits

and

ever,

no cases

Carcinogeof effect

with

The

latter

deposition. enhancer

conflicting

the intake

results

found

from

vitamin

feeding

diet

rats

that

it is not

genetic

damage

and animal-cell culture carotene do not produce offi-carotene

or canthaxanthin E by halfbut

A high

(2 mg/g

enhanced

the

diet) T- and

carcinogenic,

mutagenic,

containing

large

Hypercarotenemia

consumption

of ‘-36

has 000

IU/d

caused

by mutagens

It is also

both

in bacterial

systems and that large doses ofpure embryotoxicity in rodents (186).

fl-

in humans

generally

recognized

as safe as a dietary

supple-

ment and as a nutrient (I 87). fl-Carotene was successfully used at doses of2O- 180 mg/d to treat patients with the genetic disease erythropoietic protoporphyria. This inherited disease is characterized by abnormal photosensitivity reactions in the skin. The ingestion of large amounts of fl-carotene did not produce any toxic effects in these patients ( 188, 190). In addition, these patients did not serum

concentrations

rate study normal volunteers given wk did not have any sign of vitamin

ofvitamin

oftoxicity

running,

vegetables at

were

stress,

resulting

ofamenorrhea 180

for

the

Hypercarotene-

and/or

in carotenemia were

mg/d

observed.

found

high (196,

in women

treatment

intakes 199).

of How-

consuming

of photosensitivity

diseases (200). No differences were found in carotene intake and serum concentration of fl-carotene between normally menstruating and amenorrheic runners (20 1 ). Although leukopenia was observed in a patient consuming large amounts of fresh carrot juice (202), this was not substantiated by other (203,

204).

No

deposits

of crystalline

material

were

erythropoietic protoof fl-carotene for

On the basis of studies in animals and of epidemiological observations of plasma concentrations ofcarotenoids in cancer patients and control populations, fl-carotene has received attention as an anticancer agent (206-2 1 1). Most data suggest that fl-carotene prevents genetic damage in both bacterial and cell culture nificant

systems toxicity

and for

born with carotenemia wise normal (186).

that

growing

from

pure

fl-carotene

human

does

fetuses

high maternal

not

because

intakes

have

sig-

babies

were other-

embryotoxic,

The studies reviewed below indicate that fl-carotene is a safe food component for humans, especially when compared with equivalent amounts ofvitamin A (185). Pure crystalline fl-carotene was approved by the FDA as a color additive (exempt from the need for certification) for use in foods, drugs, and cos-

high

rang-

lOy(205).

a semipuri-

for 2 1 wk (177).

or teratogenic and does not cause hypervitaminosis A (185). Overall evidence indicates that fl-carotene administration pre-

show

after

foods

(192).

found in the retinas of 26 patients with porphyria treated with high concentrations

B-lymphocyte responses in rats (182). Both the experimental and control animals were healthy and no gross pathology was seen at the end of the experiment. These studies give support for there being an immunity-enhancing effect of fl-carotene that is separate from its provitamin A activity (1 83, 184). Overall, the experimental animal data on fl-carotene safety

metics.

carrots

man

long-distance

fl-carotene

studies

of preformed

(181).

were

of fl-carotene

plasma

gave

cases

2 mg fl-carotene/g

amount the

ofthe

lipid

as a specific

studies

identified

effects

areas.

minimal

implicated

field-based in many

not

No adverse

Toxicity

fed commercial

ground

no signs

duction,

no evidence

in periportal

with

fl-carotene

of fertility

cells

associated

but

mice,

nuclei

vented

of fl-carotene

ofdietary vitamin A activity for an uncertain period of months or even years, with about two-thirds ofthe intake from carrots ( 193). Concentration of vitamin A in serum was elevated

