SUNBEDS AND MELANOMA RISK: TIME TO CLOSE THE DEBATE

Mariano Suppa,1 Sara Gandini2

1Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium

2Molecular and Pharmaco-Epidemiology Unit, Department of Experimental Oncology, European Institute of Oncology, IRCCS, Milan, Italy

Word count: 2519 (text), 189 (abstract)

Table count: 2

Figure count: 0

Corresponding author:

Dr Mariano Suppa

Department of Dermatology, Hôpital Erasme, Université Libre de Bruxelles

808 Route de Lennik

1070 Brussels, Belgium

Tel. +32 2 555 46 12

Fax +32 2 555 49 69

e-mail: dr.marianosuppa@gmail.com

Financial support and sponsorship: None

Conflicts of interest: None

Abstract

Purpose of review. Although the established scientific evidence of the association of sunbed use with melanoma risk, some have recently expressed scepticism about the carcinogenicity of indoor tanning. This may have raised confusion among both physicians and patients. The scope of the review is to make the point about the real impact of sunbed use on melanoma risk in light of the most recently published evidences.

Recent findings. Seven themes were covered: (1) recent studies on age at first sunbed exposure and melanoma risk; (2) sunbed use and melanoma at different body sites; (3) sunbed use and development of additional primary melanomas; (4) new studies on proportion of melanomas attributable to sunbed use; (5) sunbed use and melanoma risk factors; (6) economic burden of sunbed use; and (7) recent debate over whether indoor tanning contributes to melanoma.

Summary. We were able to apply all the epidemiological criteria for causality to the relationship between sunbed use and melanoma. Together with the new evidences of the strength, dose response, and temporality of the association of sunbeds with melanoma, this will hopefully close the debate over whether indoor tanning contributes to melanoma.

Keywords: Sunbeds, Indoor tanning, Melanoma, Skin cancer, Causality

Introduction

Tanning devices emit ultraviolet (UV) radiation in order to produce a cosmetic tan (indoor or artificial tanning). Several types and denominations of tanning devices exist (sunbeds, tanning beds/booths/canopies, solarium): the term sunbeds is commonly employed to generally define them all.

Sunbeds emit UVA and UVB radiation, which are both able to cause DNA damage and immunosuppression. UV radiation is a complete carcinogen, as it is both an initiator and a promoter of carcinogenesis.1-5 A clear relationship between UV exposure, indoor tanning and skin cancer (especially melanoma) was demonstrated in the last decade by laboratory data and animal experiments,6-10 as well as human studies on healthy volunteers and epidemiological studies, systematically reviewed in meta-analyses.11-13 This prompted the International Agency for Research on Cancer (IARC) – an agency of the World Health Organization (WHO) – to classify UV-emitting tanning devices, as well as the whole spectrum of UV radiation, as a first group carcinogen in June 2009.14

Subsequent meta-analyses including later studies reinforced this decision, confirming that sunbed use significantly increases melanoma risk, particularly if first exposure occurs at a young age (Table 1).15-17 This large body of evidence prompted both the Scientific Committee on Health, Environmental and Emerging Risks (SCHEER) of the European Commission18 and the WHO19 to state that there is no safe limit for exposure to UV radiation from sunbeds.

Recently, however, a couple of publications expressed scepticism about the carcinogenicity of indoor tanning and may have raised confusion among both physicians and patients about the true relationship between sunbed use and melanoma risk.20,21

The scope of the current paper is, therefore, to make the point about the real impact of sunbed use on melanoma risk in light of the new, most recent evidences published in the literature. To this aim, we searched various databases (PubMed/MEDLINE, ISI Web of Science, and Cochrane Library) for any literature published in English up to December 2018 using the following keywords: “sunbed(s)”, “tanning bed(s)”, “sunlamp(s)”, “tanning lamp(s)”, “solarium/a”, “indoor tanning”, “artificial tanning”, “tanning parlour(s)”, “tanning salon(s)”, “tanning booth(s)” and “melanoma”. Identified articles were cross-referenced for articles missed by the database search. Only recent studies (i.e., published as of 2017) were selected, with the exception of earlier studies of outstanding importance not included in the above-mentioned meta-analyses. In particular, we will present and discuss (i) new studies investigating the influence of age at first sunbed exposure on melanoma risk; (ii) a novel association of sunbed exposure with risk of melanoma at different body sites; (iii) new data about the relevance of sunbed use for the development of additional primary melanomas; (iv) the most recent findings about how many melanomas are attributable to sunbed use; (v) brand-new data about the association of indoor tanning with melanoma risk factors; (vi) a recent analysis of the economic burden of sunbed use; and finally, (vii) the recent debate over whether indoor tanning contributes to melanoma.

