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of the population at 50 nmol/L, there is a range of serum 25OHD levels between 50 and 150 nmol/L that remains undescribed. The adjustment to the starting point of 10,000 IU/day reflects first data concerning adverse effects related to all-cause mortality, falls and fractures, and CVD risk, which, taken as a total body of evidence, provide reason for caution, as described earlier. More specifically, the evidence from the studies that focused on all-cause mortality, chronic disease, falls and fractures suggested that serum 25OHD levels between 75 nmol/L and approximately 120 nmol/L were associated with the adverse effect. There is considerable uncertainty surrounding such values, and—using information on the serum levels achieved during maximal sun exposure and to avoid being unnecessarily restrictive given the uncertainties—the committee determined that for the purposes of the UL, concern would be for levels above approximately 125 to 150 nmol/L.

Further, there are emerging data concerning the possible differences in adverse event response for African Americans and perhaps other dark-skinned population groups. The cross–sectional study from Freedman et al. (2010) reported a positive association between serum 25OHD levels and calcified atherosclerotic plaque in the aorta and carotid arteries of African Americans, and preliminary reports from NHANES suggest that the risk for all-cause mortality among non-Hispanic blacks compared with whites occurs at a lower serum 25OHD level (60 vs. 75 nmol/L).6 These data are limited, are not necessarily consistent with other findings, and may eventually be explained by factors other than serum 25OHD levels, but they are concerning. Although data on race and ethnic differences are much too sparse to justify providing different ULs for different racial or ethnic groups, they can be incorporated as a source of uncertainty.

To determine an adjustment from the starting point of 10,000 IU/day as a NOAEL taking into account the uncertainties introduced by reports concerning all-cause mortality and other chronic disease outcomes as well as the possibility that blacks in the North American population may experience adverse effects at lower serum 25OHD concentrations than whites, the committee considered the work of Heaney et al. (2003). As suggested by the study, vitamin D intakes of 5,000 IU/day achieved serum 25OHD levels that range between 100 and 150 nmol/L, but do not surpass 150 nmol/L after 160 days of administration. Almost no other studies have assessed the safety of long-term maintenance of serum 25OHD levels in this range in relation to chronic disease risk and all-cause mortality, so the information about the increases in serum levels is useful for the purposes of establishing a UL. Given the uncertainties surrounding the data and the reliance on a

6

Personal communication, R. Durazo-Arvizu, Loyola University, Maywood, IL, May 28, 2010.



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