Ames

with

indicate

in infants

from

tumor rates. Histological findings in the livers and mice but not rats included vacuolated cells

lowered

observed

the

on spontaneous oftreated dogs

dietary

30 mg

supplements

mia can also be caused by a rare genetic inability to convert fl-carotene to vitamin A (194, 195). There were reports ofamenorrhea associated with weight re-

nicity

fled diet

took

I 80 mg/d for 10 wk had serum concentrations 1 1 .9 to 25.3 zmol/L (189, 19 1). Hypercarotenemia

offinely

spe-

who

concentrations

consuming

slightly

found

vitamin

containing ing from

by high serum

in individuals

Volunteers

amounts

doses

occur

1000

the micronucleus

finding

fl-carotene/d.

was

in either

at maternal

indicated

may

was

rats and rabbits.

found

in rats

of fl-carotene,

rats,

offi-carotene

with

was

effects

with

Hypercarotenemia,

5

kg

Mutagenicity

and

were

A beadlet

no teratogenic

in the rats

malities.

(1 80).

AL

. Although

no functional

test

from

‘ .d or in rabbits at doses of 400 mg. the offspring of rats receiving a maternal mg . kg ‘ . d ‘ had slightly reduced body weight, abnormalities were observed. A three-generation

of up to 1000 d

endpoints

dogs

in an embryotoxicity

cies.

study

diet

groups.

rabbits,

dose

fed a dry-food

day 15 ofpregnancy in doses of 1, 2, or 3 mL (179). in the number of resorptions and abnormal fetuses 25%, and 42%, respectively) were found in the three

(21%,

I

to rats

ET

A (I 88).

180 mg fl-carotene/d A toxicity (191).

In a sepa-

for 10


Adverse

effects

ofcarotenoids

other

than

fl-carotene

Many carotenoids that are ingested, such as lycopene, lutein, zeaxanthin, neoxanthin, canthaxanthin, and violaxanthin, are not precursors of vitamin A. However, they are active as antioxidants and therefore have physiological importance. There are few studies on the adverse effects of these carotenoids in humans. Only three carotenoids are approved for use as food colorants in the United States: fl-carotene, fl-apo-8’-carotenal, and canthaxanthin. The safety of fl-carotene has already been discussed. Most studies on the other carotenoids are on fi-apo8’-carotenal, which has 72% ofthe vitamin A activity of fl-carotene. Canthaxanthin, which has no vitamin A activity, has substantial use as a food-color additive. Canthaxanthin (fl-carotene-4,4’-dione) is a red-orange pigment found in plants, edible mushrooms, bacteria, crustaceans, sea trout, and algae and in the axion tissues of flamingo and other red-feathered birds. Canthaxanthin was approved by the FDA as a food color additive (2 12). However, it is not approved as a drug for producing a skin color similar to a suntan. There are several indications that excessive intake of canthaxanthin may have adverse effects. Plasma discoloration of persons ingesting canthaxanthin was well documented (213). In one study the fundi of the eyes of 50 persons who had con-

VITAMIN TABLE Some

11 recommendations

concerning

vitamin

A TOXICITY

A supplementation

Source American Society American

Recommendation

Institute ofNutrition, for Clinical Nutrition Medical Association

Council

for Responsible

International

Vitamin

American

Nutrition A Consultative

Research Society

Group

Council

sumed large numbers oftanning tablets containing mainly canthaxanthin were examined and 12% had crystalline golden deposits on their retinas (2 14). The occurrence of deposits was correlated with the total dose ingested: 37 g canthaxanthin induced retinal deposits in 50% of the patients (2 1 3) and 60 g induced

deposits

in 100%

to the onset of retinopathy cal disease ofthe pigment concurrent toses

tene

use

who

also

had

(2 14). Factors

xanthin-induced

a patient

lower dosages included foocular hypertension, and (2 15, 2 16). Patients with derma-

a mixture

retinal

predisposing

at much epithelium,

of fl-carotene

consumed

deposits

of canthaxanthin

and

(2 17). In a recent

retinopathy

was found

fl-caro-

study

to be both

cantha-

functionally

and anatomically

reversible upon discontinuation of the drug (218). A significant decrease in the number of retinal deposits was found only after 26 mo, and some remained even 7 y after canthaxanthin treatment was discontinued. The physiological and pharmacological consequences of canthaxanthin-colored plasma, brick-red stools, and crystalline

retinal

Until

deposits

further

of unknown

studies

composition

are performed,

continued.

