A Critique of the IARC Meta-Analysis of the Association of Sunbed Use with Melanoma

1. A Critique of the IARC Meta-Analysis of the Association of Sunbed Use with Melanoma William B. Grant, Ph.D. Director, SUNARC Presentation to the FDA, March 25, 2010

2. Main Points • A causal link between sunbed use and risk of melanoma has not been made, since several of the criteria for causality in a biological system have not been satisfied. • The health benefits of sunbed use greatly outweigh any health risks.

3. Criticism No. 1 • The IARC report included studies from the UK without correction for skin type and genetic risk (variant of the MC1R gene) for melanoma. • When the 5 UK studies are omitted, the odds ratio of melanoma from ever use of sunbeds drops to about 1.05 (95% CI, 0.93-1.19). • WB Grant. Critique of the International Agency for Research on Cancer meta-analyses of the association of sunbed use with risk of cutaneous malignant melanoma. Dermato-Endocrinology, Nov-Dec 2009; 1(1) epub.

4. The Five UK Studies

5. The Other 14 Studies + 1:Not Statistically Significant

6. Criticism No. 2 • In the only US study of melanoma incidence with respect to first use of sunbeds prior to age 35 years in the IARC report, the commercial sunbed data were conflated with those from home sunlamp use. The lamps and use patterns differ for the two UV systems. • An estimate for the odds ratio for commercial sunbed data prior to age 30 years based on 23 cases was 0.80 (95% CI, 0.43-1.49), not 1.3 as used in the IARC report. • Chen YT, Dubrow R, Zheng T, Barnhill RL, Fine J, Berwick M. Sunlamp use and the risk of cutaneous malignant melanoma: a population-based case-control study in Connecticut, USA. Int J Epidemiol. 1998 Oct;27(5):758-65.

7. Graph of Relative Risk for Melanoma for First Use Before Age 35 Years vs. Latitude I I I I I I RR

8. Criticism No. 3 • Using studies from Northern Europe for first use of sunbeds prior to age 35 years to guide policies in the U.S is incorrect: • Sunbeds used in Europe are limited to 1.5% UVB of total UV; those in the U.S. generally have 3-5% UVB, as does midlatitude, midday solar UV. • UVB in moderation and vitamin D reduce the risk of melanoma.

9. Criticism No. 4 • Many of the studies in the IARC meta-analysis did not control for confounding factors. • Several authors admitted that it is very difficult to separate out the effects of solar UV irradiance from sunbed use.

10. Confounding Factors for Melanoma • Risk factors: • Skin type 1, variant of the MC1R gene among those with Celtic ancestry (red hair, freckles) • Travel to sunny locations & sunburning • Nevi • Use of sunscreen that increases exposure to UVA when sunburning is not a risk • High-fat diet • Risk reduction factors: • UVB, vitamin D, fruits, vegetables, sunscreen to reduce sunburning, dark skin, smoking

11. Criticism No. 5 • Chronic sun exposure as from occupation is not a risk factor for melanoma.* • Sunbed use in the United States does not result in sunburning. • Therefore, sunbed use is likely akin to chronic sun exposure and should not increase risk of melanoma. • *Chang YM et al. Sun exposure and melanoma risk at different latitudes: a pooled analysis of 5700 cases and 7216 controls. Int J Epidemiol. 2009 Jun;38(3):814-30.

12. Meta-Analysis of Chronic Sun Exposure [Chang et al., 2009]

13. Meta-Analysis of Recreational Sun Exposure

14. The Roles of UVA and UVB in Risk of Melanoma • Evidence from sunscreen use • Evidence from latitude in Europe • Evidence from studies of second cancers

15. Do sunscreens increase risk of melanoma in populations residing at higher latitudes? • BACKGROUND: Sunscreens may allow overexposure to ultraviolet A (UVA) in fair-skinned persons and prevent symptoms of sunburn, but their benefits for the prevention of melanoma are uncertain. • METHODS: A PubMed search was performed that identified all known studies of the association of sunscreen use with melanoma risk during 1966-2007. A total of 18 studies were identified, of which 17 met criteria for inclusion in the analysis. Of these, 10 were conducted at latitudes >40 degrees from the equator and 7 at <or=40 degrees . Data were pooled for all latitudes combined and also according to these latitude strata. The association of skin pigmentation and latitude with odds ratios was estimated using linear regression. • RESULTS: There was an interaction with latitude. At >40 degrees from the equator, the odds ratio was 1.6 (95% C.I. 1.3-1.9; p for heterogeneity = 0.006), whereas it was 0.7 at <or=40 degrees (95% C.I. 0.4-1.0; p for heterogeneity = 0.0002). • CONCLUSIONS: Use of common sunscreen formulations that absorb UVB almost completely, but transmit large quantities of UVA, may contribute to risk of melanoma in populations at latitudes >40 degrees. • Gorham ED, Mohr SB, Garland CF, Chaplin G, Garland FC. Ann Epidemiol. 2007 Dec;17(12):956-63.

