with r² values of ~0.30 for each model. While the positive association between vitamin A and carotene intake and change in BMD may not be causal, the data provide evidence that vitamin A does not adversely affect premenopausal bone health within this range of intake.

The findings from these studies are provocative but conflicting, and therefore, they are not useful for setting a UL for vitamin A. More research is needed to clarify whether chronic vitamin A intake, at levels that characterize upper-usual intake ranges for many American and European populations, may lead to loss in BMD and consequent increased risk of hip fracture in certain population groups, particularly among pre- and postmenopausal women.

Teratogenicity. Concern for the possible teratogenicity of high vitamin A intake in humans is based on the unequivocal demonstration of human teratogenicity of 13-cis-retinoic acid (Lammer et al., 1985) after supplementation with high doses of vitamin A (Eckhoff and Nau, 1990; Eckhoff et al., 1991). Numerous studies in experimental animals clearly establish the teratogenic potential of excessive intakes of vitamin A (Cohlan, 1953, 1954; Geelen, 1979; Hutchings and Gaston, 1974; Hutchings et al., 1973; Kalter and Warkany, 1961; Pinnock and Alderman, 1992).

Epidemiological data show the possibility of teratogenic effects with high intakes of preformed vitamin A (Table 4-8). The critical period for susceptibility appears to be the first trimester of pregnancy and the primary birth defects associated with excess vitamin A intake are those derived from cranial neural crest (CNC) cells such as craniofacial malformations and abnormalities of the central nervous system (except neural tube defects), thymus, and heart. Examination of the data suggests a likely dose-dependent association between vitamin A intake at excessive levels and the risk of birth defects. One case-control report showed a statistically nonsignificant association between a reported maternal intake of greater than 12,000 μg/day and malformations, but not below that level (Martinez-Frias and Salvador, 1990). Two other large case-control studies showed no relationship between risk of malformation and likely supplemental daily doses of 2,400 to 3,000 μg by mothers (Khoury et al., 1996; Shaw et al., 1996). An observational study by Rothman and coworkers (1995) involving 22,748 pregnant women found that those who ingested greater than 4,500 μg/day of preformed vitamin A from food and supplements were at greater risk of delivering infants with malformations of CNC cell origin (e.g., cleft lip or palate) than were women consuming less than 1,500 μg/day. But questions have