In the

associated

with

few

reports

are

the safety

xanthin for coloring the skin cannot In summary, no adverse effects ported when the daily supplementation times the normal intake for > 1 5 y. fl-carotene at less than this amount odermia, which is reversible when

not

known.

of using

cantha-

be determined. in humans have of fl-carotene The

only

side

been rewas 120

effect

of pure

of amenorrhea

and

foods,

the

leukopenia

effects

may

be

responses from other components of carotene-containing foods because similar effects have not been observed in persons taking are

large several

amounts suggestions

of fl-carotene. that

ingestion

On

the

other

of excessive

canthaxanthin for tanning may not be safe. Crystalline occurred in the retinas of persons who consumed amounts of canthaxanthin.

hand,

of

deposits excessive

hepatitis. mm

The

threshold

intake

for its adverse

available on vitamin A toxicity provide a specific minimum effects.

Nevertheless,

an intake


222

3, 7

223 224

ofboth

as the duration

dietary

and

supplemental

ofconsumption

vita-

are important

in

determining the risk oftoxicity. Infants may show toxicity after lower total intakes that are higher on a body-weight basis than those required to produce adverse effects in most adults. Normal infants rarely show toxicity from vitamin A intakes as low as 1500 IU . kg .d’. There are, however, more reports of toxicity from intakes in the 2000-3000 IU . kg ‘ d range. Presently

available

is

data

are

not

sufficient

to determine

the

maternal dosages necessary to generate sufficient prenatal exposure to increase the risk of birth defects. It is clear, however, that exposure to therapeutic doses ofcertain analogs of vitamin A, eg, 13-cis-retinoic acid, results in substantially increased risk defects.

Similarly,

in one

case

the

ingestion

ofa

single,

maternally toxic dose of vitamin A (estimated to be 500 000 LU) early in pregnancy was followed by the birth ofa baby with developmental defects. As the dose decreases, the strength of the apparent relationship between excess vitamin A ingestion and birth defects becomes more tenuous. The lowest maternal doses associated with credible reports ofbirth defects characterofexcess

Clinically

information to definitively

amounts

A as well

istic

Summary The scientific not sufficient

221

of 25 000 IU/d is nutritionally excessive and carries some risk oftoxicity. Similarly, the available scientific data do not permit identification ofthe upper limit ofthe intake range that can be considered safe. An intake of 10 000 IU/d is more than adequate to provide for good nutrition but is low enough to avoid toxicity in most people. The effects of vitamin A at intakes between these approximate boundaries cannot be anticipated. The clinical case studies reviewed provide substantial support for the conclusion that exposure to high doses of vitamin A ( 100 000 IU/d) for relatively short periods (days or a few weeks) or lower doses (25 000-50 000 IU/d) for periods of several months or more can produce multiple adverse effects. Most of the evidence for the toxicity at the lower end of this dosage range (ie, -.-25 000 IU/d) comes from reports of mdividuals who had concomitant hepatic damage from other contributing factors, such as alcohol abuse, severe PEM, or viral

ofbirth

there

amounts

2 19, 220

.

seems to be hypercarotenthe supplementation is dis-

carotene-containing

Reference

Supplements not for everyone. RDAs are best guidelines for safety and adequacy; there are no benefits from higher intakes. No supplements for most adults. Therapeutic amounts should not exceed 2- 10 times the US RDA. For adults, 10 000 IU limit per unit dose for general use; 8000 IU limit for prenatal products. Supplementation daily limits for women, 10 000 IU only ifdeficiency exists; for well-nourished pregnant and lactating women, 1900-2500 IU; for men and nonreproductive women, 25 000-30 000 IU for prophylactic uses and 125 000- 150 000 IU for therapeutic uses. Avoid taking supplements in excess ofthe RDA in any one day. Maximum unit (usual daily) dose 5000-8000 IU; identify chemical form of vitamin A on label. No high dosages of 25 000 IU as retinol or retinyl esters.

