Cedric F. Garland

The Role of Vitamin D in Cancer Prevention

Vitamin D status differs by latitude and race, with residents of the northeastern United States and individuals with more skin pigmentation being at increased risk of deficiency. A PubMed database search yielded 63 observational studies of vitamin D status in relation to cancer risk, including 30 of colon, 13 of breast, 26 of prostate, and 7 of ovarian cancer, and several that assessed the association of vitamin D receptor genotype with cancer risk. The majority of studies found a protective relationship between sufficient vitamin D status and lower risk of cancer. The evidence suggests that efforts to improve vitamin D status, for example by vitamin D supplementation, could reduce cancer incidence and mortality at low cost, with few or no adverse effects.

Do Sunlight and Vitamin D Reduce the Likelihood of Colon Cancer

It is proposed that vitamin D is a protective factor against colon cancer. This hypothesis arose from inspection of the geographic distribution of colon cancer deaths in the U.S., which revealed that colon cancer mortality rates were highest in places where populations were exposed to the least amounts of natural light--major cities, and rural areas in high latitudes. The hypothesis is supported by a comparison of colon cancer mortality rates in areas that vary in mean daily solar radiation penetrating the atmosphere. A mechanism involving cholecalciferol (vitamin D3) is suggested. The possibility that an ecological fallacy or other indirect association explains the findings is explored.

DIETARY VITAMIN D AND CALCIUM AND RISK OF COLORECTAL CANCER: A 19-YEAR PROSPECTIVE STUDY IN MEN

Mortality rates from colon cancer in the USA are highest in populations exposed to the least amounts of natural sunlight; differences in endogenous vitamin D production and calcium absorption could be responsible. To investigate this possibility, the association of dietary vitamin D and calcium with 19-year risk of colorectal cancer was examined in 1954 men who had completed detailed, 28-day dietary histories in the period 1957-59. Risk of colorectal cancer was inversely correlated with dietary vitamin D and calcium. In the quartiles of a combined index of dietary vitamin D and calcium, from lowest to highest, observed risks of colorectal cancer were 38.9, 24.5, 22.5, and 14.3/1000 population. This association remained significant after adjustment for age, daily cigarette consumption, body mass index, ethanol consumption, and percentage of calories obtained from fat.

Geographic variation in breast cancer mortality in the United States: A hypothesis involving exposure to solar radiation

Epidemiologic and laboratory evidence suggests that vitamin D may play a role in reducing breast cancer risk. Lack of exposure to ultraviolet sunlight can increase the prevalence of vitamin D deficiency. This deficiency may place some populations at higher risk for breast cancer. The association between total average annual sunlight energy striking the ground and age-adjusted breast cancer mortality rates in 87 regions of the United States was evaluated. Annual age-adjusted mortality rates for breast cancer varied over a 1.8-fold range, from 17-19 per 100,000 in the South and Southwest United States to 33 per 100,000 in the Northeast; the overall U.S. rate was 27.3 per 100,000. Risk of fatal breast cancer in the major urban areas of the United States was inversely proportional to intensity of local sunlight (r = -0.80, P = 0.0001); multiple regression with stratospheric ozone measurements, r = -0.82, P = 0.0001). Vitamin D from sunlight exposure may be associated with low risk for fatal breast cancer, and differences in ultraviolet light reaching the United States population may account for the striking regional differences in breast cancer mortality. The ecological nature of this study is emphasized, and the possibility that an indirect association with dietary and socioeconomic factors could explain these findings is discussed.

Vitamin D and prevention of breast cancer: pooled analysis.

BACKGROUND Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence and mortality rates of breast cancer in ecological and observational studies, but the dose-response relationship in individuals has not been adequately studied. METHODS A literature search for all studies that reported risk by of breast cancer by quantiles of 25(OH)D identified two studies with 1760 individuals. Data were pooled to assess the dose-response association between serum 25(OH)D and risk of breast cancer. RESULTS The medians of the pooled quintiles of serum 25(OH)D were 6, 18, 29, 37 and 48 ng/ml. Pooled odds ratios for breast cancer from lowest to highest quintile, were 1.00, 0.90, 0.70, 0.70 and 0.50 (p trend<0.001). According to the pooled analysis, individuals with serum 25(OH)D of approximately 52 ng/ml had 50% lower risk of breast cancer than those with serum <13 ng/ml. This serum level corresponds to intake of 4000 IU/day. This exceeds the National Academy of Sciences upper limit of 2000 IU/day. A 25(OH)D level of 52 ng/ml could be maintained by intake of 2000 IU/day and, when appropriate, about 12 min/day in the sun, equivalent to oral intake of 3000 IU of Vitamin D(3). CONCLUSIONS Intake of 2000 IU/day of Vitamin D(3), and, when possible, very moderate exposure to sunlight, could raise serum 25(OH)D to 52 ng/ml, a level associated with reduction by 50% in incidence of breast cancer, according to observational studies.

Vitamin D for cancer prevention: global perspective.

PURPOSE Higher serum levels of the main circulating form of vitamin D, 25-hydroxyvitamin D (25(OH)D), are associated with substantially lower incidence rates of colon, breast, ovarian, renal, pancreatic, aggressive prostate and other cancers. METHODS Epidemiological findings combined with newly discovered mechanisms suggest a new model of cancer etiology that accounts for these actions of 25(OH)D and calcium. Its seven phases are disjunction, initiation, natural selection, overgrowth, metastasis, involution, and transition (abbreviated DINOMIT). Vitamin D metabolites prevent disjunction of cells and are beneficial in other phases. RESULTS/CONCLUSIONS It is projected that raising the minimum year-around serum 25(OH)D level to 40 to 60 ng/mL (100-150 nmol/L) would prevent approximately 58,000 new cases of breast cancer and 49,000 new cases of colorectal cancer each year, and three fourths of deaths from these diseases in the United States and Canada, based on observational studies combined with a randomized trial. Such intakes also are expected to reduce case-fatality rates of patients who have breast, colorectal, or prostate cancer by half. There are no unreasonable risks from intake of 2000 IU per day of vitamin D(3), or from a population serum 25(OH)D level of 40 to 60 ng/mL. The time has arrived for nationally coordinated action to substantially increase intake of vitamin D and calcium.

