In a recent review article, Giovannucci presents the biological plausibility of the vitamin D hypothesis [1]. Ultraviolet radiation from sunlight produces vitamin D in the skin, which is then hydroxylated in the liver to produce 25(OH)D. Many cell types, including some cancerous cell types, are able to convert 25(OH)D into the more active form of 1,25(OH) 2 D by 1-α-hydroxylase. This function is also performed by the kidneys. Circulating vitamin D activates vitamin D receptors that are located on many cells [43], including cancerous cells, arresting tumor progression and metastasis. The variable efficacy of the vitamin D conversion function by different organs and cell types may account for some of the variation in risk seen between different cancer sites.

For individual cancer sites, the relative incidence risk and relative mortality risk tended to be similar. Among sites with strong evidence of an inverse association with solar UV-B exposure, there was a higher relative mortality risk for breast, colon, rectum, esophagus, other biliary, and vulva. These differences could possibly be related to regional differences in screening, treatment and medical utilization practices; for this reason, incidence data are generally considered preferable to mortality data. But this would imply that there was something about the medical care infrastructure of northern states that was inferior to that of southern states. Recalling that a wide range of factors have been adjusted for in the model, this hypothesis does not make much sense. If anything, the greater concentration of established research hospitals in the older cities in the northern half of the country would be expected to produce an effect opposite the one seen. Even if important regional differences in the medical care infrastructure did exist, there is no reason to expect them to vary latitudinally in the same manner as solar UV-B levels.

A more plausible hypothesis is that the differences between incidence and mortality are related to solar UV-B exposure. Several recent studies that focused on the time of diagnosis and death concluded that vitamin D levels are more relevant to disease progression than disease onset [7, 12]. In these studies, little or no pattern was seen in the season of diagnosis (except for a reduction during major holidays, when the level of non-emergency care is reduced), but a strong association was found with the season of death, with death rates higher in winter months when circulating vitamin D levels are at a minimum. Thus it may be that one's overall risk of contracting colon cancer may be moderately influenced by reduced solar UV-B exposure (with an increased risk of 10% to 15% in the northern versus southern United States), while the risk of dying from the disease is more strongly related to reduced solar UV-B exposure (with an increased risk of 25% to 30%).

Incomplete control of confounding may have influenced our findings. For example, there may exist regional variations in viruses and organisms that are believed to be linked with cancer, such as hepatitis B and C infection and aflatoxin for liver cancer, and HPV infection for cervix, vulva, and anal cancer. The enormous racial grouping "white" also may be problematic, insofar as there exist important regional ethnic variations within the grouping as well as geographically variable degrees of racial mixing or miscoding. For example, the high gallbladder cancer mortality rates among whites in the Southwest, which would not be expected under the vitamin D hypothesis, probably reflect the influence of Hispanics and American Indians, who have much higher rates of this disease [44]. Smokeless tobacco use, which is a leading risk factor for oral cancer and strongly concentrated in the rural South, was not adjusted for at all because of insufficient data. Regional variation in diet may have also influenced the findings, particularly for the digestive cancers, although Grant [13] and others argue against this.

Systematic coding problems for several of the cancer sites likely influenced the results. Many advanced cancers metastasize to the bone, so that the geographic pattern of bone and joint cancer mortality, for example, may be influenced by geographically differential misclassification of metastatic tumors as primary tumors. The existence of such misclassification is strongly suggested by sharp differences in rates of miscellaneous cancers between adjacent states [45] (Miscellaneous cancer is a catch-all category incorporating ambiguous, vague or ill-defined sites such as "abdomen" or "thorax", along with unknown sites). Both the tendency to classify cases ambiguously and the tendency to misclassify metastatic tumors are related to resource issues at both the state and hospital levels.

Finally, this being an ecologic study, all of the usual limitations of an ecologic study apply. The ecologic adjustments that were made for smoking, outdoor occupation, particulate matter, and so on were not optimal, relying on proxy measures, survey data, spatial interpolations and other imperfect instruments. The central premise of the study – that where you live determines your sun exposure – while reasonable, is subject to many possible local exceptions, and no data are available that distinguish the solar exposure levels of those with cancer to those without cancer in a given location.