(IVACG)

National Teratology

197

vitamin controlled,

A ingestion prospective

are

‘-.-25 studies

000 ofthe

IU/d. human

tera-

togenicity ofvitamin A are not possible for ethical reasons. Any epidemiological study that attempts to define the lowest dose that may result in birth defects will have to be very large to have

198

HATHCOCK

sufficient

power

to eliminate

her, the preliminary Health Department wide

enough

vitamin

range

ofdosages

A intakes

With

potential

biases.

As discussed

data reported by the either were not sufficient that

to identify

might

the firm evidence

the excessive

be required

to elicit

that high vitamin

a wide needed

range of vitamin A intakes, epidemiologic to determine whether this adverse effect health

the human

ofvitamin

dose during critical siently overwhelms

periods maternal

Conversely,

with

vitamin

in a large

conditions On

consuming

research constitutes

is a

especially

that

hand,

tendency

to bioac-

a possibility that excessive intake or months preceding conception risk. cannot be guaranteed safe for all

as pregnancy,

other

on an excessive

development that tranand homeostatic mech-

A has a strong

substances the

A may depend

population,

such

to potentiating toxicity.

can be tera-

population

of fetal transport

cumulate, and hence there is ofvitamin A during the weeks may contribute to teratogenic An intake of 10 000 IU/d individuals

MD:

defects.

problem.

The teratogenicity

anisms.

with

A intakes

in animals

an

liver

may

for those disease,

predispose

intake

persons

or exposure

to vitamin

of ‘-P25 000

IU/d

A does

not cause adverse effects in all individuals (83). Nevertheless, several recommendations have been made to limit vitamin supplementation or the potency ofvitamin A supplements because of safety concerns (Table I 1 ). Any educational effort on vitamin

A hazard

and

no well-established ingestion of intakes possible

from

safety

should

emphasize

that

therapeutic or prophylactic above the usual RDA and

excessive

there

are

benefits to the that toxicity is

intakes.

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Vitamin toxicity.

A nontoxic case of vitamin D toxicity.

The mechanisms of vitamin D toxicity.

Vitamin D transport in an infant with vitamin D toxicity.

Influence of excess vitamin E on vitamin A toxicity in rats.

Acute vitamin d toxicity in an infant.

Toxicity of aflatoxin B1 towards the vitamin D receptor (VDR).

Potentiation of acute paraquat toxicity by vitamin E deficiency.

Chlorpyrifos chronic toxicity in broilers and effect of vitamin C.

Effects of vitamin B12 on cadmium toxicity in rats.

Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency.

Introduction to toxicity evaluation session.

Evaluation of subacute bisphenol - A toxicity on male reproductive system.

Evaluation of the acute toxicity of silahydrocarbon.

Toxicity evaluation of crankcase oil in rats.

Letter: Evaluation of vitamin B12 assay kits.

Drug-biomolecule interactions: drug toxicity and vitamin coenzyme depletion.

Growth factors and vitamin E modify neuronal glutamate toxicity.

Vitamin E protects nerve cells from amyloid beta protein toxicity.

A mycological evaluation and in vivo toxicity evaluation of feed from 41 farms with equine leukoencephalomalacia.

Effect of vitamin A on hexachlorocyclohexane (HCH) toxicity in the rat.

Early effects of vitamin A toxicity on hepatic glycolysis in rat.

A combined toxicity study of zinc oxide nanoparticles and vitamin C in food additives.

Iatrogenic vitamin D toxicity in an infant--a case report and review of literature.