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been raised about the accuracy of intake estimates and birth defects diagnosed. It has been argued further that the limited number of excess cases used to identify a toxicity threshold of 4,500 μg/day of preformed vitamin A (or 3,000 μg from supplements) permits the study’s findings to be consistent with a larger threshold than other studies would suggest (Brent et al., 1996; Mastroiacovo et al., 1999; Watkins et al., 1996; Werler et al., 1996). Thus, while few dispute a causal association between excessive periconceptual vitamin A intake and risk of malformation, the threshold at which risk increases remains a matter of debate. However, in the context of the totality of data on vitamin A and birth defects, the data of Rothman and coworkers (1995) provide supportive evidence of a causal association. Case reports of malformations exist to support an increased risk of birth defects above a maternal intake of 7,800 μg/day of vitamin A (Bauernfeind, 1980; Bernhardt and Dorsey, 1974). Human case reports support a temporal association between maternal exposure to elevated vitamin A intakes and birth defects (Bernhardt and Dorsey, 1974; Von Lennep et al., 1985).

Liver Abnormalities. There is a strong causal association shown by human and animal data between excess vitamin A intake and liver abnormalities because the liver is the main storage site and target organ for vitamin A toxicity. The wide spectrum of vitamin A-induced liver abnormalities ranges from reversibly elevated liver enzymes to widespread fibrosis, cirrhosis, and sometimes death. Table 4-9 shows consistency and specificity of the following effects in liver pathology: spontaneous green fluorescence of sinusoidal cells, perisinusoidal fibrosis, hyperplasia, and hypertrophy of Ito cells. Human data are potentially confounded by other factors related to liver damage such as alcohol intake, hepatitis A, B, and C, hepatotoxic medications, or preexisting liver disease. A thorough evaluation of the liver data is provided in the later section, “Dose-Response Assessment”.

Adverse Interactions. Alcohol intake has been shown to enhance the toxicity of vitamin A (Leo and Lieber, 1999). In particular, the hepatotoxicity of vitamin A may be potentiated by alcohol use. Therefore, alcohol drinkers may be distinctly susceptible to the adverse effects of vitamin A.

Adverse Effects in Infants and Children

There are numerous case reports of infants (Table 4-10), toddlers, and children who have demonstrated toxic effects due to ex-



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