16. Evidence that UVB Reduces Risk of Melanoma • In Western Europe, melanoma rates increase with latitude while non-melanoma skin cancer (NMSC) rates decrease. Skin pigmentation also plays a role. • Melanoma mortality rate inversely correlated with NMSC mortality rate in Spain. Total UVB irradiance is the primary risk factor for NMSC deaths. • Grant WB. An ecologic study of cancer mortality rates in Spain with respect to indices of solar UVB irradiance and smoking. Int J Cancer. 2007 Mar 1;120(5):1123-8. • Second cancer incidence rate was increased in sunny countries after melanoma, but decreased for NMSC. • Tuohimaa P, et al. Does solar exposure, as indicated by the non-melanoma skin cancers, protect from solid cancers: vitamin D as a possible explanation. Eur J Cancer. 2007 Jul;43(11):1701-12.

17. Causality in a Biological System • AB Hill laid down the criteria in 1965, including: • Strength of association • Consistent findings in different populations • Dose-response relation, possibly linear • Mechanism(s) • Analogy with other findings • Experiment (e.g., randomized controlled trial) • Later, two more factors were added: • Accounting for confounding factors • Removing bias

18. The Sunbed-Melanoma Link Does NOT Satisfy Hill’s Criteria for Causality • Sunbed use fails causality • for failing to account for confounding factors in many studies. • on strength of association • on dose-response relation • by analogy to solar UV irradiance, since chronic sun exposure is not associated with increased risk for melanoma [Chang, 2009]. • because the link has not been experimentally verified. Note that the IARC demanded randomized controlled trials to prove that vitamin D reduces risk of cancer.

19. IARC Working Group Report 5: Vitamin D and Cancer (2008) • “The few studies on cohorts of cancer patients (and in patients with cardiovascular disease) suggest that a low serum 25-hydroxyvitamin D level could be associated with decreased survival, but it remains to be established whether the association is a causal one.” • “The only way to disentangle the issue of ‘indicator or predictor’ versus ‘causal factor’ is tomount new randomised trials for verifying the impact of vitamin D on all-cause mortality and on the incidence and mortality from common cancers and other conditions.”

20. Ting et al. Tanning Bed Exposure; Int J Dermatol 2007 • This study had only 79 cases of melanoma compared to 5979 cases from non-Celtic studies in IARC report (1.3%). • It did not control for confounding factors. • No data were used regarding natural UV exposure and other risk-modifying factors. • Of the 551 with completed questionnaires (out of 1518 patients with some data), data were provided but not included in the analysis: • 29 had a history of melanoma • 80 burn rather than tan (2.8x melanoma) • 196 had 2-5 sunburn episodes (6.8x melanoma) • 48 had >6 sunburn episodes (1.7x melanoma)

21. Vitamin D Production in Sunbeds • A few-minute sunbed session produces >10,000 IU of vitamin D3. • Documented benefits of sunbed use: • reduced incidence of endometrial cancer and thrombotic events in Sweden. • associated with higher serum 25(OH)D levels and bone mass density in Boston.

22. Benefits of Vitamin D • Vitamin D reduces the risk of about 18 types of cancer including melanoma, cardiovascular disease, diabetes, respiratory infections, septicemia, autoimmune diseases such as multiple sclerosis, etc., as reported in ecological, cross-sectional, observational studies and RCTs • New benefits being identified almost weekly. • Increasing serum 25(OH)D levels to 45 ng/mL from 26 ng/mL (White Americans) should reduce mortality rate by 15% and increase life expectancy by 2 years.

23. WB Grant. In defense of the sun: An estimate of changes in mortality rates in the United States if mean serum 25-hydroxyvitamin D levels were raised to 45 ng/mL by solar ultraviolet-B irradiance.* • This study estimates increases in melanoma and nonmelanoma skin cancer mortality rates and decreases in chronic and infectious disease mortality rates in the US from doubling population doses of solar UVB to increase mean serum 25(OH)D levels from 16 ng/mL for black Americans and 25 ng/mL for white Americans to 45 ng/mL. Although a few thousand excess deaths per year might occur from melanoma and skin cancer, the avoided premature death rate could be near 400,000/year, with most of the avoided deaths coming late in life. While oral sources of vitamin D could be used instead of UVB or when UVB irradiance is not available, public health policies do not yet recommend the 3000-4000 IU/day required to raise serum 25-hydroxyvitamin D levels to the levels required for optimal health, which would be required before vitamin D fortification levels in food can be raised. Until then, moderate solar UVB irradiance remains an import source, and the health benefits greatly outweigh the risks. • * Dermato-Endocrinology 1(4), 207, 2009

24. After Carefully Weighing the Risks and Benefits ...

25. Summary and Conclusion • The IARC meta-analysis did not claim or establish that sunbed use is a significant risk factor for melanoma in the United States. • For sunbeds with 3-5% of the UV in the UVB spectral region, the health benefits of moderate use greatly outweigh the adverse effects for most people.