Cover Page. The handle holds various files of this Leiden University dissertation

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1 Cover Page The handle holds various files of this Leiden University dissertation Author: Miller, Sharon Title: Optimization of UV exposure schedules for tanning Issue Date:

2 Chapter 1 Introduction 11

3

4 Introduction Background The main source of human exposure to UV is the sun. However, approximately 1,000,000 individuals patronize indoor tanning salons in the US on any given day (De Leo, 1994). Of the approximately 28,000,000 Americans (ca. 10% of the current population) who frequent tanning salons (ibid.), over 2/3 are women (Todays Image, 2000). Additionally, although not well quantified, large numbers of people use tanning lamps in the home. Thus, assuming that people who attempt to tan indoors will do the same outdoors, these tanning lamp users currently receive significant cumulative doses of UV radiation, both from artificial UV sources and the sun. People who choose to tan (either indoors or outdoors) typically report that a tan makes them feel more attractive (Robinson, 2008). There is also limited information indicating that tanning causes increased endorphin levels (Levins, 1983). Other benefits purported by the indoor tanning industry include the protection afforded by a base tan, production of Vitamin D (Today s Image, 2000), and lowering of blood pressure thru nitric oxide (NO) release by UVA (Liu, 2014.). It is well-known that UV radiation from either the sun or artificial sources can cause erythema and DNA damage in human skin in the short-term (Gange, 1982; Katiyar, 2000) and that repeated exposures can lead to carcinogenesis and photoaging in the long term (Fears, 1977; Scotto, 1987; Armstrong, 2001; Karagas, 2002; van Weelden, 1988). More than 3,500,000 new cases of skin cancer (including basal cell, squamous cell and melanoma) are diagnosed each year in the U.S., and over 15,000 deaths are expected in 2015 that can be attributed to skin cancer (American Cancer Society, 2015). These effects become apparent predominantly later in life, but, in the US, a rising trend of melanoma incidence has been noted in women aged (Purdue, 2008), possibly associated with increased use of indoor tanning (Coelho, 2009). Tanning courses/exposure schedules and erythema The current recommended exposure schedule for indoor tanning in the U.S. (FDA Policy Letter, 1986) suggests that a patron should receive no more than 0.75 Minimal Erythema Doses (MED*) *1 MED = 156 J/m 2 calculated according to the FDA Policy Letter, 1986, using the CIE Lytle action spectrum. 13

5 per session for the first 3 sessions (during 1 st week), and that this dose can be increased to up to 4 MED* per session, 3 times per week, by the 4 th week, and thereafter for maintenance. This pattern of exposure, if carried out over a year s time, could lead to an individual receiving up to 890 SED/yr [SED = Standard Erythemal Dose; one SED = 100 J/ m 2, weighted with the CIE Reference Action Spectrum for Erythema, CIE, 1998]. This is more than 3.5 times the average annual UV exposure received from the sun in the U.S. (25,000 J/m 2 =250 SEDs; range: SEDs) (Scotto, 1983). However, typical annual use is reportedly significantly lower than what is allowed by the FDA guidance; with estimated annual doses for typical users of 40 MED/yr (ca. 80 SED/yr) and for frequent users of 400 MED/yr (ca. 800 SED/yr) (Miller, 1998). A more recent study from the US (Hillhouse, 2012) found that a small percentage of university students (classified as dependent tanners) reported more than 100 sessions/yr (ca. 800 SED/yr if each exposure is at the maximum 4 MED). Thus, it is quite possible that frequent tanners in the US receive more than 800 SED/yr, or close to the maximum allowed by the FDA guidance of 890 SED/yr. Supporting this is a recent study from the UK reporting that the highest users of sunbeds could receive over 850 SED/yr, based on the output from the sunbeds with the most intense output (Tierney, 2015). The FDA guidelines on exposure schedules were based on limited knowledge on repeated exposure to UV radiation that was available at the time (Parrish, 1982; Gange, 1982; Pathak, 1983; Kaidbey, 1981). Because there was not a universally-accepted action spectrum for erythema, the FDA developed its own, based on a proposed action spectrum for erythema circulated by the International Commission on Illumination (CIE) and called it the CIELytle action spectrum. The CIELytle spectrum is slightly more conservative than the currently widely-accepted CIE Erythema action spectrum (CIE, 1998); the equations for both action spectra (represented as S i (λ)) are shown below and in Figure 1. FDA, 1986 CIE, 1998 S i (λ) = 1.0 (250 < λ 302 nm) S i (λ) = * (302 λ) (302 < λ 325 nm) S i (λ) = * (159 λ) (325 < λ < 400 nm) S i (λ) = 1.0 (250 < λ 298 nm) S i (λ) = * (298 λ) (298 < λ 328 nm) S i (λ) = * (140 λ) (328 < λ < 400 nm) 14

