www.landesbioscience.com Dermato-Endocrinology 17[Dermato-Endocrinology 1:1, 17-24; January/February 2009]; ©2009 Landes Bioscience
The ultraviolet-B (UVB)—vitamin D—cancer hypothesis was 
proposed in 1980. Since then, several ecological and observational 
studies have examined the hypothesis, in addition to one good randomized, controlled trial. Also, the mechanisms whereby vitamin D reduces the risk of cancer have been elucidated. This report aims to examine the evidence to date with respect to the criteria for causality in a biological system first proposed by Robert Koch and later systematized by A. Bradford Hill. The criteria of most relevance are strength of association, consistency, biological gradient, plausibility/mechanisms and experimental verification. Results for several cancers generally satisfy these criteria. Results for breast and colorectal cancer satisfy the criteria best, but there is also good evidence that other cancers do as well, including bladder, esopha-geal, gallbladder, gastric, ovarian, rectal, renal and uterine corpus cancer, as well as Hodgkin’s and non-Hodgkin’s lymphoma. Several cancers have mixed findings with respect to UVB and/or vitamin D, including pancreatic and prostate cancer and melanoma. Even for these, the benefit of vitamin D seems reasonably strong. Although ecological and observational studies are not generally regarded as able to provide convincing evidence of causality, the fact that humanity has always existed with vitamin D from solar UVB irradiance means that there is a wealth of evidence to be harvested using the ecological and observational approaches. Nonetheless, additional randomized, controlled trials are warranted to further examine the link between vitamin D and cancer incidence, survival and mortality. Introduction
The solar ultraviolet-B (UVB)—vitamin D—cancer hypothesis 
was first proposed in 1980 by Cedric and Frank Garland to explain the geographical variation of colon cancer mortality rates in the United States for 1950–1969, highest in the Northeast and lowest in the Southwest. 1 They showed a rough correlation for the cancer mortality rates with annual hours of sunshine. They later showed that dietary vitamin D and calcium were inversely correlated with colorectal cancer risk
2 as well as prediagnostic serum 25-hydroxyvi-
tamin D [25(OH)D].3 They also linked solar UVB and vitamin D 
to reduced risk of breast4 and ovarian5 cancer. Gary Schwartz added 
prostate cancer in 1990.6 After the publication of the Atlas of Cancer 
Mortality in the United States, 1950–94,7 William Grant determined 
that 14 types of cancer had mortality rates inversely correlated with solar UVB levels for July. 8,9
Much of this pioneering work was accomplished using the 
ecologic approach, in which populations and risk-modifying factors are averaged for geographically defined populations. The ecologic approach is particularly well suited for this particular task for several reasons: solar UVB is the primary source of vitamin D for most people on Earth; the amount of vitamin D generated from casual solar UVB irradiance in summer, sufficient to raise serum 25(OH)D by 10–15 ng/mL,
10,11 is sufficient to reduce the risk of many types 
of cancer by 10%–40%; and vitamin D seems to play an important role in fighting cancer in the disease’s later stages. 12,13
As convincing as the ecologic studies are to those intimately 
involved therewith, they have not met with universal acceptance. Even their having been would still not be sufficient to establish a causal relation between solar UVB, vitamin D production and cancer risk reduction. However, an approach exists that one can use to evaluate whether the association can be considered causal: apply the criteria for causality, originally postulated by Robert Koch to show that tubercu-losis was caused by a bacterium,
14 and codified in recent times by A. 
Bradford Hill.15 Others have also discussed applying these criteria.16,17 
Although these criteria were developed with respect to “causal” rather than to “preventive” agents, there is no a priori reason why most, if not all, criteria would not also apply to preventive agents. The Hill criteria are as follows:(1) Strength of association,(2) Consistency (repeated observation),(3) Specificity (one agent, one result),(4) T emporality (exposure precedes effect),(5) Biological gradient (dose-response relation),(6) Plausibility (e.g., mechanisms),(7) Coherency (no serious conflict with the generally known facts 
of the natural history and biology of the disease),
Correspondence to: William B. Grant; Sunlight, Nutrition and Health Research Center 
(SUNARC); P.O. Box 641603; San Francisco, California 94164-1603 USA; Tel. : 1.415.409.1980; Email: wbgrant@infionline.net
Submitted: 11/09/08; Accepted: 11/10/08Previously published online as a Dermato-Endocrinology E-publication: 
http://www.landesbioscience.com/journals/dermatoendocrinology/article/7388Review
How strong is the evidence that solar ultraviolet B and vitamin D reduce 
the risk of cancer? An examination using Hill’s criteria for causality
William B. Grant
Sunlight Nutrition and Health Research Center (SUNARC); San Francisco, California USA
Key words: association, breast cancer, colon cancer, dose-response, ecologic, mechanisms, observational, supplements, viral infections
Vitamin D and cancer: Causality? In general, the cancers fall under the categories of digestive tract, 
female organs, urogenital organs and hematopoietic cancers. These 
cancers are generally those that are common in Western developed countries. Smoking is an important risk factor for many of these types of cancer,
48 as are diets high in animal products.9,49,50 Among 
other factors, smoking reduces serum 25(OH)D levels.51 Because 
many of these cancers are related to diets high in animal products, insulin-like growth factor I is a likely risk factor. 52 Vitamin D 
compounds can affect the growth-promoting pathways of insulin-like growth factor I. 53 Because these cancers have reasonably high 
incidence and mortality rates, they are easy to study. Evaluation Using Hill’s Criteria for Causality
Strength of association. Satisfying strength of association requires 
a strong correlation between a measure of vitamin D and reduced risk 
of cancer. One index of serum 25(OH)D level is solar UVB dose. Solar UVB is the primary source of vitamin D for most people on Earth, and in summer in the United States and Europe, casual solar UVB irradiance is sufficient to increase serum 25(OH)D levels by 5–15 ng/mL depending on such factors as amount of body surface area exposed, skin pigmentation, age and body mass. 11,23 Reducing 
the risk of breast and colorectal cancer by about 50% requires a vitamin D level of 10–15 ng/mL. 54,55 Thus, summertime solar UVB 
is sufficient to significantly reduce the risk of cancer. Also, those diagnosed in summer or fall in Norway have significantly increased survival rates,
13,32 and vitamin D also reduces the risk of cancer with 
a one year lag time after starting supplementation,12 indicating that 
vitamin D is important in reducing the risk of cancer in the later disease stages. Thus, one can use ecological studies of cancer inci-dence and mortality rates to look for a beneficial effect of vitamin D. Cancer data in the United States are particularly useful in this regard because the solar UVB dose for July
8 is asymmetrical, much higher in 
the western states than in the eastern states at the same latitude. The (8) Experimental verification (randomized, controlled trial) and(9) Analogy with other causal relationships.A link need not satisfy all of these to be considered causal; 
however, the more that are, the better the case that is made. As Poitschman and Weed
16 and Weed17 have indicated, some of these 
criteria are not particularly relevant, such as specificity, which applies more to a microorganism that causes a particular disease. This work aims to evaluate the extant literature on UV irradiance, 
vitamin D and cancer risk reduction for the 16 types of cancer for which the most evidence has been obtained. Approach
Using the National Institutes of Health and National Library of 
Medicine’s PubMed database (http://www.pubmed.gov), we searched the journal literature for reports of correlations with indices for solar UVB and/or vitamin D. Those selected for inclusion in this review generally found a significant correlation with UVB or vitamin D, whether direct or inverse. Those with insignificant correlations generally did not have enough values in the beneficial range to find a significant result, often because until the past several years, 400 IU/day was thought to be an adequate intake of vitamin D for many health benefits. After many such randomized, controlled trials before 2004 failed
18—most notably the 
Women’s Health Initiative, which generally found no benefit of vitamin D and calcium supplementation for hip fractures,
19 colon cancer20 or 
diabetes21—it was realized that an intake level of 400 IU/day has one 
primary benefit: reduced risk of rickets. Some studies, which we discuss as well, reported increased risk of several types of cancer with respect to higher solar UV doses or serum 25(OH)D levels. Findings
Table 1 lists the types of cancer for which a reasonable number of 
ecologic or observational studies have reported a benefit from UVB or vitamin D.
