Key References from the manuscript under review

1. Ultraviolet B (UVB) data The UVB data used for this study were obtained from the Total Ozone Mapping Spectrometer (TOMS) data for July 1992 and digitized by state. Solar UVB represents the largest source of vitamin D for most Americans. Note that UVB is highest in the southwest and lowest in the northeast. A number of factors contribute to this distribution including surface elevation (higher west of the Rocky Mountains) and column ozone (lower west of the Rockies). The pronounced inverse correlation between UVB and mortality rates for such cancers as breast and colon was the indication that vitamin D reduces the risk of cancer, first identified by Cedric and Frank Garland in 1980. Table 1. Selected regression results for cancer mortality rates, 1970-94, for white Americans in the 48 contiguous states plus DC. UVB is for July unless indicated S for September. Ecologic studies of diet and cancer Ecologic studies using multi-country cancer mortality rates and dietary supply data 15-20 years prior to the mortality data can be used to estimate the links to major dietary factors. For breast, colon, and prostate cancer, animal products are the highest risk factors, while vegetable products are the highest risk reduction factors in general. For breast cancer, alcohol is also a risk factor, while fish is a risk reduction factor. For prostate cancer, onions and other allium vegetables are the most important risk reduction factor. These results indicate that the unmodeled mortality rates in the U.S. are strongly linked to diet. Objective. The objective of this work is to explain the geographic variations in cancer mortality rates in the United States. Materials and Methods. An ecologic analysis of variations for a number of internal cancers for the period 1970-94 in the U.S. was performed using the mortality rate data along with data for alcohol consumption, Hispanic heritage, lung cancer mortality rates, (an index for smoking), fraction living below the poverty level, and degree of urbanization. A multifactor ecologic analysis of the geographic variation in cancer mortality rates in the USA William B. Grant, Ph.D., Sunlight, Nutrition and Health Research Center (SUNARC)2107 Van Ness Avenue, Suite 403B, San Francisco, CA 94109-2529, wgrant@sunarc.org, www.sunarc.org Cancer Adj r2, F, * 1st Term 2nd Term 3rd Term 4th Term Bladder-M 0.70, 29 UVB -5.0,* Pov -4.8,* Alc 4.7, * LuCan 4.7,* Breast – F 0.81, 51 UVB -10,* Urb 6.2,* Alc 3.7, * Pov -1.0, 0.35 Colon – M 0.74, 36 UVB -9.2,* Urb 5.8,* LuCan 4.5,* Pov -1.9, 0.068 Endomet-F 0.69, 37 UVB -8.5,* His 4.0,* Pov -3.3, 0.002 Esoph–F 0.70, 38 LuCan 5.3,* Alc 4.5,* UVB -4.0 Gallblad-M 0.44, 19 UVB -5.9,* His 4.9,* Gastric-M 0.45, 21 UVB -6.1,* His 4.9,* Hepatocel-M 0.66, 47 LuCan9.2,* His 5.6,* Hodgkin’s-F 0.41,18 UVB 2nd order Laryng–M 0.69, 28 LuCan 8.3,* UVB -5.4,* Alc 3.3, 0.002 Urb 3.1, 0.003 NHL–M 0.46, 21 UVB -6.1,* Urb 3.6,* Oral–M 0.58, 17 LuCan7.4,* Urb 3.0, 0.004 UVB-S -3.0, 0.005 Alc 2.6, 0.012 Other–M 0.35,14 LuCan5.0,* Alc 2.4, 0.020 Ovarian–F 0.78, 42 UVB -10,* His 2.9, 0.006 Urb 2.9, 0.006 Pov -2.7, 0.010 Pan–M 0.38, 11 LuCan 5.7,* His 2.7, 0.010 UVB-S -2.6, 0.014 Prostate–M 0.52, 18 Latitude 6.5,* UVB 2.9, 0.006 Urb -1.6, 0.108 Rectal–M 0.72, 42 UVB -9.1,* His 3.8,* Pov -3.4, * Renal–F 0.37, 15 UVB 2nd order, * * p<0.001; Alc = alcohol consumption, 1970; His = Hispanic heritage fraction, 1995; LuCan = Lung cancer mortality rates, 1970-94; Pov = fraction living below the poverty Level, 1980; Urb = degree of urbanization, 1990 Table 2. Contributions to cancer mortality rates for white Americans for selected cancers (deaths/100,000/year). The mean values for each factor are used along with the relative importance determined in the regression analysis. The regression sum approximately equals the population mean value. The unmodeled portion is given by the constant term, which is largely attributed to diet (see discussion to right). Ecologic Approach The ecologic approach was used in this study. In the ecologic approach, populations defined geographically are treated as entities, and average values for disease outcomes and potentially influencing factors for each population are used. The ecologic approach was largely abandoned for health studies in 1981 since it was considered useful only for generating hypotheses but not establishing causality [Doll and Peto, 1981]. However, this approach has been applied very successfully for the first identification of important dietary and/or environmental links for a number of diseases including several types of cancer [Burkitt, 1971, Armstrong and Doll, 1975; Garland and Garland, 1980] and Alzheimer’s disease [Grant, 1997], and can be quite powerful when applied carefully. The advantages of the ecologic approach include: 1– very large data bases are available, making it possible to generate robust results for diseases with small numbers of affected people; 2 – additional factors can be added easily if the data sets are available; 3 – there is generally sufficient variation in the data that random errors are overshadowed. Cancer, Sex Const UVB LuCan Urban Alcohol Poverty Hispanic Breast-F 24.0 -6.8 0.0 5.1 4.3 0.0 0.0 Colon-M 17.0 -7.7 5.4 6.2 0.0 -1.4 0.0 Colon-F 18.2 -4.7 2.6 0.0 0.0 -1.3 0.0 Endometrial-F 5.5 -1.5 0.0 0.0 0.0 -0.4 0.1 Laryngeal-M -0.3 -0.7 2.1 0.6 0.6 0.0 0.0 NHL-M 7.2 -1.2 0.0 0.9 0.0 0.0 0.0 Ovarian-F 10.3 -2.5 0.0 1.0 0.0 -0.6 0.2 Rectal-M 8.6 -3.5 0.0 0.0 0.0 -1.0 0.3 Note that melanoma mortality rates are much lower than variations for other cancers. Key References from the manuscript under review 1. 