6 1.00E+00 Relative Effectiveness 1.00E E E 03 FDA CIELytle CIE 1998 Erythema 1.00E Wavelength, nm Figure 1. Comparison of the FDA CIELytle action spectrum with the widely-accepted CIE Reference Action Spectrum for Erythema (CIE, 1998). The FDA also chose a conservative value for one MED for phototype II skin of 156 J/m 2 (weighted with the CIELytle action spectrum). This was based on a somewhat arbitrary choice of one-half of the 24 hr MED value found in Parrish et al. (Parrish, 1982) at the peak wavelength for 24 hr erythema of 296 nm. The FDA required that no single exposure from a tanning bed could exceed 4 MEDs FDA. This dose is approximately equivalent to 4.5 SEDs (Dowdy, 2011), but this value will vary with UV source emission spectrum (range for sources evaluated in Dowdy study was SED). It should be noted that the international standard for sunlamps/tanning appliances (IEC, 2012) calls for a maximum dose per exposure of 6.0 SEDs. In order to work towards harmonization between the FDA and the IEC standards, we chose a maximum 6.0 SEDs per exposure in this study. In their 1986 guidance, the FDA also stated that, since the UV radiation dose that causes a barely discernible pink coloration (i.e. MED) is not the same for different skin types, the exposure schedule should vary according to the skin type of the user. One has to be careful in selecting both the dose per exposure and the frequency of the exposure, in order to avoid erythema/sunburn because sunburns have been linked to an increased risk for melanoma (Lazovich, 2010). It has been shown that 2 wks of daily exposures to sub-erythemal doses (0.65 MED) of SSR leads to marked erythema in skin type II and mild erythema in skin type IV by the end of the first week (Sheehan and Young, 2002). Ravnbak et al. (Ravnbak, 2008) found that daily sub-erythemal exposures (0.4, 0.6 and 0.8 MMD) to narrowband UVB led to excessive erythema in some of their subjects. These studies indicate that exposures should be given less frequently than every 24 hr, since it has 15

7 been shown that daily exposures can lower the MED (Parrish, 1981) and produce significant sunburns. Tanning courses/exposure schedules and pigmentation Since 1986, when the FDA guidelines were published, there have been additional studies (Bech-Thomsen, 1994; Bech-Thomsen, 1995; Caswell, 2000; de Winter, 2001; Ruegemer, 2002; Ravnbak, 2007) that examined the effects of repeated exposure to UV. In particular, M. Caswell (Caswell, 2000) published a study that evaluated the kinetics of tanning in 11 subjects who followed the manufacturer-recommended exposure schedule over an 8-week period. This exposure schedule had been developed by the manufacturer using the 1986 FDA guidance. Changes in skin color were assessed by trained observers and using a chromameter to measure the E value in L*a*b* color space (Fullerton, 1996). The L*a*b* color coordinate system was developed by the CIE for measuring color as perceived by a human observer. Caswell reported in this study that the initial tan was noted after 6 exposures (2 wks) and increased throughout the remainder of the study with little observable erythema. The mean change in skin color measured by E ( E ( L*) ^ 2 ( a*) ^ 2 ( b*) ^ 2 ) ranged from 7.5 to 15 chromametric units (CU). Even after 8 wks of 3 exposures/wk of increasing doses each week, the pigmentation had not reached a plateau. Regarding the minimal repeated dose needed to induce tanning, a study by Ravnbak et al. (Ravnbak, 2008) found that daily exposures of 0.2 minimal melanogenic dose (MMD) (range: SED in their Caucasian subjects) was insufficient to induce tanning after 3 weeks. In addition, 23/24 subjects did not develop pigmentation after daily exposures of 0.4 MMD (i.e SED). Thus it appears that daily repeated exposures of < 3 SED are not sufficient to induce pigmentation, at least with the two sources used in Ravnbak s study (narrowband UVB and solar simulated radiation (SSR)). In 2002, Ruegemer et al. (Ruegemer, 2002) examined UV-induced skin changes in 99 human subjects who were instructed to use a commercial sunbed (0.9% UVB) 2x/wk for 6 weeks and reported an obvious increase in pigmentation. Doses per exposure were between 1.0 to 1.5 SED (Dr. Peter Bocionek, Cosmedico Light, Inc., personal communication) and cumulative doses were 12 to 18 SEDs. Instrumentally, the L* values (measure of skin lightness ) changed by a modest 2.6 chromametric units (CU) or less. This study shows that 16