18 Dermato-Endocrinology 2009; Vol. 1 Issue 1Table 1 Sixteen vitamin D-sensitive cancers determined by ecologic and cohort studies by geopolitical region
Cancer North america North america cohort Europe Asia Multicontinent
Esophageal 22, 23, 10, 24 25 26 27, 28
Gastric 22, 23, 10, 24 25* 26 27, 28 29*
Colon 1, 22, 30, 23, 10, 24 25 31, 32, 26 27, 28* 33, 29*
Rectal 22, 23, 10, 24 25 31, 26 27, 28* 29*
Gallbladder 10, 24  26 27
Pancreatic 22, 10, 24 25 31, 26 34, 27, 35 29*
Lung 22, 23 36, 25* 37, 38 28* 29, 39
Breast 4, 22, 30, 23, 10, 24  9, 31, 32, 26, 40
Uterine corpus 22, 10, 24    41
Ovarian 5, 22, 30, 10, 24  31, 26  33, 42, 29*
Vulvar 24, 43
Prostate 6, 22, 30, 10, 24 25* 31, 32  29
Bladder 22, 10, 24 25*   29*
Renal 22, 10, 24 25*   33, 44, 29*
Hodgkin’s lymphoma 10, 24  45, 46, 26
NHL 22, 47, 10, 24 25* 31, 46, 26  33
*Marginally insignificant. References are indicated by numbers. www.landesbioscience.com Dermato-Endocrinology 19Vitamin D and cancer: Causality? index is latitude, found a significant inverse correlation with solar 
UVB for July. Of the 16 types of cancer in Table 1, three have inconsistent 
results in ecological studies: bladder, lung and pancreatic cancer. Bladder cancer had a marginally insignificant inverse correlation with UVB in the air pollution study,
56 and smoking is an important 
risk factor for bladder cancer.48 Lung cancer is strongly linked to 
smoking, but as discussed later some evidence indicates that vitamin D reduces this risk. Pancreatic cancer was directly correlated with latitude in Spain as well as in Japan. 27,34,35
The cohort study by Giovannucci et al.60 also examined the corre-
lation between a vitamin D index and cancer incidence in the Health Professionals Follow-Up Study of 50,000 male physicians. Those types with a significant inverse correlation were colorectal, esopha-geal, oral/pharyngeal and pancreatic cancer, as well as leukemia. Those with insignificant inverse correlation were gastric, lung, pros-tate (advanced) and renal cancer, as well as NHL. Differences in cancer risk with respect to skin pigmentation can 
also support the UVB—vitamin D—cancer theory because black Americans produce vitamin D from UVB irradiance at about 20% of the efficiency of white Americans. 61 In the southeastern United 
States, hypovitaminosis D prevalence was 45% among blacks and 11% among whites. 62 In ecological studies of cancer mortality rates 
in the United States,22,23 solar UVB was inversely correlated with 
several cancers for black Americans; however, the latitudes with similar mortality rates for cancers such as breast and colon were several degrees lower for black Americans than for white Americans. 7 
In the Health Professionals Follow-Up Study, black American men with additional risk factors for poorer vitamin D status had a much higher cancer incidence (relative risk = 1.57; 95% CI, 1.16–2.11) and mortality risk (relative risk = 2.27; 95% CI, 1.57–3.28). 60
For four types of cancer, UVB and/or vitamin D has directly 
correlated with incidence or mortality rates: esophageal, pancreatic and prostate cancer, as well as NHL. We now examine such studies to see whether they contradict the UVB—vitamin D—cancer theory. T wo studies reported that vitamin D was directly correlated 
with incidence of esophageal squamous dysplasia
63 and esophageal 
cancer64 in Linxian, China, a population at high risk for developing 
esophageal squamous cell carcinoma. Human papillomavirus is an important risk factor in regions with high esophageal cancer rates in China. 65,66 Human papillomavirus is also linked to risk of NMSC 
and UVB irradiance.67 The finding that higher vitamin D correlated 
with increased risk of esophageal cancer for men but not women in China
64 is consistent with men working out of doors more. Several studies have found an inverse correlation between indices 
for solar UVB and/or vitamin D and pancreatic cancer.10,26,27,34,35,68 
However, a study of male Finnish smokers, aged 50–69 years at base-line, found that higher serum 25(OH)D at baseline was associated with a threefold increased risk of pancreatic cancer during an up to 16.7-year follow-up period (highest versus lowest quintile, >26.2 ng/mL versus <12.8 ng/mL; odds ratio, 2.92; 95% CI, 1.56–5.48; p
trend 
= 0.001).69 With many articles reporting a beneficial role of UVB 
and vitamin D, perhaps some unusual factors in Finland affected the Finnish study. Prostate cancer mortality rates have a different geographical varia-
tion in the United States from that of the preceding 12 types of cancer. It has high mortality rates across the entire northern United States reasons are twofold: the surface elevation is generally higher in the western states, and the stratospheric ozone layer is thinner because the prevailing westerly winds push the tropopause higher as the air masses prepare to cross the Rocky Mountains. One can use several ecological studies to examine strength of 
association for many types of cancer: studies using an index for solar UVB for cancer mortality rates
22 or incidence and mortality rates24 
and multifactorial studies of cancer mortality rates.10,33,43 Grant 
and Garland’s10 multifactorial study included additional indices for 
alcohol consumption, ethnic background, poverty, smoking and urban/rural residence. The associations with solar UVB remained similar to those in the original study. 22 The associations with the 
other risk-modifying factors were in general agreement with the literature. However, when the study added an index for air pollution, acid rain for 1985, solar UVB was no longer a significant risk reduc-tion factor for the respiratory cancers. 56
A related study used annual average erythemal UV doses measured 
by a NASA satellite with cancer incidence and mortality rates in the United States for 1998–2002. 24 Cancers with the strongest 
correlations with UV were bladder, colon, esophageal, gallbladder, other biliary, prostate, rectal and vulva cancer, as well as Hodgkin’s lymphoma and multiple myeloma. Cancers with weaker correlations were breast, kidney, small intestine and thyroid cancer, as well as leukemia and non-Hodgkin’s lymphoma (NHL). For two reasons, the cancers best satisfying this criterion are 
