Jenab M, Bueno-de-Mesquita HB, Ferrari P, et al. Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study. 2010;340:b5500.
Pettifor et al () measured the free 1,25(OH)2D concentration in 11 people intoxicated by the erroneous consumption of a vitamin D concentrate that they had used as cooking oil. The serum 25(OH)D concentrations in these patients covered the range (300–1000 nmol/L) that was required in the study of Heaney et al () to show a calcium-absorptive response to serum 25(OH)D itself. The mean serum free 1,25(OH)2D fraction in the study group of Pettifor et al was double the mean for normal individuals, implicating free 1,25(OH)2D as a contributor to toxicity when 25(OH)D concentrations match those used by Heaney et al. Not all of the subjects in Pettifor et al's study had elevated free 1,25(OH)2D, yet all subjects were hypercalcemic; therefore, the most likely agent causing vitamin D toxicity was a combination of inappropriate activity of both 25(OH)D and 1,25(OH)2D.
A concentration-function approach to vitamin C (ascorbate) has yielded new physiology and pharmacology discoveries. To determine the range of vitamin C concentrations possible in humans, pharmacokinetics studies were conducted. They showed that when vitamin C is ingested by mouth, plasma and tissue concentrations are tightly controlled by at least 3 mechanisms in healthy humans: absorption, tissue accumulation, and renal reabsorption. A 4th mechanism, rate of utilization, may be important in disease. With ingested amounts found in foods, vitamin C plasma concentrations do not exceed 100 μmol/L. Even with supplementation approaching maximally tolerated doses, ascorbate plasma concentrations are always μmol/L and frequently μmol/L. By contrast, when ascorbate is i.v. injected, tight control is bypassed until excess ascorbate is eliminated by glomerular filtration and renal excretion. With i.v. infusion, pharmacologic ascorbate concentrations of 25–30 mmol/L are safely achieved. Pharmacologic ascorbate can act as a pro-drug for hydrogen peroxide (H2O2) formation, which can lead to extracellular fluid at concentrations as high as 200 μmol/L. Pharmacologic ascorbate can elicit cytotoxicity toward cancer cells and slow the growth of tumors in experimental murine models. The effects of pharmacologic ascorbate should be further studied in diseases, such as cancer and infections, which may respond to generation of reactive oxygen species via H2O2.
 McDonnell SL, Baggerly C, French CB, Baggerly LL, Garland CF, Gorham ED, et al. Serum 25-Hydroxyvitamin D Concentrations ≥40 ng/ml Are Associated with >65% Lower Cancer Risk: Pooled Analysis of Randomized Trial and Prospective Cohort Study. PLoS ONE, 2016. e0152441.