Vitamin A adequacy is discussed in terms of the recommended allowances appropriate for the needs of the majority of individuals. Deficiency can result in xerophthalmia and permanent blindness and in increased mortality rates among children. Toxicity has been associated with the overconsumption of vitamin A supplements. Acute hypervitaminosis A may occur after ingestion of greater than or equal to 500,000 IU (over 100 times the RDA) by adults or proportionately less by children. Symptoms are usually reversible on cessation of overdosing. Factors influencing chronic hypervitaminosis A include dosing regimen, physical form of the vitamin, general health status, dietary factors such as ethanol and protein intake, and interactions with vitamins C, D, E, and K. Both excess and deficiency of vitamin A in pregnant animals was shown to be teratogenic. In humans, congenital malformations associated with maternal over-use of high doses of vitamin A were reported but no cause-and-effect relationship has been established. Deficiency of the vitamin during pregnancy has also been associated with congenital abnormalities. Reported incidences of vitamin A toxicity are rare and have averaged fewer than 10 cases per year from 1976 to 1987.

A comprehensive review of the literature indicates that populations with long-term consumption of higher than RDA levels of vitamin C (> or = 60 mg/day) from foods and/or supplements have reduced risks of cancer at several sites, cardiovascular disease, and cataracts. The safety of higher than RDA intakes of vitamin C is confirmed in eight placebo-controlled, double-blind studies and six non-placebo clinical trials in which up to 10,000 mg of vitamin C was consumed daily for up to 3 years. There are no clinical data which suggest that vitamin C's enhancement of non-heme iron absorption in individuals with low iron status could be a critical factor in the possible increased risk of heterozygous hemochromatosis-related cardiovascular disease. In fact, the cumulative data do not confirm that iron status is related to risk of cardiovascular disease. Moreover, higher than RDA intakes of vitamin C have been associated with several indices of lowered cardiovascular disease risk including increases in HDL, and decreases in LDL oxidation, blood pressure and cardiovascular mortality.

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IN recent work in this laboratory it was shown that an extract of flue-cured cigarette tobacco leaf (WTE) as well as cigarette smoke condensate (WCT) exhibit tumor-promoting activity (Van Duuren et al., 1966). In these experiments a single dose of 7,12-dimethylbenz[a]anthracene (DMBA) was applied on mouse skin as initiator followed by repeated skin application of the promoting agents. While this procedure proved satisfactory for bioassay of a number of fractions and subfractions derived from tobacco leaf and tars, it was desirable also to explore systemic treatment with several initiating agents followed by skin application of the promoting agents. The present report describes the bioassay of several promoting agents with DMBA, benzo[a]pyrene (BP) and urethane as initiators. The initiators were given by subcutaneous and intraperitoneal injection in mice; the promoting agents were applied on skin. The results of these experiments are compared with our earlier results, in which both the initiator and promoter were applied on mouse skin (Van Duuren and Orris, 1965;Van Duuren et al., 1966). MATERIAL.S AND METHODSThe test animals were female HA/ICR Swiss mice and 20 animals were used per group. The initiators used in these experiments were DMBA at several dosages (0.5-500 jug.), BP and urethane, each at 1 dosage level; 0-5 mg., and 20 mg. respectively. The initiators were injected in tricaprylin or saline with a 26 gauge, 3 in. needle, in a single dose, either subcutaneously on the left flank or intraperitoneally on the left side of the abdomen. The promoters used were croton resin (CR), whole tobacco extract (WTE), and whole cigarette tar (WCT). The methods of preparation of these materials were described in our earlier reports (Van Duuren and Orris, 1965;Van Duuren et al., 1966). The dosages and solvents used were as follows: CR: 25 ,ug./0 1 ml. acetone; WTE: 25 mg. /0.1 ml. acetone-water (1 : 1); WCT: 25 mg./0 1 ml. acetone. Promoters were applied to the clipped dorsal skin 3 times weekly with a No. 5 squirrel hair brush delivering close to 100 mg. of solution per application. Promotion treatments were started 2 weeks after initiation. In a few experiments a longer interval was allowed to elapse between initiation and promotion, and these are indicated under results.Included in the test series were the following control groups: animals that received initiator only, promoter only, solvent controls, and groups which received no treatment.