8 repeated exposures of < 1.5 SED, 2x/wk, cannot produce tanning as well as the current FDA schedule which yielded changes of 7.5 to 15 CU. Regarding the optimum UV spectrum for tanning, Bech-Thomsen and coworkers (Bech- Thomsen, 1994) compared pigmentation induction by exposures to 6 different UV sources and showed that UVA-rich sources induce pigmentation more effectively than UVB-rich sources (including solar simulators). A more recent study by the same group showed that a UVA1 ( nm) source was the most effective at producing new pigmentation (Ravnbak, 2007). DNA damage, surrogate of carcinogenicity Regarding the optimum frequency of exposure for minimal DNA damage, Bataille et al. (Bataille, 2000) showed that photoadaptation occurred in psoriasis patients who received UVB therapy 3x/wk for 6 wks, with 20% and 30% dose increments for skin types II and III/IV, respectively. Biopsies were taken after 1 wk, 3 wks and 6 wks of 3x/wk exposures. After 3 exposures, the levels of CPD reached a plateau and were found to decrease for subsequent exposures despite increasing UVB doses. Another relevant study that evaluated DNA damage after repeated exposures was conducted by de Winter et al. (de Winter, 2001). They found that exposures given 3x/wk for 3 wks with SSR led to a 75% reduction in erythema sensitivity (i.e. a 4-fold higher dose was needed) and 60% reduction in cyclobutane pyrimidine dimer (CPD) formation. They also found that DNA damage had returned to background levels 3-4 d after a single 1.2 MED dose. In summary, the de Winter (de Winter, 2001) and Bataille (Bataille, 2000) studies indicate that exposures administered < 3x/wk (with at least 3 d in between) may be capable of producing a tan while minimizing erythema and DNA damage. Non-aesthetic benefits attributed to UV tanning (protection against future erythema/dna damage, production of vitamin D, reduction of blood pressure) There has been some controversy as to what factors are responsible for the modest protection provided by a base tan. Significant thickening of the whole epidermis was found after 3 wks (3 times/wk) of exposures to a tanning lamp that simulates the UV spectrum of the sun (de Winter, 2001), mainly ascribed to stratum corneum thickening. However, stratum corneum thickening has been shown to provide less photoprotection than that due to increased pigmentation (i.e. tan) (Sheehan, 1998). In a more recent study by the same group (Sheehan, 17

