0031-8655191 $03.00+0.00
Phorochemi.stry and Photobiology Vol. 54, No. 5 . pp. 775-780, 1991 Printed in Great Britain. All rights reserved
Copyright
0 1991 Pergamon Press plc
EVALUATION OF SKIN CANCER RISK RESULTING FROM LONG TERM OCCUPATIONAL EXPOSURE TO RADIATION FROM ULTRAVIOLET LASERS IN THE RANGE FROM 190 TO 400 nm H. J. C. M. STERENBORG'*, F. R.
DE
G R U I J LG. ~ , KELFKENS~ and J. C.
VAN DER
LEUN'
ILaser Center, Academic Hospital of the University of Amsterdam, Meibergdreef 9, NL-1105 A Z Amsterdam zuidoost, The Netherlands and *Institute of Dermatology, State University of Utrecht, Heidelberglaan 100, NL-3584 CX Utrecht, The Netherlands
(Received 11 January 1991; accepted 16 April 1991) Abstract-The relative risk of occupational exposure to radiation from UV lasers was estimated using a mathematical model based on both epidemiological data and animal experiments. Calculations were performed for the 193 nm ArF excimer laser cornea shaping, the 308 nm XeCI excimer laser for coronary angioplasty, and other UV lasers in a laboratory environment. The model included the effects of direct exposure and exposure to scattered radiation. The results show that for the two medical applications the increase in the relative risk is comparable to that of one additional day of sunbathing per year. For subjects exposed to UV lasers in a laboratory setting, the relative risk may increase to a value comparable to that of people with an outdoor profession.
same time sophisticated mathematical models have been developed to describe the experimental results in detail. The experiments mentioned mainly concerned squamous cell carcinoma. In fact, the relation between melanoma induction and UVR is still somewhat obscure (De Gruijl, 1989). Only recently there have been reports of reproducible induction of melanoma by UV-irradiation of fish (Woodhead, 1989) and opossums (Ley et al., 1989).
INTRODUCTION
During the last decade the laser has gained widespread use in medicine as a new modality for the treatment of a variety of diseases. With the introduction of lasers that emit ultraviolet radiation (UVR), both patients and medical personnel are exposed to a carcinogenic hazard; UVR can induce cancer of the skin. In the present paper we will evaluate the long term cancer risk of occupational exposure of the skin to radiation from UV lasers. Two exposure geometries will be investigated: direct exposure of the skin to the laser beam and exposure to diffuse reflections from the irradiated surface. Also, the effects of exposure to UV produced by fluorescence inside the tissue will be evaluated.
Long term risk estimation
Skin cancer Skin cancer induced by UVR has been investigated for many decades. The first systematic studies were done by Blum and co-workers (Blum, 1943, Blum, 1959). These studies were performed on the ears of Swiss mice and revealed many interesting aspects of UV-carcinogenesis. Some 20 years ago a new, more suitable animal model became available; the hairless mouse (albino: Skh-hrl and pigmented: Skh-hr2). Since then a series of detailed investigations on the time and dose dependence (De Gruijl et al., 1983; Sterenborg et al., 1988; Van Weelden et al., 1986) and of the action spectrum of skin tumor formation, have been performed (Cole et al., 1986; Sterenborg and van der Leun, 1987). At the *To whom correspondence should be addressed. tAbbreviations: MED, minimal erythema dose; RR, relative risk.
Epidemiological data on human skin cancer show a positive correlation between cumulative UV dose and skin tumor incidence (Fears and Scotto, 1985). De Gruijl and van der Leun (1980) developed a mathematical model, linking epidemiological data and experimental carcinogenesis. Such models are used to estimate the risks of altered UV exposures of humans, e.g. due to stratospheric ozone depletion (De Gruijl et al., 1983; De Gruijl and van der Leun, 1980), protection by sunscreens (Stern et al., 1986) and UV therapy of skin diseases (Slaper et al., 1986). A model similar to the one used by Stern et al. (1986) and Slaper et al. (1985) will be employed here. This model is in line with experimental results found after discontinuation of UV irradiation (De Gruijl and van der Leun, 1991). Action spectrum In epidemiological data, the yearly effective doses are generally expressed in MEDt (Minimal Erythema Dose) per year, or in units approximating the MED. In other words, the carcinogenic effectiveness of the radiation is estimated by its ery-
