Medscape: Continuing Medical Education Online

Causality

Consideration of whether indoor UV and melanoma have a causal association requires consideration of multiple factors, including the strength and consistency of the association across diverse studies, study designs, and study populations, which is reflected in the published systematic review. The presence of a dose–response relationship (biologic gradient) in multiple studies also supports a causal link.

Particularly significant in this context is the prior finding that solar UV radiation is a cause of melanoma.⁵ The UV obtained from indoor UV is often similar to or exceeds the dose typically received from the sun over a similar period, and the character of the radiation is similar. Therefore, a priori probability of a causal link between indoor UV and melanoma is high. When combined with the direct observational investigations reviewed earlier, the evidence is compelling.

An increase is also being observed in the incidence of melanoma in young women, the demographic group with the heaviest exposure to indoor UV.⁶ This trend reinforces the evidence reviewed above of indoor UV as a cause of melanoma, and suggests that the widespread use of indoor UV by teenage girls and young women may have important public health consequences.

The association of indoor tanning with squamous cell carcinoma of the skin has not been as extensively studied as the association with melanoma. Squamous cell carcinoma generally has a more straightforward and direct association with UV radiation than does melanoma, with risk generally associated with cumulative and recent exposure, as demonstrated in both epidemiologic studies⁵ and a randomized trial showing the effectiveness of sunscreen use in reducing squamous cell carcinoma risk by 40%.^7,8 The best published evidence from analytic epidemiology supports the association of indoor UV exposure with squamous cell carcinoma risk.⁹

Based on the cumulative evidence, key portions of which were reviewed earlier, the International Agency for Research on Cancer of the WHO recently classified indoor UV as a class I carcinogen,¹⁰ and the WHO has recommended that minors not be allowed to engage in recreational indoor UV tanning.¹⁰ Governmental actions in multiple countries are limiting the use of indoor UV. The evidence is based on epidemiology, and is strengthened by the extensive evidence pertaining to the biologic mechanisms that are likely to be operative.

Scientific/Laboratory Observations

The tanning response in skin has long been known to involve the core melanin synthetic machinery, which is housed within melanosomes, specialized melanin-producing vesicles that form in melanocytes and are transported to overlying keratinocytes. UV radiation is subdivided as UVA (315–400 nm), UVB (280–315 nm), and UVC (< 280 nm). UVA and UVB are primarily responsible for tanning through distinct mechanisms of DNA damage. UVB produces direct pyrimidine dimmer lesions, whereas UVA triggers damage through reactive oxygen species intermediates. Both wavelengths are represented within indoor tanning lamps, although diminished UVB may produce less sunburn/inflammatory response. The lack of sunburning, although advantageous from the perspective of acute toxicity, does not necessarily signify absence of carcinogenicity.

Several studies performed within the past few years have focused on the “red-head” gene, the melanocortin receptor 1 (MC1R) variant that encodes a nonsignaling allele of this G protein–coupled receptor that does not transmit a robust cyclic adenosine monophosphate (cAMP) inductive signal, as is seen with dark-hair variants of MC1R.¹¹ Examination of red-furred (Mc1r-variant) mice showed their inability to tan after UV radiation, suggesting that MC1R signaling is vital to this response. UV irradiation strongly upregulates expression of pro-opiomelanocortin (POMC) and its cleavage product melanocyte stimulating hormone (MSH) in epidermal keratinocytes, suggesting that the tanning response occurs through a non–cell-autonomous response of melanocytes to the UV-induced production of secreted MSH by epidermal keratinocytes.¹²

How do epidermal keratinocytes “perceive” UV radiation? Molecular analyses showed that UV induction of POMC expression occurred through a transcriptional mechanism. A search for the regulatory element in the POMC promoter, which is induced by UV, revealed a consensus binding site for the transcription factor p53.¹³ In fact, work by Eller et al.^14,15 many years earlier already implicated both p53 and DNA damage within the UV-tanning response. Introduction of DNA damage lesions, even through restriction endonuclease exposure, could enhance melanization.¹⁵ Moreover, introduction of telomere-mimicking dinucleotide fragments was shown to induce melanin synthesis in a p53-mediated fashion.¹⁴

