Association of solar ultraviolet B with reduced mortality rates of some types of cancer: multifactorial ecologic study William B. Grant, Ph.D., Sunlight, Nutrition and Health Research Center (SUNARC)

2107 Van Ness Avenue, Suite 403B, San Francisco, CA 94109-2529, wbgrant@sunarc.org, www.sunarc.orgCedric F. Garland, Dr. P.H., Professor, Dept. of Family and Preventive Medicine, UC, San Diego, cgarland@ucsd.edu

Objective. The objective of this study is to explain the geographic variations in cancer mortality rates in the U.S.

Materials and Methods. Ecologic analyses of variations for a number of cancers for the periods 1950-69 and 1970-94 in the U.S. were performed using age-adjusted mortality rate data in association with data on alcohol consumption, Hispanic heritage, lung cancer mortality rates (as an index of cigarette smoking), poverty, degree of urbanization, and ultraviolet B (UVB) irradiance. The square root of the mortality rate was used in the analysis.

The solar ultraviolet B (UVB) data used for this study were obtained from the Total Ozone Mapping Spectrometer (TOMS) data for July 1992 and digitized by state. Photosynthesis from solar UVB is the largest source of vitamin D. UVB is highest in the southwest and lowest in the northeast. This distribution is primarily due to differences in surface elevation (higher west of the Rocky Mountains) and column ozone (lower west of the Rockies) and other factors. The pronounced inverse correlation between UVB and mortality rates for colon cancer was the first indication that vitamin D reduces the risk of cancer [Garland and Garland, 1980]. While these UVB data are convenient to use, and agree fairly well with ground-based data from the USDA UV-B Monitoring and Research Program , vitamin D production during other months is also important. In some regions of the northeastern US, there is insufficient UVB to photosynthesize vitamin D during 4-5 months of the year,

Mechanisms whereby vitamin D reduces risk of cancer include differentiation, apoptosis;reduced cell proliferation, metastasis, and angiogenesis; Attenuation of growth signaling; increased calcium flux (for the colon and breast); reduced breast density [Berube et al., 2004]. Peripheral tissues convert 25(OH)D to 1,25(OH)2D and vitamin D receptors mediate the actions of 1,25(OH)2D.

Key References Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980;9:227-231. Garland C, Shekelle RB, Barrett-Connor E, et al.. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet. 1985;1:307-9. Gorham ED, Garland CF, Garland FC. Acid haze air pollution and breast and colon cancer mortality in 20 Canadian cities. Can J Public Health. 1989;80:96-100. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation. Cancer. 1992;70:2861-2869. Lefkowitz ES, Garland CF. Sunlight, vitamin D, and ovarian cancer mortality rates in U.S. women. Int J Epidemiol. 1994; 23: 1133-6. Cross HS, Peterlik M, Reddy GS, Schuster I. Vitamin D metabolism in human colon adenocarcinoma-derived Caco-2 cells: expression of 25-hydroxyvitamin D3-1alpha-hydroxylase activity and regulation of side-chain metabolism. J Steroid Biochem Mol Biol. 1997;62:21-28. Grant WB. An estimate of premature cancer mortality in the United States due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002;94:1867-1875. Grant WB. An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates. Cancer. 2002;94:272-281. Freedman DM, Dosemeci M, McGlynn K. Sunlight and mortality from breast, ovarian, colon, prostate, and non-melanoma skin cancer: a composite death certificate based case-control study. Occup Environ Med 2002;51:257-262. Tuohimaa P, Tenkanen L, Ahonen M, et al. Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer. 2004;108:104-8. Grant WB, Garland CF. A critical review of studies on vitamin D in relation to colorectal cancer. Nutr Cancer, 2004;48:115-23. Grant WB. Geographic variation of prostate cancer mortality rates in the United States: Implications for prostate cancer risk related to vitamin D. Int J Cancer. 2004;111:470-1. Grant WB. Insufficient sunlight may kill 45,000 Americans each year from internal cancer. J Cos Dermatol. 2004;3:176-8. Smedby KE, Hjalgrim H, Melbye M, et al. Ultraviolet radiation exposure and risk of malignant lymphomas. J Natl Cancer Inst. 2005;97:199-209.