New studies on age at first sunbed exposure and melanoma risk

In 2016, Lazovich et al. published the first study examining age- and sex-specific associations between indoor tanning and melanoma.22 In this population-based study (681 cases, 654 controls), age at sunbed initiation <25 years was associated with a 6-fold increase in melanoma risk among <30 years old women, a 3.5-fold increase in 30-39 years old women and a 2.2-fold increase in 40-49 years old women. A dose response was observed among women regardless of age. Conversely, results by age were inconsistent among men. The strongest association of sunbed use with melanoma risk was found for tumours arising on the trunk of women (3.7-fold increased risk). These results imply that indoor tanning is a likely factor for the steeper increase in melanoma rates among younger women than among men observed in the United States,23 and that the melanoma epidemic can be expected to continue unless sunbed use is restricted and reduced.

In 2017, Ghiasvand et al. published an important population-based, prospective cohort study [141,045 women enrolled in the Norwegian Women and Cancer study (NOWAC), mean follow-up 13.7 years] about indoor tanning and melanoma risk.24 This study adds new, crucial information to the body of evidence of the carcinogenicity of indoor tanning. The authors found several significant, independent findings. Compared to never use:

· ever and current sunbed use increased melanoma risk by 24% and 27%, respectively;

· age at sunbed initiation <30 years increased melanoma risk by 34%;

· duration of sunbed use >10 years increased melanoma risk by 29%;

· ≤14 lifetime sessions of indoor tanning increased melanoma risk by 19% (borderline significant), 15-30 lifetime sessions by 26%, and ≥31 lifetime sessions by 32%, in a clear dose-response fashion (stronger if age at initiation was <30 years);

· sunbed use was associated with younger age at melanoma diagnosis: 2.2 years lower for women who started indoor tanning at age <30 years and 1.2 years lower among women who started indoor tanning at age ≥30 years.

These findings provide strong supporting evidence of the strength, dose response, and temporality of the association between sunbed use and melanoma risk, especially when the first exposure occurs before age 35 years. Therefore, these results will concur to “put to rest the debate over whether indoor tanning contributes to melanoma”, as pointed out by Mayer in his comment on this study.25

Association of sunbed exposure with melanoma risk at different body sites

A new investigation by Ghiasvand et al. used again data from the NOWAC prospective study (161,540 women) to assess the influence of multiple phenotypic characteristics and patterns of UV radiation on melanoma body site.26 They found that indoor tanning was associated with a 49% increased risk of trunk melanoma and a 33% increased risk of lower limb melanoma. The latter association is of particular interest, as the lower limbs represent the most common site of melanoma in women and the possible causes behind limb melanomas had been less understood up to now.26

Sunbed use and development of additional primary melanomas

In 2018, Li et al. published the first study investigating the association of additional primary melanomas and sunbed use.27 They found that as compared to patients with only one primary melanoma, patients with multiple primary melanomas had a higher probability of previous exposure to sunbeds: the odds of sunbed exposure increased by 48% with each additional primary melanoma. Moreover, previous indoor tanners acquired their second primary melanoma significantly earlier than non-tanners: indeed, 66.7% of previous indoor tanners had their second primary diagnosed at the time of or within 1 year of their original diagnosis compared with 28.3% of non-tanners. Finally, median time to diagnosis of the second primary melanoma after the original diagnosis was 225 days (0.6 years) in previous indoor tanners versus 1,280 days (3.5 years) in non-tanners. These results imply that, because indoor tanners develop additional primary melanomas earlier than non-tanners, the follow up of melanoma patients ever exposed to sunbeds should be intensified.

