Philippe AUTIER, MD, MPH

Transcription

1 Philippe AUTIER, MD, MPH International Agency for Research on Cancer (IARC) 150 Cours Albert Thomas F Lyon Cedex 08, France Tel: +33-(0) March 2, 2006 Comments on SCCP document of 13 December 2005 on Preliminary Opinion on biological effects of ultraviolet radiation relevant to health with particular reference to sun beds for cosmetic purposes. These comments represent views of Dr Philippe Autier and do not represent an official position document of the International Agency for Research on Cancer (IARC). 1 A report of the IARC Working Group on sunbeds and skin cancer has been submitted for publication. The Opinion represents a good starting point for the answers to be provided by the scientific committee. Although not being an in-depth review, the Opinion has considered a large body of scientific literature relevant to topic. 1 The IARC is mentioned on page 5 of the Opinion document as an organization contributing to the discussion, but no official demand has been addressed by the EC or by the SCCP to the IARC, asking for collaboration on this subject. 1

2 General comments 1. The Opinion does not mention that exposures to powerful sources of UVA radiations as those prevailing during indoor tanning do not exist on Earth surface (a part from high altitudes), and repeated exposures to high doses of UVA constitute a new phenomenon in human beings, and that there is little laboratory research in humans or in animals providing knowledge on likely long-term biological and health consequences of such exposures. 2. The Opinion does not sufficiently take into account the fact that indoor tanning was not frequent before 1980, and that it exploded in European populations (first in mainly Nordic countries, UK, the Netherlands, Germany) in the 1990s. At present, there is no sign of leveling-off of the sunbed fashion that is now gaining success in Southern Europe and Central Europe. Because of the time-lag existing between exposure to carcinogenic agents and cancer occurrence, the influence of high prevalence of indoor tanning that took place end of 20 th century on skin cancer incidence will probably not be noticeable before say In that respect, most epidemiological studies on sunbed use and skin cancer were done in the 1980s and 1990s, and these studies could only appraise the impact of sunbed use that took place in the 19770s and 1980s, when that fashion was much less prevalent. Hence, potential public health consequences of indoor tanning are ahead of us, and most likely that examination of consequences prevailing today largely underestimate consequences to come in next decades. 3. The Opinion refers to the IARC Monograph on UV light (1992), but does not mention that this Monograph classified the UVB and UVA radiations, as well as sunbeds, as "agent probably carcinogenic to humans" (group 2A of the IARC classification of carcinogenic agents). 4. As a general rule, technical documents intended to shape public health policies should be based on evidence-based knowledge. If evidence-based knowledge is lacking, the knowledge basis should consist in results that although still being indecisive, have 2

3 consensual support from a large body of the scientific community. Theories of speculative nature, or peculiar interpretation of research data, or data originating from study designs inadequate for investigating exposure-disease relationships (such as ecological studies), or studies done and opinions issued by scientists having conflict of interest, should be avoided in documents examining relationships possibly existing between a risk factor and a disease. 5. We found no sentence on ocular melanoma, when several studies have found an association between sunbed use and this cancer. 6. There is now a great deal of speculations on indoor tanning, vitamin D, vitamin D insufficiency, and chronic disease, including cancer. The Opinion is far too much preoccupied by that issue. We add hereafter some more documented arguments on this issue. There is still no longitudinal cohort or prospective randomized study that has evaluated the influence and side effects of increased vitamin D intakes on the incidence or mortality of any cancer, or of other chronic diseases (Giovannucci, 2005). Furthermore, several recently published important studies provide insights undermined the likelihood of an eventual vitamin D-cancer relationship. Sixteen randomized trials with oral vitamin D supplements have been conducted in elderly persons, on the basis of epidemiological observations associating high fracture risk with low serum 25-hydroxyvitamin D levels. A Cochrane review showed that these trials provided evidence of a modest protective effect of supplementation with both vitamin D and calcium on fracture risk, but not with vitamin D alone (Avenell 2005). Also, among the participants included in the 16 trials, the risk of all-cause mortality was non-significantly reduced by 5% (95% CI: -11%;2%) in subjects taking vitamin D supplements. One double blind randomized trial of vitamin D supplementation in 2686 people aged years living in the general community found after five years a significantly reduced number of fractures in the group that received the equivalent of 800 UI oral vitamin D every day (Trivedi 2005). Interestingly, that trial also reported incidence data for other diseases and found non-significant small increases in the incidence of all 3

