Perspectives The mechanisms of vitamin D toxicity

Vitamin D intoxication is a hypercalcemic and hypercalciuric state which is sugges-tive of excess 1,25(OH) 2 D-like activity. Major aspects of vitamin D toxicity have been reviewed by Coburn and Barbour [1] and by Stern and Bell [2]. Among the factors that may predispose individuals to vitamin D intoxication are increased cal-cium intake, decreased renal function, diminished estrogen levels, the existence of sarcoidosis [1] or other vitamin D-hypersensitivity syndromes associated with over-production of 1,25(OH) 2D [2]. The key issue that has not been resolved is the ques-tion of just what it is about the vitamin D endocrine system itself that makes excess vitamin D toxic even in normal individuals. The role of 1,25(OH) 2D in vitamin D intoxication was discounted once it was shown that 1,25(OH) 2D levels were relatively unchanged in affected subjects. In-stead, toxicity has been attributed to the high circulating concentrations of 25(OH)D [3]. This view was based on in vitro studies showing that high concentrations of 25(OH)D stimulated resorption of cultured fetal rat bone [4]. However, it is by no means clear that excessive 25(OH)D or some unspecified agonist will act at th