Vitamin D and prevention of colorectal cancer.

BACKGROUND Inadequate photosynthesis or oral intake of Vitamin D are associated with high incidence rates of colorectal cancer, but the dose-response relationship has not been adequately studied. METHODS Dose-response gradients from observational studies of Vitamin D intake and serum 25-hydroxyvitamin D were plotted as trend lines. The point on each linear trend line corresponding to an odds ratio of 0.50 provided the prediagnostic Vitamin D intake or 25-hydroxyvitamin D concentration associated with 50% lower risk compared to <100IU/day Vitamin D or <13ng/ml serum 25-hydroxyvitamin D. Medians of these values were determined. RESULTS Overall, individuals with >or=1000IU/day oral Vitamin D (p<0.0001) or >or=33ng/ml (82nmol/l) serum 25-hydroxyvitamin D (p<0.01) had 50% lower incidence of colorectal cancer compared to reference values. CONCLUSIONS Intake of 1000IU/day of Vitamin D, half the safe upper intake established by the National Academy of Sciences, was associated with 50% lower risk. Serum 25-hydroxyvitamin D of 33ng/ml, which is known to be safe, also was associated with 50% lower risk. Prompt public health action is needed to increase intake of Vitamin D(3) to 1000IU/day, and to raise 25-hydroxyvitamin D by encouraging a modest duration of sunlight exposure.

Trends in incidence rates of ulcerative colitis and Crohn's disease

Between 1960 and 1979, three studies were conducted in the Baltimore Standard Metropolitan Statistical Area to ascertain the incidence rates of first hospitalizations for ulcerative colitis and Crohns disease. The age-adjusted rates per 100,000 population for the 1977–1979 survey for ulcerative colitis in white and nonwhite males and females were 2.92, 1.79, 1.29, and 2.90, respectively; the Crohns disease rates were 3.39, 3.54, 1.29, and 4.08, respectively. In Baltimore the age-adjusted rate for Crohns disease has increased to exceed the ulcerative colitis rate for whites of both sexes and nonwhite females. The ulcerative colitis and Crohns disease rates for nonwhite males are similar. The rate for white males exceeds that for nonwhite males for both ulcerative colitis and Crohns disease, but the converse is true for females. Females have higher rates than males for Crohns disease in both color groups and for ulcerative colitis among nonwhites. White ulcerative colitis rates are higher for males than for females. From the first to the second surveys, the white male and female rates for ulcerative colitis converge with increasing male and decreasing female rates, but then both decline from the second to the third surveys. For Crohns disease, the age-adjusted rates increased for whites of both sexes and nonwhite females from the first to second surveys. The Crohns disease rates appeared to stabilize for whites of both sexes between the second and present surveys, but they increased for nonwhites of both sexes. Trends in age-adjusted rates for other areas are also discussed.

Incidence Rates of Ulcerative Colitis and Crohn's Disease in Fifteen Areas of the United States

A study was carried out during 1973 to determine the incidence of first hospitalizations for ulcerative colitis and Crohns disease in 15 areas of the United States, including communities of widely varied size, climatic, ethnic, racial, and socioeconomic characteristics. The following descriptions apply to incidence rates per 100,000 population for the aggregate of the 15 areas. Ulcerative colitis had a bimodal age distribution in white males (with peaks at ages 20-29 and 70-79 yr) and females (with peaks at ages 30-39 and 70-79 yr). Crohns disease had a bi- or trimodal age distribution in white males (with peaks at ages 20-29, 50-59, and 70-79 yr) and females (with peaks at ages 20-29, 50-59, and 70-79 yr). The age, sex, and geographic distributions that were observed in this study may have important etiologic implications.

Calcium and vitamin D. Their potential roles in colon and breast cancer prevention.

The geographic distribution of colon cancer is similar to the historical geographic distribution of rickets. The highest death rates from colon cancer occur in areas that had high prevalence rates of rickets‐regions with winter ultraviolet radiation deficiency, generally due to a combination of high or moderately high latitude, high‐sulfur content air pollution (acid haze), higher than average stratospheric ozone thickness, and persistently thick winter cloud cover. The geographic distribution of colon cancer mortality rates reveals significantly low death rates at low latitudes in the United States and significantly high rates in the industrialized Northeast. The Northeast has a combination of latitude, climate, and air pollution that prevents any synthesis of vitamin D during a five‐month vitamin D winter. Breast cancer death rates in white women also rise with distance from the equator and are highest in areas with long vitamin D winters. Colon cancer incidence rates also have been shown to be inversely proportional to intake of calcium. These findings, which are consistent with laboratory results, indicate that most cases of colon cancer may be prevented with regular intake of calcium in the range of 1,800 mg per day, in a dietary context that includes 800 IU per day (20 μg) of vitamin D3. (In women, an intake of approximately 1,000 mg of calcium per 1,000 kcal of energy with 800 IU of vitamin D would be sufficient.) In observational studies, the source of approximately 90% of the calcium intake was vitamin D‐fortified milk. Vitamin D may also be obtained from fatty fish. In addition to reduction of incidence and mortality rates from colon cancer, epidemiological data suggest that intake of 800 IU/day of vitamin D may be associated with enhanced survival rates among breast cancer cases.