Multiple follow-up studies showed that p53 can respond to UV-induced DNA damage and activate POMC expression, resulting in the production of MSH, which secondarily stimulates underlying melanocytes to produce melanin. These studies included evidence that p53 knockout mice were unable to mount a pigmentation response to UV. In addition, different triggers of DNA damage (such as genotoxic drugs) were seen to similarly activate p53-mediated POMC induction, and to produce p53-dependent skin darkening.¹³ Multiple animal models have shown that melanoma is accelerated by UV exposure, and it is well known that DNA repair deficiencies, such as xeroderma pigmentosum, are associated with significantly elevated melanoma risk. Collectively, these data suggest that the mechanism underlying UV-induced pigmentation involves the p53 “stress” response, which has long been described as “guardian of the genome” for its cell-autonomous capacity to block cell cycle progression and permit DNA repair before replication of a damaged genome. The tanning response is thus an extension of this stress response, in which p53 promotes “guardianship of the skin” through facilitating transient hyperpigmentation when exposed to UV-induced DNA damage.

How do these mechanistic connections impact understanding of the risks associated with UV tanning? First, they suggest that the UV–tanning response is a stress response, and one of its essential mediators is the best-known mediator of genomic damage: p53. In turn, this overwhelmingly implies that DNA damage is an essential intermediate in the UV–pigmentation response. Because DNA damage is a broadly accepted intermediate in UV carcinogenesis, UV-mediated pigmentation is likely induced by the identical genotoxic effects of UV, which are also carcinogenic. In other words, the mechanism of tanning intrinsically uses the same molecular intermediates as UV carcinogenesis. This challenges the theoretical notion of a “safe tan” that may have no carcinogenic risk, because DNA damage functions as a mechanistic intermediate for both pathways.

Second, POMC is known to encode additional bioactive peptides beyond MSH, with β-endorphin the most notable. Molecular analyses indicated that β-endorphin levels were upregulated within UV-irradiated skin, in parallel to POMC/MSH induction.¹³ Although explicit study of β-endorphin's behavioral effects secondary to UV exposure has not yet been reported, a body of clinical data strongly suggests that it may mediate very important systemic consequences that are directly pertinent to indoor tanning.

A 2004 study tested the ability of indoor tanning bed users to discriminate in blinded fashion between identical-appearing “tanning beds” that either delivered UV or did not.¹⁶ Nearly all choices favored the UV bed, indicating that under blinded conditions, frequent tanners accurately distinguish UV from non-UV exposure and seek the UV exposure, indicating that it is a reinforcing behavioral stimulus.

Additional study from the same researchers examined the consequences of opiate receptor blockade administered to frequent tanners.¹⁷ The study showed that the opiate receptor antagonist naltrexone reduced UV preference among frequent tanners, and also induced withdrawal symptoms in 4 of 8 tested subjects. Although this was a small study, its results are consistent with a role for an endogenous opiate dependency state among frequent tanners. Blinded UV exposure was also reported to produce pain relief in a case report,¹⁸ and an association has been suggested with seasonal affective disorder.¹⁹ Although mechanistic details remain to be discerned, these clinical observations suggest the existence of systemic, organic consequences of UV-tanning, which modulate human behaviors. Most importantly, an association between tanning and addiction would suggest that, as a reinforcing stimulus, UV–tanning could represent a dangerous behavioral cycle influencing human skin cancer rates.

Vitamin D

Vitamin D is an essential nutrient that can be obtained from photosynthesis in the skin, diet, or vitamin supplements. Vitamin D has received markedly increased attention recently from both researchers and the general public. It is now clear that vitamin D has important roles other than simply prevention of rickets and osteomalacia.²⁰ These studies have included a systematic review suggesting that vitamin D supplementation decreases mortality based on studies focused generally on elderly, and particularly on institutionalized, populations. The extent of these additional contributions to healthy living and preventing serious disease remain to be fully elucidated. The effect on younger populations has not been studied as often as the consequences for the elderly at risk for fractures and impaired mobility.