colorectal and breast cancer. First, the statistics are robust because of the high incidence and mortality rates; second, the other risk-modifying factors, such as smoking for colon cancer and alcohol consumption for breast cancer, are less important. Meta-analyses of observational studies have established dose-
response relations for serum 25(OH)D and reduced risk of cancer incidence for both colorectal
54 and breast54,57 cancers. Also, in a meta-analysis of 10 case-control studies covering a 
total of 8,243 cases and 9,697 control subjects in the United States, Europe and Australia, risk of NHL fell significantly. The composite measure of increasing recreational sun exposure (pooled odds ratio) was 0.76 (95% confidence interval [CI], 0.63–0.91) for the highest exposure category (p
trend = 0.01).58
Consistency (repeated observation). For consistency (repeated 
observation), we examined ecologic studies because several looked at many cancer types. In addition to the studies listed in the previous section, an ecologic study of cancer mortality rates in Spain used nonmelanoma skin cancer (NMSC) mortality rates and latitude as the indices of solar UVB irradiance and dose. 26,59 The cancers 
with large significant inverse correlations with UVB indices in all four studies if iron, zinc and air pollution were also risk-modifying factors are breast, colon, esophageal, gallbladder, gastric, ovarian and rectal cancer, as well as Hodgkin’s lymphoma and NHL. Renal and uterine corpus cancers were inversely correlated with UVB in the United States but not in Spain. Also, vulvar cancer, which Grant and Garland
10 did not include, was significantly inversely 
correlated with UVB in the iron and zinc study,43 as well as in 
Boscoe and Schymura’s ecologic study of cancer incidence and mortality rates for 1998–2002. 24 Also, evidence that vitamin D 
reduces the risk of melanoma is mounting. Thus, there are 12 types of cancer for which ecologic studies of cancer mortality rates in the United States for 1970–1994, and one for which the UVB 
20 Dermato-Endocrinology 2009; Vol. 1 Issue 1Vitamin D and cancer: Causality? research is the time lag between vitamin D increases and cancer 
risk reduction. Cancer can take anywhere from several years to several decades to progress from initiation to clinical detection or death. Vitamin D could play a role in reducing cancer initiation, such as for cancers linked to viruses (Epstein-Barr virus [EBV]) for Hodgkin’s lymphoma and probably for several others. 76 As 
mentioned, early life UVB irradiance was inversely correlated with prostate cancer risk. 73
Vitamin D also seems to play an important role late in the 
development of cancer. The vitamin D and calcium randomized, controlled trial by Lappe et al. 12 found a 77% reduction in all-
cancer risk for postmenopausal women between the ends of the first and fourth years, of which 35% was attributed to vitamin D. Because most cancers take 15–20 years to proceed from initiation to clinical detection, this study is consistent with an important role in cancer prevention at the later stages of development, possibly through antiangiogenesis
101 and antimetastasis102 mechanisms. The series of studies in Norway finding increased survival rates for those diagnosed with cancer in summer or fall compared with winter or spring for breast cancer, colorectal cancer, prostate cancer and Hodgkin’s lymphoma
13 also support the role of vitamin D 
late in cancer. Some observational studies also reported increased survival rates associated with higher serum 25(OH)D levels, as for colorectal cancer
103 and breast cancer. In a study of postmeno-
pausal Canadian women, distant disease-free survival during a period of up to 17 years was significantly worse in women with prediagnostic deficient (<20 ng/mL) versus adequate (>29 ng/mL) serum 25(OH)D levels [hazard ratio (HR) = 1.94, 95% CI, 1.16–3.24; p = 0.02], as was overall survival (HR = 1.73, 95% CI, 1.05–2.86; p = 0.02). 104
Biological gradient (dose-response relation). Demonstrating a 
dose-response relation, preferably linear, between vitamin D and cancer risk is important for supporting vitamin D’s beneficial role. Meta-analyses of case-control data have determined dose-response relations for serum calcidiol levels and incidence of breast and colon cancer. For colorectal cancer, a 50% lower risk of colorectal cancer was associated with a serum 25(OH)D level of at least 33 ng/mL compared with 12 ng/mL or less. 55 For breast cancer, a meta-analysis 
found that serum 25(OH)D of approximately 52 ng/mL had 50% lower risk of breast cancer than those with a serum level less than 13 ng/mL. 54 However, the dose-response relation in Abbas et al.57 was 
similar to that for colorectal cancer. Many vitamin D supplementation studies found no benefit in 
reducing the risk of cancer from using too little vitamin D, generally about 400 IU/day, as reviewed in Grant and Garland. 18 Even the 
Women’s Health Initiative study, started in the mid-1990s, used too little vitamin D (400 IU/day) and generally found no benefit for colorectal cancer,
20 hip fractures19 or diabetes.21 However, there was 
a positive finding for colorectal cancer when estrogen therapy was also considered. 105
Some evidence now exists that the vitamin D dose–cancer 
response relation for breast cancer is nonlinear, with a threshold effect at about 20 ng/mL. 57 This finding may help explain why 400 IU/
day seemingly has no effect on cancer rates. Evidently serum vitamin D metabolites are used for an endocrine mechanism (regulation of calcium absorption) before they are used for autocrine mechanisms (facilitation of gene expression). 106and low rates in all southern states. Prostate cancer is also unusual for vitamin D-sensitive cancers in that prediagnostic serum 25(OH)D has generally been found uncorrelated with incidence of prostate cancer;
70 however, it has also been found associated with increased 
risk29,71 and decreased risk.29,72 However, early life UVB is protec-
tive,73 as is UVB around the time of cancer discovery,74 suggesting 
that vitamin D may inhibit metastasis. Ecologic studies have consis-tently found an inverse correlation of prostate cancer with latitude. 75 