775
776
H. J . C. M . STERENBORG et al.
themal effectiveness. This is only true when the action spectra for skin cancer and erythema are identical. This assumption was made because at the time of the earlier risk estimations, an action spectrum for photocarcinogenesis was not available. In order to be able to estimate the carcinogenic risk of skin exposure to UV radiation sources, it is better to incorporate an actual carcinogenesis action spectrum into the risk estimation model. The carcinogenic action spectrum used for our calculations was derived by Sterenborg and van der Leun (1987). This action spectrum is based on a series of experiments performed on the skins of hairless mice (SkhHrl). Aim
Besides risks due to unintentional exposure of the skin, there is the risk of the induction of cancer in the treated area. For instance the (hypothetical) induction of tumors in the coronary artery wall as a result of coronary angioplasty using an excimer laser. Presently, it is impossible to evaluate these risks, as neither experimental nor epidemiological data on such types of cancer are available. For this reason the aim of the present paper is limited to an analysis of the long term effects on the skin of those who work with UV lasers. The present analysis should be regarded as a worst case study. The number of exposures chosen and the energies involved are such that it should not be difficult to keep below these figures in a normal situation. Hence, the risk estimations presented represent an upper limit.
Table 1. The action spectrum for skin cancer used for the present analysis (normalized at 296 nm) and the original, derived by Sterenborg and van der Leun (1987) (normalized at 302 nm). The value of the carcinogenic effectiveness at other wavelengths must be calculated using logarithmic interpolation. The value at 296 nm in the latter spectrum (marked with an asterisk) was not in the original publication, but was calculated. It was added here for illustration only
Wavelength
Action spectrum used here
< 190 190 254 293 296 302 313
Action spectrum by Sterenborg and van der Leun
0.0 0.156
Not defined Not defined 0.0915 0.4495 0.5867* 1.0000 0.0216 0.00022 Not defined Not defined
0.156 0.766 1.OO 1.70
0.037 0.00029 0.00037 0.0
365
400
> 400
D=
I
Ery(X) S ( h ) dh
(2)
where S ( h ) stands for the annual spectral energy distribution of the incident radiation (J m-z nm-' y-') and Ery(h) for the (dimensionless) action spectrum of erythema, as approximated by the spectral response of a Robertson-Berger meter. This action spectrum is defined as the M E D at 296 nm, divided by the M E D at wavelength A. For our calculations we shall not use this erythema spectrum, but an action spectrum for skin cancer u ( h ) . This action spectrum is given in Table 1 and Fig. 1. The quantity a ( h ) is also dimensionless and gives the carcinogenic effectiveness at wavelength A , relative to that at 296 nm. A n annual Carcinogenic Effective Dose ID is defined as
MATERIALS AND METHODS
Risk estimution. The model used predicts the relative risk, R R , as the ratio of the expected number of skin cancer cases with and without the additional U V exposures. The model assumes that the regular (annual) U V dose due to sun exposures, D,, is delivered mainly to a limited part of the body, i.e. head, neck, and hands, which is the usual location for skin cancers in Caucasians. In case the extra (annual) dose of UV, D,, is delivered to the same skin area as the sun exposure, then the model simplifies to
where a stands for age, CD, and CD, for the accumulated doses due to the additional U V exposures and the regular exposure to solar U V , respectively, and c is a constant. Obviously, the relative risk is equal to 1 as long as no additional exposure has taken place (D,= 0). The parameter c is a constant that depends on the type of cancer and is different in animals and man. Slaper et al. (1986) derived values for c from human epidemiological data of 2.9 for squamous cell carcinomas and 1.7 for basal cell carcinomas. His calculations were based on effective U V doses measured with a Robertson-Berger meter, a device with a spectral sensitivity roughly matching the human erythema action spectrum. Action spectrum. The annual U V dose as used in epidemiological studies (Fears and Scotto, 1985) can be represented as
ID = [ a ( h ) S ( X ) dh
(3)
For our risk estimations we modify E q . (1) by replacing
Action spectra relative effectiveness
0.0 100
1
IF-:
9
~00100
00010
*XlB"*I0"8
Skin Cancer
Erythema (Gange 861
O 00001 Ool O
~L
A
'\ -
0 0001
180 200 220 240 260 260 300 320 340 360 380 400
Wavelength in nanometers
Figure 1. The action spectra for skin cancer derived by Sterenborg and van der Leun (1987) and the action spectrum used for the present calculations The latter was derived by extrapolation (broken line) to cover the desired range.
