within a short time, and progress is often erratic. Some gaps are filled, while others are created.

• The etiology of disease–health relationships, especially in the case of chronic disease, is commonly multi-factorial. Even if diet has a prominent role, it is extremely unlikely that a single nutrient is directly responsible for a chronic disease or, conversely, that addition of a single nutrient will eliminate disease risk. It is possible that a focus on specific nutrients as risk factors for diseases in relatively homogeneous or diseased populations can lead to a number of spurious associations.

• Clinical trials, which are generally considered to provide the strongest evidence about the effects of nutrient intake on subsequent disease and health, are complex, expensive, and time-consuming, especially for chronic diseases that develop over decades and are influenced by a host of genetic, physiological, and environmental factors that may also affect risk.

The committee found all of the above findings to be the case for non-skeletal health outcomes for vitamin D, as the discussions of the strength, consistency, and causality of the evidence demonstrate in Chapter 4.

Finally, an important uncertainty focuses on the issue of excess intake. This is particularly true for vitamin D, which has been hypothesized to confer health benefits at relatively high levels of intake. Although the committee’s decisions for the ULs made use of emerging data concerning a U-shaped (or perhaps reverse-J-shaped) curve for risk, which suggested adverse effects at levels much lower than those associated with hypervitaminosis D, the lack of data on the safety of higher intakes of vitamin D when used chronically is very concerning. Byers (2010), in a recent editorial commenting on the outcomes of a pooling study focused on vitamin D and six types of cancer in which the only association observed was a doubling of the risk for pancreatic cancer for those in the highest quintile of circulating serum 25OHD levels, offered the following observation: “We have learned some hard lessons…. and we now know that taking vitamins in supernutritional doses can cause serious harm.”

Serum 25OHD levels have been used as a “measure of adequacy” for vitamin D, as they reflect intake from the diet coupled with the amount contributed by cutaneous synthesis. The cut-point levels of serum 25OHD intended to specify deficiency and sufficiency for the purposes of interpreting laboratory analyses and for use in clinical practice are not specifically