Grant hypothesized that the geographic variation of prostate cancer mortality rates in the United States is related to a viral risk that is more common in winter and that higher serum 25(OH)D levels in winter reduce the risk of such infections. 76,77 An ecologic study determining 
that prostate cancer is diagnosed more often in winter supports this hypothesis. 78 Stat3 is involved in prostate cancer metastasis.79 Grant 
showed that vitamin D can block Stat3, which might explain why vitamin D is beneficial once prostate cancer is discovered. 80
Solar UV has been correlated with risk of NHL in the United 
Kingdom.81 However, further study determined that other factors, 
such as economic status, were probably confounders.82 The most recent 
analysis concludes that UVB irradiance reduces the risk of NHL.58
Evidence that vitamin D reduces the risk of lung cancer is limited. An observational study of early-stage non-small-cell lung cancer (NSCLC) associated higher serum 25(OH)D levels with increased survival. 83 However, in advanced NSCLC, survival depended on 
vitamin D receptor alleles rather than on circulating serum 25(OH)D levels. 84 In Norway, there is no survival advantage for discovery of 
NSCLC in summer or fall compared with winter or spring.13 In an 
ecological study involving 111 countries, lung cancer was inversely correlated with indices of solar UVB. 39 However, this study did not 
consider dietary factors, which may have affected the finding because dietary fat seems to be a risk factor for lung cancer. 85 A recent cohort 
study in Finland found serum 25(OH)D level was inversely associated with lung cancer incidence for women [RR, 0.16; 95% CI, 0.04–0.59; P(trend) < 0.001] and younger participants [RR, 0.34; 95% CI, 0.13–0.90; P(trend) = 0.04] but not for men [RR, 1.03; 95% CI, 0.59–1.82; P(trend) = 0.81] or older individuals [RR, 0.92; 95% CI, 0.50–1.70; P(trend) = 0.79]. 86 Thus, there is modest evidence that 
higher serum 25(OH)D levels confer protection against lung cancer. Melanoma is an interesting cancer with respect to UV irradi-
ance and vitamin D. Studies have found good evidence that UVA, not UVB, is the primary risk factor for melanoma. 87-92 Also, good 
evidence exists that vitamin D reduces the risk of melanoma,93 
including findings related to diet,94 sunlight,95 NMSC,26 blocking 
solar UVB92 and vitamin D receptor alleles.96 Also, melanoma 
mortality rates increase with increasing latitude in Europe,97 which 
reflects an effect of skin pigmentation, UVA and UVB.87 UVA is 
also a double-edged sword in that it also produces elastosis, which reduces the risk of melanoma as evidenced by melanoma’s devel-oping later in life on the face and neck rather than on the trunk and legs. 98 Smoking also produces elastosis, which seems to explain why 
smokers have a reduced risk of developing melanoma.56
Specificity (one agent, one result). Specificity (one agent, one 
result) does not apply to vitamin D because it has benefits for many types of disease ranging from cardiovascular diseases to infectious diseases. 99,100
Temporality (exposure precedes effect). Temporality (exposure 
precedes effect) is generally satisfied. However, a topic of ongoing 
www.landesbioscience.com Dermato-Endocrinology 21Vitamin D and cancer: Causality? Analogy with other causal relationships. Analogy is a double-
edged sword for vitamin D and risk of cancer incidence or mortality 
rate. On the positive side, I used the principle of analogy when I viewed the Atlas of Cancer Mortality in the United States, 1950–94. 7 
Many cancers had geographical variations in mortality rate similar to those of cancers well known to be vitamin D sensitive, such as breast and colon cancer. I concluded that most of them were, therefore, also vitamin D sensitive. 22
On the negative side, some studies have suggested that various 
vitamins reduce the risk of cancer only to learn after randomized, controlled trials that they did not. The best known case is that of beta carotene. Early studies of beta carotene found an inverse rela-tion for lung cancer with respect to dietary intake for smokers
118 
and nonsmokers.119 However, when beta carotene supplements 
were taken, smokers had increased risk of lung cancer.120 For beta 
carotene, it was one component of vegetables in the diet; as far as is known, vitamin D production is the only beneficial effect of solar UVB irradiance. Response to Criticisms of the Ecological Approach
At a World Health Organization meeting in Munich in 2005, 
dermatologists expressed their opinion that ecological studies using solar UVB doses as the index of vitamin D were perhaps incorrect in that irradiance was not always correlated with dose. That state-ment spurred Grant to find a personal index of solar UVB irradiance. Because integrated lifetime UVB irradiance is the primary risk factor for squamous cell carcinoma (SCC), it seemed that incidence or death from SCC would be a suitable marker for long-term UVB irradiance. Basal cell carcinoma (BCC) is linked to both UVB and UVA irradiance, so it is also a useful index; however, melanoma is linked to UVA irradiance,
121 so it is not a useful indicator. The first 
report in this series was a meta-analysis of studies of second cancer after development of BCC, SCC or melanoma. 122 The studies had 
to be adjusted according to smoking among each population because smoking is a risk factor for both BCC and SCC but reduces the risk of melanoma. 123 Several cancers had incidence rates inversely correlated 
with BCC and/or SCC when adjusted for smoking. This study led to an ecologic study of cancer mortality rates in Spain that used NMSC as the index of solar UVB irradiance. 26 A total of 17 types of cancer 
were inversely correlated with NMSC in a linear regression analysis. However, when latitude and lung cancer mortality rate, the index used for smoking, were used with NMSC in a multiple linear regression analysis, bladder and renal cancer were no longer significantly corre-lated with NMSC. 59 Then a study of solid tumor development after 
diagnosis of BCC, SCC or melanoma for sunny and less sunny coun-tries was reported. 29 For three countries equatorward of 40°, incidence 