Skin cancer risk of UV lasers the ratio of the accumulated erythema1 doses CDJCD, by the ratio of the accumulated carcinogenic doses CD,/CD,. According to Green et al. (1976) the relation between an annual RB (Robertson-Berger) dose and another kind of annual UV dose (e.g. spectrally weighted according to the DNA absorption) at various latitudes is given by
D=KV (4) where K and p are constants. For the present analysis only the constant p is of importance (see Eq. 1). Calculations using the solar spectrum according to Kelfkens et al. (1990) yielded a value for p of 0.98. Hence, Eq. (1) changes into (5) Dosimetry. For clear sky conditions in The Netherlands (52”N latitude) we calculated using the solar spectrum according to Kelfkens et al. (1990) and the action spectrum from Table 1, an annual carcinogenic effective dose, ID,, of 1.71 x lo6 Jim2. Estimating an average cloud cover, fc, of 55% and using the formula proposed by Green et al. (1976) we find a dose reduction factor F F=1-0.56fc (6) where F is the dose-correction factor. This yields a dose reduction factor, F, of 0.69. Hence we find an ambient annual carcinogenic dose of 1.18 lo6 J/m2. According to Schothorst et ul. (1985) and Leach et al. (1978) indoor workers receive approx. 2.5% of the ambient dose, and outdoor workers 7%. We shall assume that users of UV lasers behave like indoor workers. Hence, we come to an annual carcinogenic effective dose, ID,, of 29.5 lo3 Jimz. For the calculation of the annual extra doses, ID,, we shall use the average output power of the laser, P. In the case of pulsed lasers, P equals the energy per pulse, multiplied by the repetition frequency. The spots where the laser light hits the skin directly are assumed to be randomly distributed over the area regularly exposed to sunlight, i.e. head, neck, and hands. The long term effect is assumed to be independent of the local peak power, but determined by the accumulated effective dose only. Two exposure geometries will be considered: direct exposure of the skin to t h e laser output, IDc,l, and skin exposure to back scattered radiation, IDc,*. The annual carcinogenic effective dose per unit area due to direct exposure, IDc,,, will be calculated as
where N stands for the number of exposures per year, T for the average duration (seconds) per exposure and A for the total area submitted to the accidental UV exposures. I n the case of back scattered radiation the effective annual dose follows from
777
Table 2. The laser and exposure paramctcrs used for the calculations for the Carcinogenic risk resulting from laboratory work using various UV lasers Output power: 1 W Direct exposure Maximum exposure time: Number of exposures:
SO per year
Buck scattered Maximum exposure time: Numbcr of exposures:
900 s 250 pcr ycar
Reflection coefficient: Working distance:
10 s
5 Yo 0.5 m
one of the bystanders with the laser beam. For back scattered radiation this may be different. We shall assume a diffuse reflection coefficient of the laser target area (the patient’s eye) at 193 nm of 5% and a working distance of 50 cm. The value of the diffuse reflection coefficient was based on an extrapolation of the data reported by Anderson and Parrish (1980). The attenuation of the radiation in air will be neglected. We assume 5 exposures per week, lasting each 15 min. A relatively new field in which a UV laser is used is coronary laser angioplasty. In this application the UV light of 308 nm from a XeCl excimer laser is transported through a fiber into the patient. Thus, no back scattered light reaches the attending personnel, in a normal situation. However, the laser may be fired accidentally while the fiber is not yet in position. Also, a fiber catheter may break. In such cases the bystanders may be exposed to the full output of the laser. For the calculations we assumed a weekly occurrence of such an event and an exposure equal to the clinically used pulse train (3 s) at maximum output power (2 W). With the development of powerful UV emitting lasers (Ar-ion, nitrogen, excimers) a new research tool has become available. We will analyze the possible adverse effects on laboratory personnel. In our calculations we assume a laser emitting 1 W CW. Both direct exposures and indirect exposures may occur on a regular basis. For the diffuse reflection coefficient again a value of 5% was used throughout the UV range. Most materials with a higher reflection coefficient, like metals, do not reflect in a diffuse manner. The case of a collimated reflection can be treated as a direct exposure. The exposure parameters used are listed in Table 2 . For all calculations the exposure to laser light was started at an age of 25. RESULTS AND DISCUSSION