As a direct consequence of this increased attention, many people have increased their vitamin D levels, and the incomplete understanding of vitamin D effects on health and disease extend to the effects of sustained high levels. Hypercalcuria is a concern, particularly if vitamin D supplements containing calcium are consumed in large quantities. Weak evidence shows that higher levels might be associated with serious adverse consequences in the general population.^21,22

The generally accepted measure of vitamin D status is circulating 25-hydroxy-vitamin D (25OHD). These levels cannot be reliably estimated based on history or physical examination; blood levels are generally used to determine adequacy of vitamin D stores, and are commonly used to guide therapy if levels are too low.

UVB radiation is required for photosynthesis in the skin and is a common source of vitamin D stores, but has the complication of being carcinogenic. Whether indoor UV is effective in generating vitamin D in the skin depends specifically on the amount of UVB radiation included in the indoor UV, because UVA is not effective for vitamin D photosynthesis.²³

Multiple other factors have important effects on vitamin D photosynthesis. In particular, elderly adults are much less able to generate vitamin D in the skin in response to UVB than younger adults. Obesity affects one third of the United States population and is associated with low vitamin D levels. Individuals with low cholesterol are also less able to increase their 25OHD levels in response to UVB irradiation, but those with lower baseline 25OHD levels show larger increases in response to UVB or vitamin D supplementation. Increasing 25OHD levels using sun exposure is further complicated by the variables that affect UVB flux at the skin surface, such as cloud cover, time of day and season of the year, particulates in the atmosphere, and any physical shading. These multiple factors present substantial practical difficulties for any attempt to titrate sun exposure for the purpose of augmenting 25OHD levels.²⁴ Even populations living in environments with intense solar UV exposure, such as Hawaii and Queensland, frequently have vitamin D levels that are considered suboptimal.^25,26 Hence, attempts to draw equivalences between duration of sun exposure and amount of vitamin supplementation are likely to be seriously flawed.

Although food is a source of vitamin D, the amounts available in a typical American diet are limited, and mostly come from artificially fortified foods, such as milk.²⁷

Vitamin D supplements are readily available throughout the United States and are inexpensive. They are also generally the source of vitamin D used in the studies showing the beneficial effects of higher levels of this vitamin on human health. Therefore, in people with suboptimal vitamin D levels, supplementation may provide optimal augmentation.

As a consequence of the factors noted earlier, and undoubtedly multiple others, the effect of exposure to UV radiation and ingestion of oral supplementation on vitamin D levels cannot be confidently quantified in the absence of laboratory verification. From a public health standpoint, the viability of other strategies, such as increasing fortification in common foods as an alternative to population-wide assays of 25OHD levels, followed by individual supplementation, remains to be fully evaluated.

The analogies between indoor UV tanning and tobacco are particularly concerning. The mortality associated with skin cancer in the United States is no more than 10,000 deaths per year, in contrast to tobacco smoking as the leading avoidable cause of death. However, both are associated with industries that can gain substantial profits by promoting these carcinogenic and potentially addictive products. The increasing regulatory attention being given to these issues, including the recent action of the Federal Trade Commission to restrict indoor UV promotion, may mitigate the consequences in terms of morbidity and mortality.

Prospects

Where do we go from here? With evidence from both epidemiology and biologic mechanism indicating that UV from indoor tanning is carcinogenic, it is beneficial (if not overdue) that the FDA initiated a vigorous process to review safety classification for indoor tanning beds. An FDA advisory panel hearing was held on March 25, 2010. Extensive public testimony was delivered from advocates of tighter regulatory oversight and those who believe tanning beds are safe. The results of the advisory panel's recommendations and the FDA's regulatory decisions are unknown as of this writing. Multiple countries have addressed this issue in accordance with WHO recommendations, significantly ahead of U.S. regulatory agencies. It will be of considerable interest to see where the burst of information and public scrutiny on this issue will focus in the near future.