of solid tumors is reduced after diagnosis of BCC or SCC, whereas for countries poleward of 40°, incidence is increased. The interpretation is that in the sunny countries, people can expose enough skin to produce sufficient vitamin D to reduce the risk of cancer, whereas in the less sunny countries, not enough skin is exposed. 124
Summary and Conclusion
The solar UVB—vitamin D—cancer theory now satisfies most, 
if not all, of the criteria for causality in a biological system as initially postulated by Robert Koch and expanded by A. Bradford Hill. Thus, from a scientific point of view, vitamin D reduces the Plausibility. The mechanisms whereby vitamin D reduces the risk 
of cancer are generally well known. These mechanisms include effects on cells such as improved differentiation and apoptosis, as well as effects at the tumor level such as antiangiogenesis
101 and antimetas-
tasis.102 One can find thorough reviews in several reports.107-110
Grant recently proposed that vitamin D, through strengthening 
the innate immune system, reduces the risk of viral infections that 
lead to cancer. The basis for this hypothesis was that the prostate cancer mortality rate distribution in the United States varies with latitude in a manner similar to that for multiple sclerosis. EBV is an important risk factor for multiple sclerosis. 111 EBV has also 
been associated with gastric, prostate and thyroid cancer, as well as Hodgkin’s lymphoma and NHL, with references given in Grant. 76 
These cancers, as well as testicular cancer and multiple myeloma, have the square of latitude correlated with mortality rate for 1950–1969, and some do for 1970–1994. Because latitude is an index of wintertime vitamin D production from solar UVB irradiance, and winter is the period of many viral infections such as EBV
112 and 
influenza,113 this hypothesis is reasonable. Evaluating this hypothesis 
will, of course, require more work. Coherency (no serious conflict with the generally known facts of 
the natural history and biology of the disease). Coherency is gener-
ally satisfied. However, it may not be useful because the Koch and Hill criteria may be more directly related to increased risk due to an agent rather than decreased risk due to a preventive agent. Experiment. For the association between UVB and vitamin D, 
experimentation in general means a randomized, controlled trial. T wo such trials were successful. In one, the primary outcome was fracture incidence, and the principal secondary outcome was cancer incidence. 12 The subjects were 1179 community-dwelling women 
randomly selected from the population of healthy postmenopausal women aged more than 55 years in a nine-county rural area of Nebraska centered at latitude 41.4° N. Subjects were randomly assigned to receive 1400–1500 mg of supplemental calcium/day alone (Ca only), supplemental calcium plus 1100 IU of vitamin D3/day (Ca + D), or placebo. Between the end of the first and fourth years, those taking both calcium and vitamin D had a 77% lower all-cancer incidence than those taking the placebo. Thirty-five percent of the cancer risk reduction was attributed to vitamin D, with the rest to calcium. Because of the study’s short duration, one might question the 
Lappe et al. 12 study. However, a response might be that vitamin D 
is much more effective in reducing the risk of cancer in the later 
stages than in the earlier stages, unless through combating infections that could lead to cancer. Survival for breast, colorectal and pros-tate cancer and Hodgkin’s lymphoma in Norway is better for those diagnosed in summer or fall rather than winter or spring,
13 thereby 
providing evidence for a greater benefit at the later stages of disease. In a reanalysis of results of 400-IU/day vitamin D supplemen-
tation in the Women’s Health Initiative Study, among women concurrently assigned to placebo arms of the estrogen trials, calcium plus vitamin D indicated suggestive benefits (HR = 0.71, 95% CI, 0.46–1.09; p
estrogen interaction = 0.018).105
Another line of experimental verification is to study the role of 
vitamin D on cancer by using animal models.114-116 For example, in 
a colon cancer xenograft experiment, vitamin D metabolites slowed tumor growth. 117
22 Dermato-Endocrinology 2009; Vol. 1 Issue 1Vitamin D and cancer: Causality? 21. de Boer IH, Tinker LF , Connelly S, Curb JD, Howard BV , Kestenbaum B, et al. Calcium 
plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care 2008; 31:701-7. 22. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer 2002; 94:1867-75. 23. Grant WB. Lower vitamin-D production from solar ultraviolet-B irradiance may explain some differences in cancer survival rates. J Natl Med Assoc 2006; 98:357-64. 24. Boscoe FP , Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993–2002. BMC Cancer 2006; 6:264. 25. Giovannucci E, Liu Y, Rimm EB, Hollis BW , Fuchs CS, Stampfer MJ, et al. Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006; 98:451-9. 26. Grant WB. An ecologic study of cancer mortality rates in Spain with respect to indices of solar UVB irradiance and smoking. Int J Cancer 2007; 120:1123-8. 27. Mizoue T . Ecological study of solar radiation and cancer mortality in Japan. Health Phys 2004; 87:532-8. 28. Grant WB. Does solar ultraviolet irradiation affect cancer mortality rates in China? Asian Pac J Cancer Prev 2007; 8:236-42. 29. T uohimaa P , Pukkala E, Scélo G, Olsen JH, Brewster DH, Hemminki K, et al. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: Vitamin D as a possible explanation. Eur J Cancer 2007; 43:1701-12. 30. 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; 59:257-62. 31. Grant WB. Ecologic studies of solar UV-B radiation and cancer mortality rates. Recent Results Cancer Res 2003; 164:371-7. 32. Robsahm TE, T retli S, Dahlback A, Moan J. Vitamin D3 from sunlight may improve the prognosis of breast-, colon- and prostate cancer (Norway). Cancer Causes Control 2004; 15:149-58. 33. Grant WB. The likely role of vitamin D from solar ultraviolet-B irradiance in increasing cancer survival. Anticancer Res 2006; 26:2605-14. 34. Kato I, Tajima K, Kuroishi T , T ominaga S. Latitude and pancreatic cancer. Jpn J Clin Oncol 1985; 15:403-13. 35. Kinoshita S, Wagatsuma Y, Okada M. Geographical distribution for malignant neoplasm of the pancreas in relation to selected climatic factors in Japan. Int J Health Geogr 2007; 6:34. 36. Zhou W , Suk R, Liu G, Park S, Neuberg DS, Wain JC, et al. Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev 2005; 14:2303-9. 37. Lim HS, Roychoudhuri R, Peto J, Schwartz G, Baade P , Moller H. Cancer survival is dependent on season of diagnosis and sunlight exposure. Int J Cancer 2006; 119:1530-6. 38. Porojnicu AC, Robsahm TE, Dahlback A, Berg JP , Christiani D, Bruland OS, et al. Seasonal and geographical variations in lung cancer prognosis in Norway. Does vitamin D from the sun play a role? Lung Cancer 2007; 55:263-70. 39. Mohr SB, Garland CF , Gorham ED, Grant WB, Garland FC. Could ultraviolet B irradi-ance and vitamin D be associated with lower incidence rates of lung cancer? J Epidemiol Community Health 2008; 62:69-74. 40. Porojnicu AC, Lagunova Z, Robsahm TE, Berg JP , Dahlback A, Moan J. Changes in risk of death from breast cancer with season and latitude: Sun exposure and breast cancer survival in Norway. Breast Cancer Res T reat 2007; 102:323-8. 41. Mohr SB, Garland CF , Gorham ED, Grant WB, Garland FC. Is ultraviolet B irradiance inversely associated with incidence rates of endometrial cancer: an ecological study of 107 countries. Prev Med 2007; 45:327-31. 42. Garland CF , Mohr SB, Gorham ED, Grant WB, Garland FC. Role of ultraviolet B irradi-ance and vitamin D in prevention of ovarian cancer. Am J Prev Med 2006; 31:512-4. 43. Grant WB. An ecological study of cancer mortality rates including indices for dietary iron and zinc. Anticancer Res 2008; 28:1955-63. 44. Mohr SB, Gorham ED, Garland CF , Grant WB, Garland FC. Are low ultraviolet B and high animal protein intake associated with risk of renal cancer? Int J Cancer 2006; 119:2705-9. 45. Porojnicu AC, Robsahm TE, Ree AH, Moan J. Season of diagnosis is a prognostic factor in Hodgkin’s lymphoma: A possible role of sun-induced vitamin D. Br J Cancer 2005; 93:571-4. 46. Smedby KE, Hjalgrim H, Melbye M, T orrang A, Rostgaard K, Munksgaard L, et al. Ultraviolet radiation exposure and risk of malignant lymphomas. J Natl Cancer Inst 2005; 
97:199-209. 47. Hu S, Ma F , Collado-Mesa F , Kirsner RS. Ultraviolet radiation and incidence of non-Hodgkin’s lymphoma among Hispanics in the United States. Cancer Epidemiol Biomarkers Prev 2004; 13:59-64. 48. Sasco AJ, Secretan MB, Straif K. T obacco smoking and cancer: A brief review of recent epidemiological evidence. Lung Cancer 2004; 45:3-9. 49. Armstrong B, Doll R. Environmental factors and cancer incidence and mortality in different countries, with special reference to dietary practices. Int J Cancer 1975; 15:617-31. 50. Grant WB. A multicountry ecologic study of risk and risk reduction factors for prostate cancer mortality. Eur Urol 2004; 45:271-9. 51. Brot C, Jorgensen NR, Sorensen OH. The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr 1999; 53:920-6.risk of developing many types of cancer and increases survival once 
cancer reaches the detectable stage. Unfortunately, health policy often lags scientific discoveries by years to decades. An example from the mid-19
th century was the discovery by Ignaz Semmelweis 
that doctors carried germs from autopsies to women giving birth and infected them, resulting in puerperal sepsis. 125 A more recent 
example is the announcement by Barry Marshall and Robin Warren that Helicobacter pylori caused stomach ulcers. Although Marshall 
infected himself with H. pylori in 1981 and developed an ulcer,
126 he 
concluded by 1995 that Koch’s postulates were not well satisfied.127 
However, in 2005, Marshall and Warren were awarded the Nobel Prize in Medicine. It is hoped that the acceptance of the beneficial role of vitamin D in reducing the risk of cancer and many other diseases will not have to wait much longer. It is encouraging that the National Academy of Sciences’ Institute of Medicine (http://www.iom.edu) is embarking on a two year study of vitamin D dietary requirements and is expected to issue a report in October 2010. Acknowledgements
W .B.G receives funding from the UV Foundation (McLean, 
VA), the Vitamin D Society (Canada), and the European Sunlight Association (Brussels). References
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Nakagawa K, Kawaura A, Kato S, Takeda E, Okano T . 1a,25-dihydroxyvitamin D(3) is a preventive factor in the metastasis of lung cancer. Carcinogenesis 2005; 26:429-40. 103. Ng K, Meyerhardt JA, Wu K, Feskanich D, Hollis BW , Giovannucci EL, et al. Circulating 25-hydroxyvitamin D levels and survival in patients with colorectal cancer. J Clin Oncol 2008; 26:2984-91. 104. Goodwin PJ, Ennis M, Pritchard KI, Koo J, Hood N. Frequency of vitamin D (Vit D) deficiency at breast cancer (BC) diagnosis and association with risk of distant recurrence and death in a prospective cohort study of T1-3, N0-1, M0 BC. J Clin Oncol 2008; 26:511. 105. Ding EL, Mehta S, Fawzi WW , Giovannucci EL. Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: Reanalysis of Women’s Health Initiative randomized trial. Int J Cancer 2008; 122:1690-4. 106. Heaney RP . Vitamin D in health and disease. Clin J Am Soc Nephrol 2008; 3:1535-41. 107. van den Bemd GJ, Pols HA, van Leeuwen JP . Anti-tumor effects of 1,25-dihydroxyvitamin D3 and vitamin D analogs. Curr Pharm Des 2000; 6:717-32. 108. Krishnan AV , Peehl DM, Feldman D. Inhibition of prostate cancer growth by vitamin D: Regulation of target gene expression. J Cell Biochem 2003; 88:363-71. 109. Lamprecht SA, Lipkin M. Chemoprevention of colon cancer by calcium, vitamin D and folate: Molecular mechanisms. Nat Rev Cancer 2003; 3:601-14. 110. Ingraham BA, Bragdon B, Nohe A. Molecular basis of the potential of vitamin D to prevent cancer. Curr Med Res Opin 2008; 24:139-49. 111. Ascherio A, Munger KL. Environmental risk factors for multiple sclerosis. Part I: The role of infection. Ann Neurol 2007; 61:288-99. 112. Douglas AS, Brown T , Reid D. Infectious mononucleosis and Hodgkin’s disease—A similar seasonality. Leuk Lymphoma 1996; 23:323-31. 113. Cannell JJ, Vieth R, Umhau JC, Holick MF , Grant WB, Madronich S, et al. Epidemic influenza and vitamin D. Epidemiol Infect 2006; 134:1129-40. 114. Welsh J. Vitamin D and breast cancer: Insights from animal models. Am J Clin Nutr 2004; 80:1721-4. 115. Welsh J. Targets of vitamin D receptor signaling in the mammary gland. J Bone Miner Res 2007; 22:86-90. 52. Giovannucci E. Nutrition, insulin, insulin-like growth factors and cancer. Horm Metab Res 2003; 35:694-704. 53. Lowe L, Hansen CM, Senaratne S, Colston KW . Mechanisms implicated in the growth regulatory effects of vitamin D compounds in breast cancer cells. Recent Results Cancer Res 2003; 164:99-110. 54. Garland CF , Gorham ED, Mohr SB, Grant WB, Giovannucci EL, Lipkin M, et al. Vitamin D and prevention of breast cancer: Pooled analysis. J Steroid Biochem Mol Biol 2007; 103:708-11. 55. Gorham ED, Garland CF , Garland FC, Grant WB, Mohr SB, Lipkin M, et al. Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. Am J Prev Med 2007; 32:210-6. 56. Grant WB. Air pollution in relation to U.S. cancer mortality rates: An ecological study; likely role of carbonaceous aerosols and polycyclic aromatic hydrocarbons. Anticancer Res 2008; In press. 57. Abbas S, Linseisen J, Slanger T , Kropp S, Mutschelknauss EJ, Flesch-Janys D, et al. Serum 25-hydroxyvitamin D and risk of post-menopausal breast cancer—results of a large case-control study. Carcinogenesis 2008; 29:93-9. 58. Kricker A, Armstrong BK, Hughes AM, Goumas C, Smedby KE, Zheng T , et al. Personal sun exposure and risk of non Hodgkin lymphoma: A pooled analysis from the Interlymph Consortium. Int J Cancer 2008; 122:144-54. 59. Grant WB. The health benefits of solar irradiance and vitamin D and the consequences of their deprivation. In: Holick MF , editor. Vitamin D—Physiology, Molecular Biology and Clinical Applications. New Jersey: Springer; 2009, in press. 60. Giovannucci E, Liu Y, Willett WC. Cancer incidence and mortality and vitamin D in black and white male health professionals. Cancer Epidemiol Biomarkers Prev 2006; 15:2467-72. 61. Clemens TL, Adams JS, Henderson SL, Holick MF . Increased skin pigment reduces the capacity of skin to synthesise vitamin D3. Lancet 1982; 1:74-6. 62. Egan KM, Signorello LB, Munro HM, Hargreaves MK, Hollis BW , Blot WJ. Vitamin D insufficiency among African-Americans in the southeastern United States: Implications for cancer disparities (United States). Cancer Causes Control 2008; 19:527-35. 63. Abnet CC, Chen W , Dawsey SM, Wei WQ, Roth MJ, Liu B, et al. Serum 25(OH)-vitamin D concentration and risk of esophageal squamous dysplasia. Cancer Epidemiol Biomarkers Prev 2007; 16:1889-93. 64. Chen W , Dawsey SM, Qiao YL, Mark SD, Dong ZW , Taylor PR, et al. Prospective study of serum 25(OH)-vitamin D concentration and risk of oesophageal and gastric cancers. Br J Cancer 2007; 97:123-8. 65. Lu XM, Monnier-Benoit S, Mo LZ, Xu SY, Pretet JL, Liu Z, et al. Human papillomavirus in esophageal squamous cell carcinoma of the high-risk Kazakh ethnic group in Xinjiang, China. Eur J Surg Oncol 2008; 34:765-70. 66. Shuyama K, Castillo A, Aguayo F , Sun Q, Khan N, Koriyama C, Akiba S. Human papil-lomavirus in high- and low-risk areas of oesophageal squamous cell carcinoma in China. Br J Cancer 2007; 96:1554-9. 67. Nindl I, 
Gottschling M, Stockfleth E. Human papillomaviruses and non-melanoma skin 
cancer: Basic virology and clinical manifestations. Dis Markers 2007; 23:247-59. 68. Skinner HG, Michaud DS, Giovannucci E, Willett WC, Colditz GA, Fuchs CS. Vitamin D intake and the risk for pancreatic cancer in two cohort studies. Cancer Epidemiol Biomarkers Prev 2006; 15:1688-95. 69. Stolzenberg-Solomon RZ, Vieth R, Azad A, Pietinen P , Taylor PR, Virtamo J, et al. A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers. Cancer Res 2006; 66:10213-9. 70. Nomura AM, Stemmermann GN, Lee J, Kolonel LN, Chen TC, T urner A, et al. Serum vitamin D metabolite levels and the subsequent development of prostate cancer (Hawaii, United States). Cancer Causes Control 1998; 9:425-32. 71. Ahn J, Peters U, Albanes D, Purdue MP , Abnet CC, Chatterjee N, et al. Serum vitamin D concentration and prostate cancer risk: A nested case-control study. J Natl Cancer Inst 2008; 100:796-804. 72. Li H, Stampfer MJ, Hollis JB, Mucci LA, Gaziano JM, Hunter D, et al. A prospective study of plasma vitamin D metabolites, vitamin D receptor polymorphisms and prostate cancer. PLoS Med 2007; 4:103. 73. John EM, Koo J, Schwartz GG. Sun exposure and prostate cancer risk: Evidence for a pro-tective effect of early-life exposure. Cancer Epidemiol Biomarkers Prev 2007; 16:1283-6. 74. Lagunova Z, Porojnicu AC, Dahlback A, Berg JP , Beer TM, Moan J. Prostate cancer survival is dependent on season of diagnosis. Prostate 2007; 67:1362-70. 75. Schwartz GG, Hanchette CL. UV , latitude and spatial trends in prostate cancer mortality: All sunlight is not the same (United States). Cancer Causes Control 2006; 17:1091-101. 76. Grant WB. Possible role of vitamin D-sensitive infections in cancer risk. Anticancer Res 
2008; In press. 77. Grant WB. Response to comments by Norval and Woods to my hypothesis regarding vita-min D viral infections and their Sequelae. Photochem Photobiol 2008; 84:806-8. 78. Colli JL, Grant WB. Solar ultraviolet B radiation compared with prostate cancer incidence and mortality rates in United States. Urology 2008; 71:531-5. 79. Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, et al. Stat3 promotes metastatic progression of prostate cancer. Am J Pathol 2008; 172:1717-28. 80. Grant WB. Vitamin D may reduce prostate cancer metastasis by several mechanisms includ-ing blocking Stat3. Am J Pathol 2008; 173:1589-90. 81. Bentham G. Association between incidence of non-Hodgkin’s lymphoma and solar ultravio-let radiation in England and Wales. BMJ 1996; 312:1128-31. 24 Dermato-Endocrinology 2009; Vol. 1 Issue 1Vitamin D and cancer: Causality? 116. Welsh J. Vitamin D and prevention of breast cancer. Acta Pharmacol Sin 2007; 28:1373-82. 117. Tangpricha V , Spina C, Yao M, Chen TC, Wolfe MM, Holick MF . Vitamin D deficiency 
enhances the growth of MC-26 colon cancer xenografts in Balb/c mice. J Nutr 2005; 135:2350-4. 118. Shekelle RB, Lepper M, Liu S, Maliza C, Raynor WJ Jr, Rossof AH, et al. Dietary vitamin A and risk of cancer in the Western Electric study. Lancet 1981; 2:1185-90. 119. Mayne ST , Janerich DT , Greenwald P , Chorost S, T ucci C, Zaman MB, et al. Dietary beta carotene and lung cancer risk in U.S. nonsmokers. J Natl Cancer Inst 1994; 86:33-8. 120. Albanes D, Heinonen OP , Taylor PR, Virtamo J, Edwards BK, Rautalahti M, et al. Alpha-T ocopherol and beta-carotene supplements and lung cancer incidence in the alpha-tocopherol, beta-carotene cancer prevention study: Effects of base-line characteristics and study compliance. J Natl Cancer Inst 1996; 88:1560-70. 121. Moan J, Porojnicu AC, Dahlback A. Ultraviolet radiation and malignant melanoma. Adv Exp Med Biol 2008; 624:104-16. 122. Grant WB. A meta-analysis of second cancers after a diagnosis of nonmelanoma skin cancer: Additional evidence that solar ultraviolet-B irradiance reduces the risk of internal cancers. J Steroid Biochem Mol Biol 2007; 103:668-74. 123. Grant WB. Skin aging from ultraviolet irradiance and smoking reduces risk of melanoma: Epidemiological evidence. Anticancer Res 2008; in press. 124. Grant WB. The effect of solar UVB doses and vitamin D production, skin cancer action spectra and smoking in explaining links between skin cancers and solid tumours. Eur J Cancer 2008; 44:12-5. 125. Noakes TD, Borresen J, Hew-Butler T , Lambert MI, Jordaan E. Semmelweis and the aetiol-ogy of puerperal sepsis 160 years on: An historical review. Epidemiol Infect 2008; 136:1-9. 126. Marshall B. Helicobacter connections. Chem Med Chem 2006; 1:783-802. 127. Marshall BJ. Helicobacter pylori in peptic ulcer: Have Koch’s postulates been fulfilled? Ann 
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Vitamin_D_and_cancer.txt
Summarize the following text section accurately and concisely. Maintain specific details and numerical information, and use anti-repetition mechanisms:

        www. landesbioscience. com Dermato-Endocrinology 17[Dermato-Endocrinology 1:1, 17-24; January/February 2009]; ©2009 Landes Bioscience
The ultraviolet-B (UVB)—vitamin D—cancer hypothesis was 
proposed in 1980. Since then, several ecological and observational 
studies have examined the hypothesis, in addition to one good randomized, controlled trial. Also, the mechanisms whereby vitamin D reduces the risk of cancer have been elucidated. This report aims to examine the evidence to date with respect to the criteria for causality in a biological system first proposed by Robert Koch and later systematized by A. Bradford Hill. The criteria of most relevance are strength of association, consistency, biological gradient, plausibility/mechanisms and experimental verification. Results for several cancers generally satisfy these criteria. Results for breast and colorectal cancer satisfy the criteria best, but there is also good evidence that other cancers do as well, including bladder, esopha-geal, gallbladder, gastric, ovarian, rectal, renal and uterine corpus cancer, as well as Hodgkin’s and non-Hodgkin’s lymphoma. Several cancers have mixed findings with respect to UVB and/or vitamin D, including pancreatic and prostate cancer and melanoma. Even for these, the benefit of vitamin D seems reasonably strong. Although ecological and observational studies are not generally regarded as able to provide convincing evidence of causality, the fact that humanity has always existed with vitamin D from solar UVB irradiance means that there is a wealth of evidence to be harvested using the ecological and observational approaches. Nonetheless, additional randomized, controlled trials are warranted to further examine the link between vitamin D and cancer incidence, survival and mortality. Introduction
The solar ultraviolet-B (UVB)—vitamin D—cancer hypothesis 
was first proposed in 1980 by Cedric and Frank Garland to explain the geographical variation of colon cancer mortality rates in the United States for 1950–1969, highest in the Northeast and lowest in the Southwest. 1 They showed a rough correlation for the cancer mortality rates with annual hours of sunshine. They later showed that dietary vitamin D and calcium were inversely correlated with colorectal cancer risk
2 as well as prediagnostic serum 25-hydroxyvi-
tamin D [25(OH)D]. 3 They also linked solar UVB and vitamin D 
to reduced risk of breast4 and ovarian5 cancer. Gary Schwartz added 
prostate cancer in 1990. 6 After the publication of the Atlas of Cancer 
Mortality in the United States, 1950–94,7 William Grant determined 
that 14 types of cancer had mortality rates inversely correlated with solar UVB levels for July. 8,9
Much of this pioneering work was accomplished using the 
ecologic approach, in which populations and risk-modifying factors are averaged for geographically defined populations. The ecologic approach is particularly well suited for this particular task for several reasons: solar UVB is the primary source of vitamin D for most people on Earth; the amount of vitamin D generated from casual solar UVB irradiance in summer, sufficient to raise serum 25(OH)D by 10–15 ng/mL,
10,11 is sufficient to reduce the risk of many types 
of cancer by 10%–40%; and vitamin D seems to play an important role in fighting cancer in the disease’s later stages. 12,13
As convincing as the ecologic studies are to those intimately 
involved therewith, they have not met with universal acceptance. Even their having been would still not be sufficient to establish a causal relation between solar UVB, vitamin D production and cancer risk reduction. However, an approach exists that one can use to evaluate whether the association can be considered causal: apply the criteria for causality, originally postulated by Robert Koch to show that tubercu-losis was caused by a bacterium,
14 and codified in recent times by A.
Cedric and Frank Garland
Who proposed the UVB-vitamin D-cancer hypothesis in 1980?
Solar UVB irradiance
What is the primary source of vitamin D for most people on Earth?
None, as they are not generally regarded as able to provide convincing evidence of causality
What is the main limitation of ecological and observational studies in establishing a causal relation between solar UVB, vitamin D, and cancer risk reduction?
Improved differentiation and apoptosis, as well as anti-angiogenesis and antimetastasis
What is the main mechanism by which vitamin D reduces the risk of cancer?
To examine the evidence to date with respect to the criteria for causality in a biological system
What is the purpose of the study being discussed in the text?