Toxicity of Vitamin A

Vitamin A is both acutely and chronically toxic. Acutely, large doses of vitamin A (in excess of 300 mg in a single dose to adults) cause nausea, vomiting, and headache, with increased pressure in the cerebrospinal fluid - signs that disappear within a few days. After a very large dose, there may also be drowsiness and malaise, with itching and exfoliation of the skin; extremely high doses can prove fatal. Single doses of 60 mg of retinol are given to children in developing countries as a prophylactic against vitamin A deficiency -an amount adequate to meet the child's needs for 4 to 6 months. About 1% of children so treated show transient signs of toxicity, but this is considered to be an acceptable adverse effect in view of the considerable benefit of preventing xerophthalmia.

The chronic toxicity of vitamin A is a more general cause for concern; prolonged and regular intake of more than about 7,500 to 9,000 ^g per day by adults (and significantly less for children) causes signs and symptoms of toxicity affecting:

1. The skin: excessive dryness, scaling and chapping of the skin, desquamation, and alopecia.

2. The central nervous system: headache, nausea, ataxia, and anorexia, all associated with increased cerebrospinal fluid pressure.

3. The liver: hepatomegaly, hyperlipidemia, and histological changes in the liver, including increased collagen formation. Alcohol potentiates the hepatotoxicity of vitamin A.

4. Bones: joint pains, thickening of the long bones, hypercalcemia, and calcification of soft tissues, but with reduced bone mineral density. High intakes of vitamin A are associated with an increased rate of loss of bone mineral density with age, and some studies have shown that intakes above 1,500 ^g per day are associated with increased incidence ofosteo-porosis and hip fracture, although other studies have not shown any relationship between vitamin A intake and osteoporosis (Institute of Medicine, 2001). At high levels of intake, vitamin A both stimulates bone

Table 2.5 Prudent Upper Levels of Habitual Intake (^g of preformed vitamin A/day)

Upper Limit of Safe Habitual Tolerable Upper Intake Age (y) Intake (U.K., 1991) Level (U.S./Canada, 2001)

Birth-1

900

600

1-3

1,800

600

4-6

3,000

4-8

900

7-10

4,500

Males

9-13

1,700

11-18

6,000

14-18

2,800

Adult females

9,000

3,000

9-13

600

11-18

6,000

14-18

2,800

Adult

7,500

3,000

Pregnant

3,300

2,800-3,000

Lactating

2,800-3,000

Sources: Department of Health, 1991; Institute of Medicine, 2001.

resorption and inhibits bone formation (Binkley and Krueger, 2000), largely as a result of antagonism of the actions of vitamin D (Section 3.3.5). As the tissue concentration of 9-ds-retinoic acid increases, so there is increased formation of RXR homodimers, leaving an inadequate amount of RXR to dimerize with the vitamin D receptor.

Prudent upper levels of habitual intake of retinol are shown in Table 2.5.

As the intake of vitamin A increases, there is an increase in the excretion of metabolites in bile, once adequate liver reserves have been established. However, the biliary excretion of retinol metabolites reaches a plateau at relatively low levels, and it seems likely that this explains the relatively low toxic threshold (Olson, 1986). Vitamin A intoxication is associated with the appearance of both retinol and retinyl esters bound to albumin and in plasma lipoproteins, which can be taken up by tissues in an uncontrolled manner; the amount of circulating retinol bound to RBP does not increase. Retinol has a membrane lytic action; it was noted in Section 2.2.2.3 that one of the functions of RBP binding seems to be to protect tissues against retinol, as well as to protect retinol against oxidation (Meeks et al., 1981).

At relatively high levels of intake, vitamin A induces synthesis of glycine N-methyltransferase. This can lead to depletion of methyl groups and undermethylationofDNA, a potential factor in carcinogenesis (Section 10.9.5; Rowling et al., 2002).

Carotenoids do not cause hypervitaminosis A. As discussed in Section 2.2.2.1, the conversion of provitamin A carotenoids to retinol is limited; therefore, vitamin A intoxication is unlikely to occur even at high intakes of carotene. Accumulation of even abnormally large amounts of carotene seems to have no short-term adverse effects, although plasma, body fat, and skin can have a strong orange-yellow color (hypercarotinemia) after prolonged high intakes of carotenoids. A small number of people lack carotene dioxygenase and suffer from (asymptomatic) carotinemia with normal modest intakes. However, as discussed in Section 2.6.3, two large-scale intervention trials have shown an increased incidence of cancers in subjects receiving supplements of P-carotene.

2.5.1.1 Teratogenicity of Retinoids 13-Q's-retinoic acid and etretinate (Section 2.6.2) are highly teratogenic. After women have been treated with retinoids for dermatological problems, it is generally recommended that contraceptive precautions be continued for 12 months, because of the retention of retinoids in the body. With embryonic limb bud cells in culture, it is those retinoids that bind to RAR that are teratogenic; those that bind to RXR are not. However, retinoids that bind to RXR potentiate the teratogenicity of those that bind to RAR (Soprano and Soprano, 1995; Collins and Mao, 1999). There is considerable species variation in sensitivity to the teratogenic effects of 13-ds-retinol; in species such as rats and mice, it has low teratogenicity because it is metabolized rapidly to the glucuronide. In primates, it is mainly oxidized to 13-ds-4-oxoretinoic acid, which is transported across the placenta (Nau, 2001).

By extrapolation, it has been assumed that retinol is also teratogenic, although there is little evidence; in case control studies, intakes between 2,400 to 3,300 fig per day during pregnancy have been associated with birth defects. Other studies have not demonstrated any teratogenic effect at this level of intake, and it has been suggested that the plasma concentration associated with teratogenic effects is unlikely to be reached with intakes below 7,500 f g per day (Miller et al., 1998; Ritchie et al., 1998; Wiegand et al., 1998). Arnhold and coworkers (2002) demonstrated formation of all-frans-retinoic acid in en-terocytes after feeding relatively large amounts of retinol that saturated the intestinal CRBP (Section 2.2.4) and suggested that there is indeed a threshold intake of retinol above which teratogenic metabolites are formed. Pregnant women are variously advised not to consume more than 2,800 to 3,000 f g per day (Institute of Medicine, 2001) or 3,300 /g per day (Department of Health, 1991).

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