Vitamin D synthesis and photocarcinogenesis What’s the right balance for sun exposure?

Ultraviolet radiation is a carcinogen Sun exposure is the major environmental cause of skin cancer BCC, SCC Melanoma International Agency for Research on Cancer, 1992 National Toxicology Program, Report on Carcinogens, 2000, 2002

Skin cancer is common > 80,000 Canadians were diagnosed with skin cancer in 2005 - 1/3 of new cancers Source: Canadian Cancer Statistics 2005

…and is becoming more common Melanoma incidence and mortality rates have risen 2-3 fold in 30 years Melanoma incidence and mortality, Ontario, 1971-2002 Source: Cancer Care Ontario (Ontario Cancer Registry, 2004). 3-year moving averages standardized to the Canadian 1991 population.

Ambient UV, type and amount of exposure and susceptibility determine risk Skin cancer risk is higher in susceptible populations living closer to the equator The higher the total lifetime amount of UV exposure, the greater the risk of skin cancer An intermittent pattern of intense exposure appears to increase the risk of melanoma People with sun-sensitive skin (i.e., burn easily, tan poorly), blue eyes, many nevi are at greater risk of developing skin cancer

UV: DNA damage Cyclobutane pyrimidine dimers : signature mutation 6-4 pyrimidine pyrimidone photoproducts Single strand breaks DNA protein crosslinks

UV: membrane damage Lipid peroxidation Activation of surface receptors with induction of multiple signal transduction pathways: alteration in activation of many cellular proteins……alteration in gene expression and cellular function

UV induces an alteration in immune surveillance Decreased ability to eliminate cancerous growths Interference with development of contact hypersensitivity

Public health message: sun protection/skin cancer prevention Shade Clothing Education Public policy Sunscreen use

Vitamin D Definitions Vitamin D: UVB induced production in the skin Vitamin D and bones Vitamin D and other disorders Public health message

Definitions 7-dehydrocholesterol: provitamin D3 Previtamin D3: cholecalciferol Vitamin D3: produced in the skin from irradiated 7-DHC, isomerized previtamin D3 Vitamin D2: from plants, from irradiated ergosterol

Vitamin D synthesis

Definitions Vitamin D3 is hydroxylated in the liver: 25 OH vitamin D: inactive, measured in serum as the biomarker of vitamin D status from all sources Second hydroxylation: 1,25 (OH)2 vitamin D in the kidney *** These hydroxylation steps can also occur in keratinocytes, prostate cells and others

1,25 (OH)2 vitamin D Serum levels are tightly regulated Do not vary by latitude

Sources of vitamin D Sunlight (UVB) Food (vitamin D3 and vitamin D2) Fortification of foods: milk, orange juice Dietary supplements

Action spectra UVB is the waveband required for vitamin D synthesis The action spectra for sunburn, cyclobutane pyridine dimers all peak in the UVB range With longer UVB exposure, vitamin D synthesis does not continue, but DNA damage does

Function of vitamin D Increases calcium absorption from the gut Calcium homeostasis Maintenance of bone mineral density

Vitamin D deficiency Rickets Osteomalacia

Vitamin D insufficiency 25-OH vitamin D level Optimal concentration remains undecided In a meta-analysis of fracture prevention in the elderly, showed that fracture prevention was greatest when 25-OH vitamin D levels were ~100 nmol/L: these studies used oral supplementation This required vitamin D intakes of 700-800 IU/day, higher than currently recommended doses

People at risk for low 25-OH vitamin D Elderly Northern latitudes in winter Black skin (melanin) Cultural or lifestyle choices Sun avoiders, post-organ transplant

2005 Dietary Guidelines for Americans Individuals at high risk (older adults, people with dark skin, those with little sunlight exposure) should consume extra vitamin D from fortified foods or supplements Recommendation of 25ug (1000 IU) vitamin D daily to maintain adequate 25-OH vitamin D Do not use UV exposure to obtain additional vitamin D Johnson MA et al. Nutr Rev 64:410,2006

Vitamin D supplementation Prevention of fractures in the elderly Prevention of falls in the elderly Prevention of periodontal disease in the elderly

Colorectal neoplasia Epidemiologic data are generally consistent with a protective effect of a higher 25(OH)D concentration and higher vitamin D intake The biologic basis for the sensitivity of “digestive malignancies” to vitamin D status is unclear” Randomized control studies are needed Bischoff-Ferrari H et al. Am J Clin Nutr 84:18, 2006 Giovannucci E. Cancer Epidemiol Biomarkers Prev 15:2467, 2006

Prostate and breast cancer Studies have shown geographic gradients in risk. Case control studies and cohort studies have shown a decreased risk of these diseases with increased sunlight exposure Hypothesis generating: Is it the vitamin D that is protective? The potential for cancer prevention by oral intake of vitamin D must be tested in clinical trials van der Rhee HJ et al Eur J Cancer 42:2222, 2006 Gallagher RP et al. Lancet Oncology 6:634, 2005

Epidemiologic studies Less evidence exists for a role for sunlight in: Multiple sclerosis Diabetes

Life is not so simple Vitamin D is important for bone health There is some data supporting vitamin D as protective against certain diseases Agreement on appropriate levels of 25-OH vitamin D have not been established Sunlight, a source of vitamin D, is a carcinogen

What to do? Some advocate for increased unprotected UV exposure This advice is complex: latitude, weather dependent, time of day and season. It will not be effective in higher latitudes during the winter It is inefficient in the elderly, blacks Many people (such as teenagers, many adults) already are exposed to enough unprotected UV exposure that more UV exposure will not be helpful

What to do? Many advocate for taking vitamin D supplements Advocate for increased fortification of foods where it is not in place

What to do? Many people do not avoid the sun, and produce adequate vitamin D in the skin depending on the time of year. Incidental sun exposure throughout the year likely produces adequate vitamin D in the skin for many people Vitamin D supplementation for those at increased risk

What to do? Further research on the role of sunlight and vitamin D in cancer prevention Randomized controlled trials of dietary vitamin D as a cancer prevention agent

Sun protection messages Remains important Prevention of skin cancer and photoaging Protection using hats, clothing, shade and sunscreen during leisure time/occupational exposure Standard use of sunscreens has not caused vitamin D deficiency Marks R et al. Arch Dermatol 131:415, 1995 Wolpowitz D et al. J Amer Acad Dermatol 54:301, 2006