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carotenoids and retinoids. A third group (Kolonel et al., 1987) found a positive association with carotenoids and retinoids for men aged 70 or older but not for younger men.

In a prospective study by Nomura et al. (1985), there was no statistically significant association between concentrations of serum b-carotene and 10-year risk of cancers of the colon, stomach, rectum, and urinary bladder, although, as noted above, an inverse association with lung cancer was observed. However, since the statistical test was not particularly powerful and the mean concentrations of serum b-carotene in cases of stomach and colon cancer (22.8 and 23.5 µg/dl, respectively) were lower than those in the comparison group (29.0 µg/dl), these data are consistent with a hypothesis of an inverse association as well as the hypothesis of no association. In another prospective study, Willett et al. (1984) found no association between serum total carotenoid concentration and 5-year risk of cancer. The implications of this evidence for hypotheses specifically about b-carotene are limited, because b-carotene comprises only about 20 to 25% of total carotenoids in serum (Katrangi et al., 1984), and the correlation between concentrations of b-carotene and total carotenoids in serum is only .6 to .7 (Russell-Briefel et al., 1985).

Several clinical trials testing supplemental b-carotene as a chemopreventive agent are currently under way, but no results have yet been published. There has been one study, however, in which dietary supplementation with retinol and b-carotene was found to decrease markedly the proportion of micronucleated buccal mucosal cells in Filipino betel chewers (Stich et al., 1984).

Only a few studies have explored the potential chemopreventive effects of carotenoids on experimentally induced tumors in animals. The incidence of tumors decreased and the latent period for development of tumors increased in mice fed supplemental b-carotene before inoculation with Moloney's sarcoma virus; the rate of tumor regression markedly increased when b-carotene was fed after tumors were already present (Seifter et al., 1982). Similar results were obtained in mice inoculated with C3HBA adenocarcinoma cells. Injection of b-carotene decreased the incidence of skin cancer in hairless mice exposed to ultraviolet-B (UV-B) radiation (Epstein, 1977a). Both b-carotene and canthaxanthin, a carotenoid without vitamin A activity, decreased the incidence of skin cancer in mice exposed to benzo[a]pyrene and UV light (Santamaria et al., 1983). b-Carotene, canthaxanthin, and phytoene, another carotenoid without vitamin A activity, decreased the incidence of skin tumors and increased the latent period in mice exposed to UV-B only, but only b-carotene exerted these effects in mice exposed to dimethylbenzanthracene (DMBA) (Mathews-Roth and Krinsky, 1984). In at least one study, growth of tumor cells was not suppressed in mice injected with b-carotene (Tomita, 1983). More information is clearly needed concerning the potential roles of specific carotenoids as chemopreventive agents for specific neoplasms in laboratory animals.

Peto et al. (1981) suggested several possible mechanisms through which dietary carotenoids might be able to affect cancer risk. These include (1) a direct or indirect retinoid-like effect (as described below) on cellular differentiation in target tissues (including possible conversion to retinoids in the target tissue), (2) their action as antioxidants, thereby protecting against transformation, and (3) protection afforded through some other mechanism (for example, by enhancing some immunologic function). See also Dimitrov (1986) and Willett and MacMahon (1984) for reviews and references. Bendich and Shapiro (1986) reported that T- and Blymphocyte responses were enhanced in rats fed b-carotene or canthaxanthin. b-Carotene is highly effective in quenching singlet oxygen and in trapping free radicals. These potent antioxidant effects of carotenoids may protect cells against oxidative damage to DNA, thereby exerting a chemopreventive effect against cancer (Dimitrov, 1986).

Hypercarotenemia

The intake of very large quantities of b-carotene can result in elevated plasma carotene levels (hypercarotenemia) and a yellow-orange pigmentation of the skin (carotenodermia). This condition is clinically innocuous and reversible. Furthermore, abnormally elevated plasma levels of vitamin A and clinical evidence of hypervitaminosis A do not result from the consumption of high doses of b-carotene. The medical induction of hypercarotenemia has been used successfully in the treatment of photosensitive conditions in humans (Mathews-Roth, 1982).

Other Diseases

Carotenoids in plants and long-chain retinyl esters in animal tissues are the major natural