4 cancers (274 events), colon cancer (55 events), respiratory cancers (32 events) and cardiovascular diseases (980 events) in subjects who received vitamin D supplements. A recent meta-analysis of longitudinal cohort studies on omega-3 intakes, essentially through consumption of fish or fish oil supplements showed no impact on breast and colorectal cancer risk (MacLean et al, 2006). Oily fish and fish oil are also significant sources of vitamin D, and thus this study does not support a preventive impact of vitamin D intakes on risk of major cancers. These results give little support to the hypothetical ability of vitamin D to reduce mortality from many common and potentially fatal diseases. People wishing to increase their vitamin D status may rely on vitamin D oral supplements and on various foods fortified with vitamin D, rather than increasing their UV exposure either through sun exposure or indoor tanning, as these exposures are associated with increased risk of skin cancers, particularly of melanoma (Lim 2005). Specific comments Page 8 Melanoma: Vitamin D is not relevant in this section, and there is at present no known relations hip between lower vitamin D and lower melanoma incidence in Blacks. The discussion of melanoma incidence according to skin colour should be shortened: If skin colour is a key determinant of melanoma risk, indoor tanning is more prevalent in light than in ark skinned people, and many subjects who have only little ability to tan do use sunbeds. Page 9, third paragraph There is some confusion between numbers and size of acquired nevi, and the atypical mole syndrome. Most subjects with numerous or large nevi do not suffer from the atypical mole syndrome. Twin studies show that genetic factors would account for 4

5 around 80% of nevi counts, but only for 20% of large and/or atypical nevi and of melanoma. Although numerous nevi and their size are the strongest individual risk factor for melanoma, there is growing evidence that genetic factors implicated in nevi development are distinct from those implicated in melanoma occurrence. Also, sun exposure is the main environment determinant of nevi number and size. Page 11, positive effects The concept of vitamin D insufficiency promoted by M Holick is essentially speculative. Ecological studies are not adequate designs. Vitamin and internal malignancies is the suggestion of few scientists, and alternative hypothesis may be formulated (eg., omega 3). All that paragraph should be deleted, or it should be clearly stated that at present, these ideas have only the status of hypothesis (see section on Vitamin D). Page 12, third line Do authors mean that epidemiological studies done before 1995 addressed low rates of sunbed use? (see general comment No. 2). Page 12, last paragraph We agree about that PUVA is not relevant to indoor tanning, and that all but one PUVA cohorts found no increase in melanoma incidence, but the study by Stern et al showing increased melanoma incidence in one cohort of PUVA patients should be cited (Stern et al 1997; Stern et al, 2001). Page 19, paragraph 2 I do not at all agree with last line support the view only that frequent use is deleterious : After adjustment for intermittent sun exposure and host characteristics, the Norway- Swedish study found a 55% increase in melanoma risk (95% CI: 4 to 132%) among the 5

6 18% women 10 to 39 years old who reported having used sunbed at least once a month when they were 10-19, or years old. Twelve sunbed sessions per year correspond to the twelve-session tanning programme proposed by many commercial tanning facilities, and thus the 55% increase in melanoma risk relates to 40 hours of sunbed use or more. This amount of sunbed use is common and thus deleterious effects occur for common amounts of sunbed use. Page 19, third paragraph The meta-analysis of Gallagher et al is particularly important as it show the consistent increase in melanoma risk with indoor tanning starting in adolescence of young adulthood. It is well established that young age is a period of greater vulnerability to carcinogenic effects of UV radiation. Since many sunbed users start when being young, the result on young adults should be much more emphasized in the Opinion document. Page 19, last sentence Combination of SPF is not appropriate as controversies also surround the role of sunscreens in melanoma occurrence (see IARC handbook on sunscreens), and that the small SPF afforded by sunbed-induced tan does not protect against sun-induced DNA damage, but may well conduct to longer stays in the sun, hence increasing the melanoma risk (Hemmincki et al, 1999). Page 20, first paragraph This paragraph should be deleted. 6

7 Page 22 and 23: Numbers of melanoma deaths attributable to indoor tanning Invoking the argument of numbers of deaths in the Opinion is unacceptable on ethical grounds and more difficult to assess than assumed in the Opinion. Ethical aspects The Opinion puts into perspective a death toll attributable to a purely cosmetic fashion, as if acceptable number of deaths could eventually be envisioned for cosmetic products. As a matter of fact, in the state of current knowledge, no Ethical Committee would accept an intervention study with indoor tanning that implies the possible causation of cutaneous melanoma. When it goes about cosmetics, just one death due to use of a given cosmetic is perfectly unacceptable, mainly when it is not an accidental or an unforeseeable event, but well a known fact due to cutaneous melanoma triggered by indoor tanning fashion. Sunscreens containing 5-metoxypsoralens (a tanning activator and potent photcarcinogen) were according EC regulations, considered as cosmetic products. Cosmetic products containg > 1 ppm of 5-MOP were banned in the EC in Calculations show that use of 5-MOP in France until 1995 caused 130 deaths from cutaneous melanoma 2. Hence, arguments resting on possible numbers of deaths associated with sunbed use are of little relevance. Methodological aspects On methodological grounds, calculations of numbers of deaths attributable to indoor tanning may be very different than displayed in the Opinion. First, results displayed in Table in the Opinion do not provide a correct appreciation of death toll attributable to indoor tanning in the UK. There is a time-lag of 15 to 30 years between exposure and melanoma occurrence, and since indoor tanning steadily increases, numbers of deaths will also increase with time, and thus figures in the 2 Details of calculations available from Ph Autier. 7

