ing in age from 21 to 60 years and without tuberculosis were in one study group. Statistically significant increases in serum calcium were observed in these subjects at vitamin D doses of 60 and 95 µg (2,400 and 3,800 IU)/day. However, increases in serum calcium level in some subjects, while statistically significant, were not necessarily adverse, or indicative of hypercalcemia (for example, serum calcium levels above 2.75 mmol/liter). For example, the mean serum calcium level in normal controls following administration of 60 µg (2,400 IU)/day of vitamin D increased from 2.43 mmol/liter to 2.62 mmol/liter (p < 0.01). The mean serum calcium level in normal controls treated with 95 µg (3,800 IU)/day of vitamin D increased from 2.46 mmol/liter to 2.83 mmol/liter. At 30 µg (1,200 IU)/day, in normal controls, the increase was from 2.35 mmol/liter to 2.66 mmol/liter, but this was not a significant increase. The study thus demonstrates an effect of relatively low doses of supplementary vitamin D on serum calcium levels, although the degree of hypercalcemia was modest. It should also be noted that the effect developed over a relatively short time (3 months or less), so it is not known whether the effect would have progressed and worsened, or whether it would have disappeared, over a longer time period.

Hypercalcemia, defined as a serum calcium level above 2.75 mmol/liter (11 mg/dl), was observed at the highest dose of 95 µg (3,800 IU)/day, which is, therefore, the lowest-observed-adverse-effect level (LOAEL). Although a significant rise in serum calcium levels occurred at 60 µg (2,400 IU)/day, they were still within a normal range. Therefore, 60 µg (2400 IU)/day is designated as a no-observed-adverse-effect level (NOAEL).

Uncertainty and Uncertainty Factors. In using a NOAEL of 60 µg (2,400 IU)/day based only on the results of Narang et al. (1984) to derive a UL for adults, it appears to be uncertain whether any increase in serum calcium, even though still within normal limits, might be adverse for sensitive individuals and whether the short duration of this study and small sample size affected the results. The selected uncertainty factor (UF) of 1.2 was judged to be sufficiently conservative to account for the uncertainties in this data set. A larger UF was judged unnecessary due to the availability of human data and a reasonably well-defined NOAEL in a healthy population.

Derivation of a UL. Based on a NOAEL of 60 µg (2,400 IU)/day divided by a composite UF of 1.2, the estimated UL for adults is 50 µg (2,000 IU)/day. Supportive evidence for a UL of 50 µg (2,000 IU)/day is provided by Johnson et al. (1980) and Honkanen et al.



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