In contrast with this, Muller et al. recently found that internal factors such as family history and genetic variants, as well as number of nevi and actinic damage on the back are more relevant than sunbed use for the development of subsequent melanomas after the diagnosis of the first melanoma.28

Proportions of melanomas attributable to sunbed use

Two recent studies calculated the melanoma burden attributable to the use of sunbeds in the French and in the German populations over 30 and 35 years of age, respectively.29,30 Arnold et al. found that 4.6% of melanoma cases in women and 1.5% in men in 2015 could be attributed to exposure to indoor tanning in France.29 Similarly, Gredner et al. found that 6.1% of melanoma cases in women and 3.5% in men in 2018 could be attributed to exposure to indoor tanning in Germany.30 Additional analyses indicated that the vast majority of these cases could be due to high intensity of sunbed use (>10 sessions/year), and that the proportions of melanomas attributable to sunbed use are higher in the youngest age categories. These data highlight that sunbed use is an important contributor to estimated melanoma cases both in France and Germany, and strengthen the need for setting prevention priorities for skin cancer, which should include anti-sunbed campaigns especially targeting younger ages.

Association of indoor tanning with melanoma risk factors

To date, the relationship of sunbed use with melanoma’s risk factors such as high nevus count, atypical nevi and sun damage has not been extensively studied. In a brand-new, large investigation on 227,888 participants in the Euromelanoma prevention campaign, we found that ever sunbed use was independently associated with high nevus count, presence of atypical nevi, lentigines, and suspicion of melanoma, after adjustments for age, gender, education, skin type, family history of melanoma, personal history of skin cancer, any sun exposure, and any sunscreen use.31 This study represents the first evidence that indoor tanning is significantly associated with well-recognized risk factors for melanoma in a thorough multivariate analysis.

Economic burden of sunbed use

Sunbed use has not only negative health consequences on individuals but also negative financial impacts on the society. Waters et al.32 recently calculated that the cost of direct medical care for melanomas and non-melanoma skin cancers (NMSCs) attributable to sunbed use in the US is $343.1 million annually, and they will lead to a total economic loss of $127.3 billion over the lifetime of the individuals affected. The authors claim that these figures may even underrepresent the reality, as there is no national registry NMSCs. Therefore, indoor tanning represents a major economic burden in terms of the costs of medical care and lost productivity.

Recent debate over whether sunbed use contributes to melanoma

In 2018, Burgard et al. published a meta-analysis of observational studies investigating the association of sunbed use with melanoma risk.20 Although they found similar results to those obtained by all previous meta-analyses on the subject (Table 1), surprisingly the authors interpreted their own findings in a different way. In their view, (i) the quality of the included observational studies is generally poor and biased; (ii) interventional trials on sunbed use and melanoma risk are lacking; and (iii) observational (cohort and case–control) studies can merely prove associations but not causality. Therefore they claim “there is no convincing evidence that moderate/responsible solarium use increases melanoma risk”.

We strongly disagree with Burgard et al.’s conclusions. First, the authors evaluated the quality of the included studies using the Newcastle-Ottawa Quality Assessment Scale, which can lead to arbitrary results.33 Secondly, in the case of sunbed use and melanoma, randomized clinical trials would be obviously unethical to perform given the carcinogenicity of indoor tanning. Thirdly, we believe that even in the lack of interventional studies, the large body of evidence coming from meta-analyses of observational studies provide enough data to infer that sunbed use does cause melanoma: indeed all the criteria for causality famously described by Hill in 1965 are met (Table 2).34 In particular, as for the strength of the association between sunbed use and melanoma risk, Burgard et al. argued that the increased risk of melanoma of around 20% for ever sunbed use could be merely due to a lack of good adjustments for confounders; however we would like to point out that first exposure in youth is associated with an increased risk of at least 59% in all meta-analyses, including their own study. The only exception is the study by Colantonio et al.,17 which included a cross-sectional study,35 a type of study design which by definition provides lower level of evidence. Finally, as previously pointed out by others,36 Burgard et al. did not consider two crucial studies – Lazovich et al. (2016)22 and Ghiasvand et al. (2017)24 – that confirmed the significant influence of age at first sunbed exposure on melanoma risk. These two studies, which we discussed early on in the current paper, were available prior to the publication of Burgard’s et al.’s meta-analysis but regrettably were not taken into account, nor mentioned.