Gallbladder and gastric cancer morality rates show elevated risk associated with Hispanic heritage. The association of UVB with prostate cancer is complex and will require further research; both low and high vitamin D appear associated with risk..

Other diseases related to vitamin DThere is evidence that vitamin D sufficiency is associated with reduced incidence of bone and muscle diseases, multiple sclerosis (MS), type 1 diabetes mellitus (DM), myocardial infarction, and end stage renal disease and secondary hyperparathyroidism (HPT) [Grant and Holick, submitted]. There is also observational or other evidence that vitamin D sufficiency may be associated with reduced severity of rheumatoid arthritis, tuberculosis, and type 2 diabetes.

Solar ultraviolet B and vitamin D

Solar UVB is the primary source of vitamin D. Skin pigmentation has adapted through millennia to prevailing solar UV irradiance. Hispanic and black Americans have skin that protects against erythema but reduces the production of vitamin D. With care, all can obtain their vitamin D from UVB. Melanoma and basal cell carcinoma (BCC) appear related mostly to UVA (315-400 nm) overexposure, while actinic keratoses and squamous cell carcinoma are mostly associated with UVB overexposure. Use of sunscreen does not protect against melanoma or BCC, and reduces the production of vitamin D.

Vitamin D supplements should contain vitamin D3 and should not contain vitamin A, which diminishes the effectiveness of vitamin D by competition at the receptor level. If taking vitamin D supplements, 1,000 I.U./day is required for substantial reduction of incidence of colorectal cancer. This dosage is safe according to the National Academy of Sciences [NAS-Institute of Medicine, Dietary reference intakes for calcium, phosphorus, magnesium, vitamin D, and fluoride. Washington DC: National Academy Press, 1997].

Factors ranked in order of standardized regression (beta) coefficients; I (inverse)

Digestive Tract Cancers (males)Esophageal: UVB (I), smoking, alcohol, poverty (I)Gastric: UVB (I), Hispanic ancestryColon: UVB (I), smoking, urban, poverty (I)Rectal: UVB (I), poverty (I), Hispanic ancestry, smoking, alcohol

Breast and Reproductive System CancersBreast: UVB (I), urban, alcoholCervical: smoking, UVB (I), urban (I)Endometrial: UVB (I), poverty (I)Ovarian: UVB (I), poverty (I), alcohol

Urogenital Cancers (males)Bladder: poverty (I), smoking, UVB (I)Prostate: latitude, urban (I), UVB, poverty (I), alcoholRenal: UVB (I), smoking

Other Cancers (males)Gallbladder: UVB (I), Hispanic, urbanLaryngeal: smoking, UVB (I), urbanPancreatic: smoking, UVB (I)Hodgkin’s lymphoma: UVB (I), poverty, urbanNon Hodgkin’s lymphoma: UVB (I)

Skin Cancers (males)Melanoma: latitude (a proxy for UVA)Other skin cancer: latitude (I), alcohol, poverty

Summary of Findings of This Study

Data Sources Devesa SS, Grauman DJ, Blot WJ, Pennello GA, Hoover RN, Fraumeni JF Jr. Atlas of Cancer Mortality in the United States, 1950-1994. NIH Publication No. 99-4564, 1999. http://cancer.gov/atlasplus/new.html July 1992 DNA-weighted UVB irradiance: http://toms.gsfc.nasa.gov/ery_uv/dna_exp.gif Nephew TM, Williams GD, Yi H, Hoy AK, Stinson FS, Dufour MC. Surveillance Report #59: Apparent Per Capita Alcohol Consumption: National, State, and Regional Trends, 1977-99. Washington, DC: NIAAA, 2002. http://www.niaaa.nih.gov/publications/pcyr7099.txt Hispanic heritage: http://www.census.gov/population/censusdata/urpop0090.txt Gibson C, Jung K. Historical Census Statistics on Population Totals By Race, 1790 to 1990, and By Hispanic Origin, 1970 to 1990, For The United States, Regions, Divisions, and States. Population Division. U. S. Census Bureau. Washington, DC 20233. Working Paper Series No. 56. 2002.

Data Maps

Cancer mortality rates on left; Risk factors below and on right