8 Table 3 of the Opinion are misleading because they provide no idea of increasing deaths numbers likely to occur in the near future as a consequence of indoor tanning. Second, we calculated death toll in 2002, using figures displayed in Table 3 of the Opinion, and using the classic Levin s formulae (1953) for attributable risk (AF), also cited in Heller et al, BMJ, 2003: AF = prevalence* ( RR 1) [ prevalence* ( RR 1) ] + 1 Our computations in Table 1 suggest 114 deaths due to indoor tanning in the UK in year Table 1 Estimation of deaths from cutaneous melanoma* caused by indoor tanning in the UK in 2003, using figures in Table 3 of the Opinion. Prev Sunbed use P(RR-1) P(RR- 1)+1 AF No cut. mel. deaths in 2002 Males 5% % 41 Females 9% % 73 *No. of cutaneous melanoma deaths in the UK in 2002 taken as 1685 (Globocan, IARC 2002). Potential time-trends for deaths attributable to indoor tanning in the EU Thirdly, we estimated deaths due cutaneous melanoma taking summary relative risk (RR) from the meta-analysis of Gallagher et al, who found a RR of 1.25 for ever vs. never use of indoor tanning, and a RR of 1.69 for sunbed use starting in adolescence or in young adulthood. We took the total annual number of deaths due to melanoma in year 2002 in the EU countries, i.e., deaths (data Globocan 2002 from IARC). We estimated a 8

9 mean of 0.5% annual increase in mortality from cutaneous melanoma, hence melanoma deaths in In 2002, most deaths attributable to indoor tanning can be derived from the prevalence of ever/never use that took place some 15 years hence, say, no more than 5% for the entire EU (see table 2). Prevalence of sunbed use is highly variable across the EU but tend to increase in all nations. With successive generations starting indoor tanning use at young age, by 2040, the RR of 1.69 related to sunbed use starting before approximately 30 years of age will become applicable to all age groups, and as many as 20% of EU citizens of all age could have started sunbed use during adolescence or young adulthood. In these circumstances, the death toll attributable to indoor tanning is likely to substantially increase. Table 2 Number of deaths from cutaneous melanoma Attributable to sunbed use in the EU State Members Year 2006 Year 2040 Prevalence sunbed use AF* No. Deaths AF No. Deaths 5% 1.2% % % 2.4% % % 4.8% % 1679 *RR for ever sunbed use vs. never = 1.25 (95%CI: ) (Gallagher et al, 2005) RR for sunbed use starting in adolescence or in young adulthood = 1.69 (95%CI: ) (Gallagher et al, 2005) In conclusion, we think it s better to delete deaths estimates in the Opinion document. If death estimates were kept, then the full picture in the EU should be given, according to known indoor tanning prevalence in EU countries, with the evolution over the next 30 or 40 years. Page 24, question 2 9

10 Melanoma risk associated with sunbed use in young adulthood should be a point specifically raised in this summary point section. Page 25, question 4 Same remark as for Question 2 on page 24. Page 25, second bullet point 25 SED per hour is far too high, and is difficult to accept in the current state of absence of knowledge of health effect of exposure to high UV fluxes, while there are strong suggestions of cancerous effects, mainly when sunbed use start during adolescence or young adulthood. Norms suggested by Nordic countries should represent the upper limit. References Avenell A, Gillespie WJ, Gillespie LD, O'Connell DL. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. The Cochrane Database of Systematic Reviews 2005, Issue 3. Art.No.: CD pub2. DOI: / CD pub2. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: A review (United States). Cancer Causes Control 2005; 16: Hemminki K, Bykov VJ, Marcuson JA. Re: Sunscreen use and duration of sun exposure: A double-blind, randomised trial. J Nat Cancer Inst 1999, 91, International Agency for Research on Cancer Expert Group (2001). Sunscreens. IARC Handbooks of Cancer Prevention, Vol. 5. Lyon, Levin ML. The occurrence of lung cancer in man. Acta Unio Internationalis Contra Cancrum. 1953;9: Lim HW. Sunlight, tanning booths, and vitamin D. J. Am. Acad. Dermatol. 52, (2005). MacLean CH, Newberry SJ, Mojica WA et al. Effects of Omega-3 Fatty Acids on Cancer Risk. A Systematic Review. JAMA. 2006;295:

11 Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. N Engl J Med 1997, 336, Stern RS, and the PUVA Follow-up Study. The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol 2001, 44, Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D 3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomized double-blind controlled trial. BMJ 2003; 326: