IJE Advance Access originally published online on November 22, 2005
International Journal of Epidemiology 2006 35(2):220-222; doi:10.1093/ije/dyi230
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Commentary |
Commentary: Progress of a paradigm
1 Department of Family and Preventive Medicine, University
of California, San Diego, 9500 Gilman Drive 0631C, La Jolla, CA 92093,
USA.
2 Naval Health Research Center, PO Box 85122, San Diego, CA 92186-5122, USA.
‘It is proposed that vitamin D is a protective factor against colon cancer.’ These 13 words started the abstract of our paper1 and said it all. The concept that vitamin D can prevent cancer was born. Vitamin D was raised from being a nearly forgotten compound that once enabled the conquest of rickets, but had been tossed into the dustbin of medical history. Mention of rickets or vitamin D evoked images from Victorian fiction—Dickens's Tiny Tim hobbling on his crutch.
Soon after Dickens's description, it was found that the similar plight of hundreds of thousands of real children was due to inadequate sunlight, whose ultraviolet B (UVB) irradiance (290–315 nm) is the source of photosynthesis of vitamin D. Yet a hundred years had passed, and UVB became regarded as a carcinogen by the American Cancer Society and National Cancer Institute. Advice from experts to the public was to avoid the sun completely or to apply sunscreens that absorbed UVB.
The idea that UVB irradiance and vitamin D might save thousands of lives would require not only backing away from the idea that any sunlight was risky, but replacement of the accepted paradigm that colon and breast cancers were due to too little fibre, too much fat, and, possibly, a few bad genes. These were entrenched paradigms.
The prevailing approach in cancer research at the time was a hunt for carcinogens, with the hope of reducing exposure. The vitamin D concept was the opposite—namely, that a deficiency rather than a carcinogen was the factor. Yet we realized that one paper would not change this familiar approach. It would take further epidemiological work and the progression of science through a sequence of studies.
Theories do not advance without nurturing. Edward Gorham joined our team in this scientific progression, and was author of the first two papers noting the inverse association of UVB with breast cancer mortality rates in Canada2 and incidence rates in the then-USSR.3 These two studies were quickly followed by a study in the US that found higher levels of solar radiation and thinner stratospheric ozone were associated with lower breast cancer mortality rates.4 With the publication of a study reporting that sunlight exposure was associated with lower mortality rates of ovarian cancer,5 it was becoming apparent that vitamin D resulting from UVB exposure had a beneficial role across a broad range of cancers.
Vitamin D comes from two sources, diet and solar radiation. This is unique, and is one reason why the association was not immediately obvious. Either could mask the other, making it hard to recognize vitamin D's importance. Another reason that the role of vitamin D deficiency had gone unrecognized was that it was broadly accepted that there was no vitamin D deficiency in the US.
The next step in the progression of developing evidence was a historical prospective study based on detailed dietary records from a cohort of 1954 men in Chicago that had been followed-up for 19 years.6 The cohort's organizers and Dr Elizabeth Barrett-Connor provided an opportunity for us to look in this cohort for an association of vitamin D with incidence of colon cancer. The study found that people in the upper half of intake of vitamin D had half the incidence rate of colon cancer than those in the lower half.
Dietary studies could tell only half the story, though. While dietary Vitamin D was inversely associated with risk in a Northerly population, it remained to be shown that vitamin D in the serum had a similarly powerful association.
The main circulating vitamin D metabolite, 25-hydroxy-vitamin D [25(OH)D], is stable over time, and can be readily measured in serum that has been frozen for years. A good way to account for both the solar and dietary contributions to vitamin D status could be a study of this vitamin D metabolite in the serum, since it varies considerably according to solar UVB exposure and oral intake. We had an opportunity to perform a nested case–control study in a cohort of 25 620 volunteers that we helped assemble 8 years earlier at the Johns Hopkins Community Laboratory in Hagerstown MD. The study revealed that risk of colon cancer in those whose serum 25(OH)D was 
20 ng/ml was only a third that of those with <20 ng/ml.7
We received an unexpected invitation in 1990 from Dr Sam Broder, Director of the National Cancer Institute, to present a Director's Seminar. Dr Broder understood the potential of vitamin D in reducing incidence of colon and breast cancer, and invited us to present the concept and our data in a unique forum that brought together heads of all departments of the Institute. The result was a lively discussion, followed by a telephone call by Dr Broder to Dr Bernadine Healy, Secretary of Health and Human Services, who had proposed, and was designing, the Women's Health Initiative, the largest clinical trial ever conducted. Dr. Broder asked that a vitamin D arm be included the study. Before long, 
30 000 women were randomized to this arm of the trial and are being followed-up for events.
We were struggling in the meantime to create a public health recommendation based on the data that we had. We did not want to suggest even modest exposure to solar radiation if it would increase risk of melanoma. Startlingly, melanoma incidence rates rose 12-fold during 1935–90 in the US, a rise that was unique to industrialized countries.8 The prevailing explanation was that it was due to excessive intermittent UVB exposure.
One of the primary preventive measures was use of UVB-absorbing sunscreens. Unfortunately, the sunscreens were transparent to UVA, and far greater exposure to UVA than ever was a result of the false sense of security and longer duration of exposure that they allowed.8 We published a study marshalling the evidence that the melanoma epidemic was due to increased exposure to UVA (315–400 nm),8,9 to the surprise of the dermatological community.
The evidence revealed that sunscreens were subverting the normal photoprotective response—thickening of the epidermis, release of melanin, and upregulation of DNA repair enzymes due solely to UVB exposure.8 Within a year, almost all sunscreen formulas were changed to include UVA absorbers or physical barriers such as titanium dioxide, and the scientific community began to reconsider the benefits and risks of exposure to each part of the solar spectrum. This evidence led to the recognition that overexposure to UVA is harmful, while moderate exposure to UVB may be beneficial for photosynthesis of vitamin D.
William Grant performed an ecological study of US states that identified several other cancers as inversely associated with solar UVB irradiance, including bladder, oesophageal, kidney, lung, pancreatic, stomach, and corpus uteri.10 In parallel with this work, the effects of vitamin D are now being explored widely for cancer prevention.11 The 1989 serum study led to three similar studies, the largest of which replicated the initial serum study, in a far larger cohort.12 Meanwhile, Dr Heide Cross and her co-workers made the important discovery that peripheral tissues convert 25(OH)D to 1,25(OH)2D, adding greatly to the understanding of the mechanism of vitamin D metabolites in cancer prevention and helping to account for the effect of UVB on risk.13 Their current work is disclosing the roles of certain micronutrients in vitamin D metabolism.
Studies of the role of vitamin D in cancer prevention are now under way in many cohorts. Promising new results supporting vitamin D's role in reducing incidence and mortality rates of a broad range of cancers in the Harvard Nurses' Health Study and Health Professionals' Follow-Up Study were reported by Dr Edward Giovannucci.14 The results of the Women's Health Initiative are now being analysed.
Based on research to date, the current recommendation of 200–600 IU/day of vitamin D is too low. It is reasonable to suggest, based on current data, that 1000–1950 IU per day would be a more optimal level of intake for adults and children 6 years. Oral intake should, of course, be kept below the National Academy of Sciences's No Adverse Health Effect Level of 2000 IU/day. UVB exposure should be limited to no more than 15 min per day in whites, 30 min in those of other races, and should be minimized in the very fair or those with specific disorders that would preclude any solar exposure.
There is excitement regarding a role of vitamin D as part of cancer therapy. Cancer patients who live in places with high solar UVB radiation have better survival rates than those in areas deprived of solar UVB radiation, and patients whose cancers are treated during the summer months also have better survival rates. This has led to the search for vitamin D derivatives that could play a role in less toxic approaches to chemotherapy.
As Professor Abe Lilienfeld, our mentor and friend at Johns Hopkins, said, the basic observational and inferential aspects of epidemiology—time, place, and person—are the key elements in the understanding of disease. There elements have almost faded into history as epidemiologists pursue clinical trials and study the genome. When observation and inference from time, place, and person are applied, though, they bring new perspectives and paradigm shifts that benefit the orderly progression of scientific knowledge.
 |
References |
|---|
 Top References |
|---|
1 Garland C, Garland F. Do sunlight and vitamin D reduce the likelihood of colon cancer? Int J Epidemiol 1980;9:227–31. (Reprinted Int J Epidemiol 2006;35:217–20.)
2 Gorham E, Garland C, Garland F. Acid haze air pollution and breast and colon cancer in 20 Canadian cities. Can J Publ Health 1989;80:96–100.
3 Gorham ED, Garland FC, Garland CF. Sunlight and breast cancer incidence in the USSR. Int J Epidemiol 1990;19:820–24.
4
Garland F, Garland C, Gorham E, Young J Jr. Geographic variation in
breast cancer mortality in the United States: a hypothesis involving
exposure to solar radiation. Prev Med 1990;19:614–22.[CrossRef][Web of Science][Medline]
5 Lefkowitz ES, Garland CF. Sunlight, vitamin D, and ovarian cancer mortality rates in US women. Int J Epidemiol 1994;23:1133–36.
6
Garland C, Shekelle RB, Barrett-Connor E, Criqui MH, Rossof AH, Paul O.
Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year
prospective study in men. Lancet 1985;1:307–09.[CrossRef][Web of Science][Medline]
7
Garland C, Comstock G, Garland F, Helsing K, Shaw E, Gorham E. Serum
25-hydroxyvitamin D and colon cancer: eight-year prospective study. Lancet 1989;2:1176–78.[Web of Science][Medline]
8 Garland C, Garland F, Gorham E. Rising trends in melanoma: a hypothesis concerning sunscreen effectiveness. Ann Epidemiol 1993;3:103–10.[Medline]
9
Garland C, Garland F, Gorham E. Epidemiologic evidence for different
roles of ultraviolet A and B radiation in melanoma mortality rates. Ann Epidemiol 2003;13:395–404.[CrossRef][Web of Science][Medline]
10 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.[CrossRef][Web of Science][Medline]
11 Holick MF. Vitamin D: A millenium perspective. J Cell Biochem 2003;88:296–307.[CrossRef][Web of Science][Medline]
12 Feskanich D, Ma J, Fuchs CS et al. Plasma vitamin D metabolites and risk of colorectal cancer in women. Cancer Epidemiol Biomarkers Prev 2004;13:1502–08.
13
Bareis P, Bises G, Bischof MG, Cross HS, Peterlik M. 25-hydroxy-vitamin
D metabolism in human colon cancer cells during tumor progression. Biochem Biophys Res Commun 2001;285:1012–17.[CrossRef][Web of Science][Medline]
14 Giovannucci E. The Goodman Lecture: The role of vitamin D in cancer incidence and mortality. In Annual Meeting of the American Association for Cancer Research, 2005. Anaheim CA: American Association for Cancer Research, 2005.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. H. JONGBLOET Do sunlight and vitamin D reduce the likelihood of colon cancer? Time for a paradigm shift? Int. J. Epidemiol., October 1, 2006; 35(5): 1359 - 1360. [Full Text] [PDF]
|
|
|
|
|
|
G. DAVEY SMITH Cultural climate, physical climate, life, and death Int. J. Epidemiol., April 1, 2006; 35(2): 211 - 212. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