9 2002), it was reported that the tan may not be the major factor in photoprotection, but that DNA repair mechanisms may be enhanced by the repeated stress caused by UV irradiation, especially in skin phototypes that are melano-competent. Regarding enhanced Vitamin D production, de Gruijl and Pavel (de Gruijl, 2012) found that 3 sub-erythemal exposures/wk over 8 wks to a commercial sunbed caused a significant increase in Vitamin D status. In addition to the well-accepted role that Vitamin D plays in bone health, it has also been hypothesized that it can increase resistance to infections (Cannell JJ, 2006). However, the de Gruijl study did not find any significant effect on the number or severity of colds in their subjects during the course of the study. It has been shown that hypertension is related to environmental UV levels, i.e. blood pressure levels are lower in summer than in winter in mild hypertensives (Brennan, 1982) and mean population blood pressure increases with distance from the equator (Rostand, 1997). Liu et al. (Liu, 2014) found that 2 SEDs of whole-body UVA exposure significantly lowered mean arterial blood pressure. They concluded that UVA exposure (equivalent to 30 min at noon on a sunny day in Southern Europe) vasodilates the arterial vasculature in a nitric oxide synthase-independent manner. However, the authors noted that it is unknown whether this effect is maintained for repeated exposures. No changes in Vitamin D levels were observed, indicating that the decrease in blood pressure was independent from effects on Vitamin D. Aim and outline of the thesis The results of the above-mentioned studies prompted us to explore varying the parameters of dose, exposure frequency and UV source emission spectrum and the subsequent effects on perceived benefit (i.e.melanogensis, or tan) and risks (erythema, DNA damage as a surrogate of skin cancer and loss of skin elasticity as a surrogate for photoaging) of repeated exposure to UV. The aim of this project was to develop the most efficient exposure schedule for achieving and maintaining a tan while minimizing the negative side effects of erythema, DNA damage (photocarcinogenesis) and photoaging. We proposed to select the optimal schedule using two criteria: (1) that which produces the desirable effect (i.e. the tan) with the lowest cumulative UV dose and (2) that which produces the desirable effect with the smallest amount of DNA damage. This schedule would be used for amendment of the FDA publication Policy on maximum timer intervals and exposure schedule for sunlamps, dated August 21,

10 (FDA, companion document to the 1985 FDA Performance Standard for Sunlamp Products; the actual amendments based in large part on the present work were published by the FDA in Proposed Rule on December 18, 2015, see chapter 7). In addition, this information would be shared with our counterparts in other countries so that international standards for sunlamps (e.g. IEC ) (IEC, 2012) can be harmonized with that of the FDA. In order to develop an optimal exposure schedule for indoor tanning in terms of benefits and risks we planned the project in two stages: first, a pilot study on a small number of subjects before embarking on the main study. Six subjects were used for this initial feasibility study to fine-tune 3 proposed schedules. The 3 proposed exposure schedules (A, B, and C) that were administered to each of the 6 subjects in the pilot study are described in Chapter 2 and the schedules used for the 40 subjects in the main study are detailed in Chapter 3. The spectra of the 2 different UV sources, or sunlamps, used in the main study are shown in Chapter 3. The exposure schedules were modified throughout the pilot study of 6 subjects (Chapter 2) to achieve the goals of the study, i.e. (1) development of at least one schedule that produced a tan comparable to that achieved in the Caswell study (Caswell, 2000), (2) more rapid development of the tan than in the current recommended schedules, (3) exploration of whether or not the cumulative dose could be reduced compared to current practice and (4) detection of possible saturation of pigmentation. Regarding goal 1, the Caswell study produced skin color changes, measured as E, ranging from 7.5 to 15 CU. The E measured for subjects 5 and 6 in the pilot study had values ranging from 6.5 to 16 CU, similar to that of Caswell. The 40 subjects in the main study were divided into 2 groups (21 subjects for Lamp 1; 19 subjects for Lamp 2). Lamp 1 had UV emissions in a similar proportion to summer sun in temperate climates (5% UVB, 95% UVA) which is also similar to typical tanning lamps used commercially in the US over the past several decades. Lamp 2 was relatively more UVA-rich (2% UVB, 98% UVA) and represents another popular UVA tanning lamp spectrum that has been used in the US since the 1990s. Chapter 3 focusses on the dynamics and spectral dependence of pigmentation induction by the 3 different exposure schedules and 2 different sources of UV (i.e. Lamp 1 and Lamp 2). Chapter 4 explores the dependence of pigmentation development on skin type. Chapter 5 focusses on the DNA damage and melanogenesis that occurred after the 3 different exposures 19

11 schedules for Lamp 1. Chapter 6 is an evaluation of the potential to use a non-invasive biomarker (Erythema Index and oxy-hb levels in the skin measured through diffuse reflectance spectrometry) as a surrogate for the invasive measure of DNA damage, to better elucidate the risks of different exposure schedules and exposure sources. In Chapter 7 (Summary/Conclusions) the overall results are discussed and a final evaluation is made on what the comparisons of the tanning treatments taught us with respect to an optimal tradeoff between the desired tanning and the cumulative UV exposure or DNA damage incurred as a proxy of skin cancer risk. 20

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