Concurrently to Burgard et al., Reichrath et al.21 published a critical appraisal of the recent reports on sunbeds from the European Commission’s SCHEER18 and from the WHO,19 which –in their view– would be unbalanced, inaccurate and not scientifically sound. In addition to the same motives used by Burgard et al.,20 that we addressed above, Reichrath et al. adopted two further argumentations. First, that the meta-analysis by Colantonio et al.17 did not show a statistically significant association of sunbed use with melanoma risk in Europe. In fact, we would like to point out that in the Colantonio et al.’s study, (i) the summary estimate for Europe was 1.10 [95% confidence intervals (CI) 0.98-1.24] which, although borderline significant, was consistent with the estimates from the other regions [North America 1.23 (95% CI 1.03-1.47), Oceania 1.33 (95% CI 0.99-1.78)]; (ii) indeed, there was no statistically significant difference between estimates from Europe and other regions (p=0.38); and (iii) the overall risk estimate was statistically significant (Table 1). The fact that the risk estimate did not reach significance in some subgroup analyses of one single meta-analysis does not make the overall conclusions of the IARC/WHO14,19 and the European Commission18 unreliable. We would also like to point out that Colantonio et al. themselves concluded their paper by stating that “clinicians should continue to educate patients on the harms of indoor tanning and encourage its cessation”.17

Second, Reichrath et al. claimed that indoor tanning should be considered beneficial to humans in terms of its ability to increase serum vitamin D levels, a justification also employed by the sunbed industry.37 It is important to note that the International Commission on Illumination recently found that sunbeds cannot be recommended for maintaining optimal vitamin D levels during the winter, because of the risk and uncertainty surrounding the UV output of tanning beds.38 Indeed, sunbed use to improve vitamin D status cannot and should never be justified because of its well-established carcinogenic risk, as recently summarised by our group.39

Conclusion

We reported a review of the newest studies about the association of sunbed use with melanoma risk.

Recent research efforts have reinforced the previous knowledge about the detrimental effects of first sunbed exposure at a young age, especially in women. Moreover new insights regarding sunbed use have emerged, such as its relevance for the development of additional primary melanomas, its association with melanoma of the lower limbs (the most common body site in women), its relation with melanoma risk factors such as high nevus count, atypical nevi and sun damage, and its major economic burden on the society in terms of costs of medical care and lost productivity.

The current, updated body of scientific evidence strongly suggests that indoor tanning significantly increases the risk of melanoma. Some authors, as well as pro-sunbeds stakeholders, have used the lack of randomized clinical trials (which would be unethical) to imply that the relationship between sunbed use and melanoma is not causal. Interestingly, we showed that the large amount of data coming from observational studies provides enough information to infer that sunbed use does cause melanoma. Indeed, we were able to demonstrate the applicability of all the epidemiological criteria for causality to the relationship between sunbed use and melanoma. Hopefully, this will bury all scepticism and conclusively close the debate over whether sunbed use contributes to melanoma risk.

Key points

· New insights regarding sunbed use include its relevance for the development of additional primary melanomas, its association with melanoma of the lower limbs, its relation with melanoma risk factors, and its major economic burden on the society in terms of costs of medical care/lost productivity.

· The current, updated body of scientific evidence strongly suggests that indoor tanning significantly increases the risk of melanoma.

· The large amount of data coming from observational studies provides enough information to infer that sunbed use causes melanoma: all the epidemiological criteria for causality apply to the relationship between sunbed use and melanoma, especially for exposure at younger ages.

· The debate over whether sunbed use contributes to melanoma risk should be considered conclusively closed.

Tables

Table 1. Meta-analyses on melanoma risk associated with sunbed use

Meta-analysis

(First author, year)

Included studies [number (type)]

Included studies (timeframe)

Ever exposure*

First exposure in youth**

Gallagher et al. (2005)12

10 (9 CC, 1 CO)

1984-2004

1.25 (1.05-1.49)

1.69 (1.32-2.18)

IARC (2007)13

19 (18 CC, 1 CO)

1979-2005

1.15 (1.00–1.31)

1.75 (1.35–2.26)

Hirst et al. (2009)15

20 (19 CC, 1 CO)

1981-2006

1.22 (1.07–1.39)

-

Boniol et al. (2012)16

27 (24 CC, 3 CO)

1979-2012

1.20 (1.08-1.34)

1.87 (1.41-2.48)

Colantonio et al. (2014)17

31 (27 CC, 3 CO, 1 CS)

1981-2012

1.16 (1.05-1.28)

1.35 (0.99-1.84)

Burgard et al. (2018)20

31 (29 CC, 2CO)

1981-2015

1.19 (1.04- 1.35)

1.59 (1.38-1.83)

Summary risk estimate with 95% confidence intervals are shown both for ever exposure and first exposure in youth. CC, case-control study; CO, cohort study; CS, cross-sectional study.

*All summary risk estimates for ever exposure showed heterogeneity.

**All summary risk estimates for first exposure in youth showed no heterogeneity, but Colantonio et al.17 Cut offs for “youth” were: <25 years in Colantonio et al.17 and Burgard et al.20; <35 years in IARC13 and Boniol et al.16; various (<20, <25, <30, and ≤35 years, according to the particular study) in Gallagher et al.12

Table 2. Applicability of Hill’s causality criteria to meta-analyses on sunbed use and melanoma

Hill’s criteria for causality34

Applicability to meta-analyses on sunbed use and melanoma risk12,13,15-17,20

1. Strength of the association (effect size).

The larger the association, the more likely that it is causal. Nonetheless, a small association does not mean that there is not a causal effect

Ever exposure: risk estimate around 20%.

First exposure in youth: risk estimate ≥59% in all meta-analyses, with the exception of Colantonio et al.17 that included a cross-sectional study,35 a type of study design that by definition provides lower level of evidence.

2. Consistency (reproducibility).

Consistent findings observed by different persons in different places with different samples strengthens the likelihood of an effect

Ever exposure: significant between-study heterogeneity.

First exposure in youth: consistent lack of between-study heterogeneity.

3. Specificity.

Causation is likely if there is a very specific population at a specific site and disease with no other likely explanation. The more specific an association between a factor and an effect is, the bigger the probability of a causal relationship

Specific population: the risk estimates are higher for first exposure in youth, a sensitive period for skin cancer risk accumulation.

Specific site: sunbed exposure targets the skin and melanoma and NMSC are cutaneous diseases.

Other likely explanation: another likely explanation for skin cancer is obviously sun exposure, but:

· all previous meta-analyses included risk estimates adjusted for all available confounders, e.g. sun exposure, sunburn and phenotype;

· sunbed use has an effect on melanoma risk independently from the effect of sunburns.40,41

4. Temporality.

The effect has to occur after the cause (and if there is an expected delay between the cause and expected effect, then the effect must occur after that delay)

Three prospective cohort studies found significant associations of sunbed use in youth with melanoma risk

· Veierød et al. (2003):42 compared with women who never used a solarium at ages 20–29 years, women who reported using a solarium ≥1 time/month during that age period had a relative risk of melanoma later in life of 2.58 (95% CI 1.48-4.50) (adjusted for age, region, hair colour, sunburn, summer vacations; n=89,142).

· Nielsen et al. (2011):43 compared with women who never used a solarium at ages 25–39 years, women who reported using a solarium >10 times/year during that age period had a relative risk of melanoma later in life of 2.5 (95% CI 1.0-6.2) (adjusted for host factors, UV exposure and sunscreen use).

· Ghiasvand et al. (2017):24 compared with women who never used a solarium, women who started using sunbeds before age 30 had an odds ratio of melanoma 1.34 (95% CI 1.05-1.66).

5. Biological gradient.

Greater exposure should generally lead to greater incidence of the effect.

Boniol et al. (2012) found a 1.8% (95% CI 1.0%-3.8%) increase in risk of melanoma for each additional annual session of sunbed use (dose-response effect).16

Ghiasvand et al. (2017) found increasing risk of melanoma with increasing number of lifetime sessions of indoor tanning.24

6. Plausibility.

A plausible mechanism between cause and effect is helpful in determining causality.

The association is plausible because (i) laboratory, animal and human studies on healthy volunteers showed that UVA and UVB are carcinogens; and (ii) sunbeds emit UVA and UVB (summarized by IARC).1

7. Coherence.

Coherence between epidemiological and laboratory findings increases the likelihood of a causal effect.

Laboratory findings showed that UVA and UVB are able to cause DNA damage and immunosuppression.1 Evidences from epidemiological studies, summarized in meta-analyses,11-13,15-17 are coherent with the laboratory findings. For these reasons, the whole spectrum of UV radiation is now classified as a first group carcinogen by the IARC.14

8. Experiment.

Experimental evidence is helpful in determining causality.

Randomized controlled trials would be unethical and therefore cannot be performed, as it was the case with cigarette smoking and lung cancer.

However, Hill noted that: (i) "... lack of such evidence cannot nullify the epidemiological effect on associations"; and (ii) "… occasionally it is possible to appeal to experimental evidence".34

9. Analogy.

The effect of similar factors may be considered.

The effect of the most similar factor (sun exposure) on melanoma risk is widely established.11

CI, confidence intervals; IARC, International Agency for Research on Cancer (an agency of the World Health Organization).

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12.Gallagher RP, Spinelli JJ, Lee TK. Tanning beds, sunlamps, and risk of cutaneous malignant melanoma. Cancer Epidemiol Biomarkers Prev. 2005;14(3):562-6.

13.IARC. The association of use of sunbeds with cutaneous malignant melanoma and other skin cancers: A systematic review. Int J Cancer. 2007;120(5):1116-22.

14.El Ghissassi F, Baan R, Straif K, et al. A review of human carcinogens--part D: radiation. Lancet Oncol. 2009;10(8):751-2.

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16.Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ. 2012;345:e4757.

17.Colantonio S, Bracken MB, Beecker J. The association of indoor tanning and melanoma in adults: systematic review and meta-analysis. J Am Acad Dermatol. 2014;70(5):847-57 e1-18.

**18.SCHEER (Scientific Committee on Health Environmental and Emerging Risks). Opinion on Biological effects of ultraviolet radiation relevant to health with particular reference to sunbeds for cosmetic purposes, 17 November 2017. Available at http://ec.europa.eu/health/scientific_committees/scheer/docs/scheer_o_003.pdf (accessed: December 15th, 2018).

** Important official document from the European Commission, stating that there is no safe limit for UV exposure coming from sunbeds. It nicely summarizes the scientific data about sunbed use.

*19.World Health Organization. Artificial tanning devices: public health interventions to manage sunbeds. 2017; available at https://www.who.int/uv/publications/artificial-tanning-devices/en/ (accessed: December 15th, 2018).

* Elegant and practical document from the WHO, giving clear indications about public health interventions with regard to sunbed use.

**20.Burgard B, Schope J, Holzschuh I, et al. Solarium Use and Risk for Malignant Melanoma: Meta-analysis and Evidence-based Medicine Systematic Review. Anticancer Res. 2018;38(2):1187-99.

** Meta-analysis on sunbed use and risk of melanoma. This paper openly criticises the quality/strenght of the evidence linking indoor tanning with melanoma obtained by several meta-analyses (including their own)

**21.Reichrath J, Lindqvist PG, FR DEG, et al. A Critical Appraisal of the Recent Reports on Sunbeds from the European Commission's Scientific Committee on Health, Environmental and Emerging Risks and from the World Health Organization. Anticancer Res. 2018;38(2):1111-20.

** Another paper that openly questions the evidence for the association of sunbed use with melanoma, using vitamin D as one of the main motives.

**22.Lazovich D, Isaksson Vogel R, Weinstock MA, et al. Association Between Indoor Tanning and Melanoma in Younger Men and Women. JAMA Dermatol. 2016;152(3):268-75.

** First study examining age- and sex-specific associations between indoor tanning and melanoma. This study implies that indoor tanning is a likely factor for the steeper increase in melanoma rates among younger women.

23.Coelho SG, Hearing VJ. UVA tanning is involved in the increased incidence of skin cancers in fair-skinned young women. Pigment Cell Melanoma Res. 2010;23(1):57-63.

**24.Ghiasvand R, Rueegg CS, Weiderpass E, et al. Indoor Tanning and Melanoma Risk: Long-Term Evidence From a Prospective Population-Based Cohort Study. Am J Epidemiol. 2017;185(3):147-56.

** Large population-based, prospective cohort study. This study provides strong evidence of the strength, dose response, and temporality of the association between sunbed use and melanoma risk, especially for first exposure at young ages.

25.Mayer JE. Re: "Indoor tanning and melanoma risk: long-term evidence from a prospective population-based cohort study.". Am J Epidemiol. 2017;186(6):748.

**26.Ghiasvand R, Robsahm TE, Green AC, et al. Association of Phenotypic Characteristics and UV Radiation Exposure With Risk of Melanoma on Different Body Sites. JAMA Dermatol. 2018.

** First study to demonstrate an association between indoor tanning and increased risk of melanoma of the lower limbs, the most common site of melanoma in women

**27.Li Y, Kulkarni M, Trinkaus K, Cornelius LA. Second primary melanomas: Increased risk and decreased time to presentation in patients exposed to tanning beds. J Am Acad Dermatol. 2018;79(6):1101-8.

** First study demonstrating that indoor tanners develop additional primary melanomas earlier than non-tanners. It implies that the follow up of melanoma patients ever exposed to sunbeds should more intense.

28.Muller C, Wendt J, Rauscher S, et al. Risk Factors of Subsequent Primary Melanomas in Austria. JAMA Dermatol. 2018.

*29.Arnold M, Kvaskoff M, Thuret A, et al. Cutaneous melanoma in France in 2015 attributable to solar ultraviolet radiation and the use of sunbeds. J Eur Acad Dermatol Venereol. 2018;32(10):1681-6.

* Important study calculating the melanoma burden attributable to sunbed use in French individual aged >30 years.

*30.Gredner T, Behrens G, Stock C, et al. Cancers Due to Infection and Selected Environmental Factors. Dtsch Arztebl Int. 2018;115(35-36):586-93.

* Important study calculating the melanoma burden attributable to sunbed use in German individual aged >35 years.

**31.Suppa M, Gandini S, Njimi H, et al. Association of sunbed use with skin cancer risk factors in Europe: an investigation within the Euromelanoma skin cancer prevention campaign. J Eur Acad Dermatol Venereol. 2019; (in press).

** First study to clearly demonstrate an independent association between indoor tanning and melanoma risk factors. It reinforces the evidence that sunbed use contributes to melanoma risk.

*32.Waters HR, Adamson A. The health and economic implications of the use of tanning devices. Journal of Cancer Policy. 2018;17(Sept):45-50.

* Important study calculating the health-related economic burden of sunbed use in the US

33.Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603-5.

34.Hill AB. The Environment and Disease: Association or Causation? Proc R Soc Med. 1965;58:295-300.

35.Schmitt J, Seidler A, Heinisch G, Sebastian G. Effectiveness of skin cancer screening for individuals age 14 to 34 years. J Dtsch Dermatol Ges. 2011;9(8):608-16.

*36.ANSES. Opinion of the French Agency for Food, Environmental and Occupational Health & Safety on exposure to artificial ultraviolet radiation emitted by sunbeds. 2018; available at https://www.anses.fr/en/content/opinion-anses-exposure-artificial-ultraviolet-radiation-emitted-sunbeds (accessed: December 15th, 2018).

* Excellent summary of the scientific data about sunbed use and melanoma risk.

37.Union of Concerned Scientists website. The Indoor Tanning Association Used Misleading Ad Campaigns to Distort Skin Cancer Science. Available at https://www.ucsusa.org/distorting-science-skin-cancer - .WvM_stOFM_N (accessed: December 15th, 2018).

38.International Commission on Illumination. Maintaining Summer Levels of 25(OH)D During Winter by Minimal Exposure to Sunbeds: Requirements and Weighing the Advantages and Disadvantages. CIE Technical report 219. 2016; available at https://www.techstreet.com/mss/products/preview/1922662 (accessed: December 15th, 2018).

*39.Pierret L, Suppa M, Gandini S, et al. Overview on vitamin D and sunbed use. J Eur Acad Dermatol Venereol. 2019; (in press).

* Up-to-date overview on the hot topic "vitamin D and sunbed use". It rectifies the misleading messages often delivered by the sunbed industry.

40.Vogel RI, Ahmed RL, Nelson HH, et al. Exposure to indoor tanning without burning and melanoma risk by sunburn history. J Natl Cancer Inst. 2014;106(7).

41.Boniol M, Dore JF, Greinert R, et al. Re: Exposure to indoor tanning without burning and melanoma risk by sunburn history. J Natl Cancer Inst. 2015;107(5).

42.Veierod MB, Weiderpass E, Thorn M, et al. A prospective study of pigmentation, sun exposure, and risk of cutaneous malignant melanoma in women. J Natl Cancer Inst. 2003;95(20):1530-8.

43.Nielsen K, Masback A, Olsson H, Ingvar C. A prospective, population-based study of 40,000 women regarding host factors, UV exposure and sunbed use in relation to risk and anatomic site of cutaneous melanoma. Int J Cancer. 2012;131(3):706-15.

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