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 (accessed April 21, 2004) 3. 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. 5. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst. 1981;66:1191-1308. 7. Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer. 1975;15:617-631. 8. Garland CF, Garland FC. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol. 1980;9:227-231. 10. Grant WB. An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates. Cancer. 2002;94:272-281. 13. U.S. Dept. Of Commerce. Statistical Abstract of the U.S., 1994:114th Edit. 14. Jemal A, Tiwari RC, Murray T, et al. Cancer statistics, 2004. CA Cancer J Clin. 2004;54:8-29. 18. Grant WB, Garland CF. A critical review of studies on vitamin D in relation to colorectal cancer. Nutr Cancer. in press. 19. Herman JR, Krotkov N, Celarier E, Larko D, Labow G. Distribution of UV radiation at the Earth's surface from TOMS-measured UV-backscattered radiances. J Geophys Res-Atmos 1999;104:12 059-12 076. http://toms.gsfc.nasa.gov/ery_uv/dna_exp.gif (accessed April 21, 2004). 23. Bigelow DS, Slusser JR, Beaubien AF, Gibson JH. The USDA Ultraviolet Radiation Monitoring Program. Bull Amer Meteorol Soc 1998;79:601-615. http://uvb.nrel.colostate.edu/UVB/home_page.html (accessed April 21, 2004). 31. 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 (accessed April 21, 2004) 34. Trapido EJ, Burciaga Valdez R, et al. Epidemiology of cancer among Hispanics in the United States. J Natl Cancer Inst Monograph 1995;18:17-28. 41. Grant WB. A multicountry ecologic study of risk and risk reduction factors for prostate cancer mortality. Eur Urol 2004;45:371-379. 88. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr. 2004;79:362-371. Other diseases related to vitamin D deficiency There is strong evidence that vitamin D deficiency is also a risk factor for musculoskeletal diseases, multiple sclerosis (MS), type 1 diabetes mellitus (DM), secondary hyperparathyroidism, hypertension, heart disease, and end stage renal disease [Grant and Holick, submitted]. There is also observational and/or other evidence that vitamin D deficiency is a risk factor for rheumatoid arthritis, tuberculosis, type 2 DM, infantile autism [Grant and Soles, in preparation], and schizophrenia. A number of original papers and reviews discussing the role of vitamin D in preventing chronic disease have appeared recently, to which the interested reader is referred [search PubMed or e-mail author for a list of papers]. Results Seven types of cancer (breast and ovarian for females; colon, esophageal, laryngeal, oral and non-Hodgkin’s lymphoma for males) were inversely correlated to both solar ultraviolet-B (UVB) radiation and rural residence (considered to be indices of vitamin D variation) for white Americans. Another ten types of cancer (bladder, gallbladder, gastric, pancreatic, prostate, rectal, renal, testicular, vulvar and Hodgkin’s lymphoma) were inversely correlated with UVB. It is estimated that 47,000 Americans die prematurely annually from cancer due to vitamin D deficiency. Ten types of cancer were significantly correlated with lung cancer, and six types with alcohol. Hispanic heritage was strongly associated with gallbladder, gastric, and hepatocellular cancer and weakly with four other cancers. Poverty status was inversely correlated with six types of cancer. For black Americans, UVB was inversely correlated with six cancers, while lung cancer was correlated with twelve cancers, urbanization with five, and alcohol with four cancers. In a related work [18], it is shown that dietary sources of vitamin D alone do not provide adequate protection against colorectal cancer – only total vitamin D from UVB, the primary source of vitamin D for Americans, diet and supplements do. The prostate cancer mortality data are consistent with population mean values of vitamin D being associated with minimum risk for prostate cancer. The stomach cancer morality rates show the elevated risk associated with Hispanic heritage along the Mexican border, attributed to high carbohydrate diet. The author is interested in exploring possibilities for joint projects and collaboration with health care professionals in the S.F. Bay Area and elsewhere on research, education, and outreach on the primary prevention of chronic and birth defect diseases through nutrition, lifestyle choices, and ultraviolet radiation and/or vitamin D. The lung cancer mortality rates for black males are higher in the northern states. Lung cancer, an index for smoking, is associated with about 60% of non-lung cancer mortality rates for black males, in agreement with Leistikow, [2004].