The indicator of hypercalcemia for vitamin D toxicity is the starting point for the UL for adults. This condition is at an extreme end of an adverse outcome continuum and it may be appropriate to consider instead as a starting point for other measures, such as hypercalciuria. However, interpretation of measures such as hypercalciuria as a predictor of adverse outcomes is unclear. Therefore, the best available option as an indicator is hypercalcemia. In this case, an intake value of 10,000 IU/day reflects a NOAEL. This NOAEL is initially adjusted for uncertainty to establish a UL of 4,000 IU/day, as described below.

Initially, it should be noted that evidence pertaining to the levels of 25OHD in serum that are associated with adverse effects is less well established than that associated with benefit, and the available literature suggests considerable variability. As shown above in Table 6-3, frank toxicity has been reported to have occurred within a wide range of serum 25OHD levels, from as low as 60 nmol/L (Byrne et al., 1995) to values above 1,500 nmol/L (Rizzoli et al., 1994; Pettifor et al., 1995; Vieth et al., 2002), although the majority of available reports of toxicity involve serum 25OHD values above 350 nmol/L. The variability in the toxicity data may mean that toxicity can be affected by numerous mitigating factors or perhaps may be a function of the diversity in the nature of the available case reports. Reports on maximal sun exposure also described previously (Barger-Lux and Heaney, 2002; Binkley et al., 2007) suggest that serum 25OHD levels under these circumstances generally remain below 125 to 150 nmol/L, although the populations studied are not diverse and generally include younger men. The emerging data related to all-cause mortality, chronic disease risk, and falls would appear to suggest that adverse events may occur with serum 25OHD levels of approximately 75 nmol/L or above (Visser et al., 2006; Ginde et al., 2009), but ranging up to approximately 125 nmol/L (Melamed et al., 2008). The vagaries of serum 25OHD measures in general, the sparse data available, and the uncertainty as to the nature of the adverse effects preclude strong conclusions. On the basis of available reports, the committee considered that serum 25OHD levels above approximately 125 to 150 nmol/L should be avoided. Given the conclusion derived in Chapter 5 that bone health benefit is achieved by 97.5 percent