The results of the calculations are shown in Tables 3 and 4. where R(h) stands for the diffuse reflection coefficient of the reflecting material and r for the distance between exposed subject and the surface reflecting the laser beam. The total carcinogenic effective dose is assumed to be the sum of the two (9)
Applications. The risks of three laser applications will be worked out in detail: cornea surgery with an ArF excimer laser, angioplasty with a XeCl excimer laser and laboratory work with various UV lasers. A promising new application of UV lasers at the moment is cornea surgery using an ArF excimer laser. The construction of the delivery system is such that it is not possible to directly “hit”
Action spectrum
In experiments with cell cultures, the mutagenicity of 193 nm radiation was found to be very small (Green et al., 1987). Hence, we might expect the horizontal extension of the carcinogenesis action spectrum to grossly overestimate the effectiveness in this wavelength region. However, when biologic tissue is exposed to UV, radiation of longer wavelengths will be produced in a broad spectrum due to autofluorescence ( A n d e r s o n et al., 1987). For
H. J. C . M. STERENBORG et a1
778
Table 3. The relative risk calculated for medical use of the ArF and the XeCl excimer lasers Type of exposure
Age
Basal
Squamous
ArF, back scattered (cornea shaping)
35 65
1.096 1.21
1.17 1.39
XeCl direct exposure (laser angioplasty)
35 65
1.0010 1.0022
1.0017 1.0037
Table 4. Relative risks for basal and squamous cell carcinomas at an age of (a) 35 years and (b) 65 years. The exposures were started at an age of 25 years. The calculations were performed for 4 commonly used laser wavelengths: ArF, XeCl excimer lasers, the nitrogen laser and a UV emitting Ar ion laser
the case of the laboratory workers this will be much the same. Moreover, exposures of this type are expected to last a few years at maximum, as scientists move on to new experiments continuously. Exposures of much longer duration caused by lasers of much higher output power can be expected in industrial applications of UV lasers. The present analysis suggests that in these cases high relative risks are possible. A more precise analysis than presented here must be performed, in order to obtain an accurate estimation of the actual relative risks occurring. Such an analysis would need precise data on the amount of back scattered light, the working distance and the exposure duration.
~
basal Laqer wavelength backsc.
squamous
direct (a) Age
=
backsc.
direct
35 years
193 308 335 35 1
1.096 1.13 1.0032 1.00077
1.0013 1.0017 1.000041 1.000010
1.17 1.23 1.0054 1.0013
1.0022 1.0029 1.000072 1.0OOO18
302
2.23
1.014
3.93
1.024
193 308 335 351
1.21 1.29 1.0069 1.0017
1.0027 1.0037 1.00009 1.000022
1.39 1.54 1.012 1.0028
1.0046 1.0062 1.00016 1.00004
302
4.10
1.030
11.10
1.051
(b) Age
=
65 years
wavelengths between 190 and 250 nm, the direct carcinogenic effectiveness may be small, but a part of the autofluorescence will be in the 300 nm wavelength range where the carcinogenic effectiveness is maximum. Autofluorescence may thus contribute to the carcinogenic effectiveness. To account for this effect in a worst case manner, the action spectrum of Sterenborg and van der Leun (1987) was extended horizontally towards the smaller wavelengths.
Exposed area
For the derivation of Eq. (1) it was assumed that only a part of the skin, i.e. head, neck, and hands, receives the UV exposures, ID,, and that the additional exposures, D,, are evenly distributed over the same skin area, A,. Especially in the case of direct exposure to laser beams, these local exposures may be limited to an area A,, much smaller than A,. Equation (1) is a special case of the more general relation between relative risk and exposures given in the Appendix. Exposing a smaller area to a higher dose increases the risk, because the risk is assumed to be directly proportional to the exposed area and directly proportional to the UV-dose per unit area to a certain power, c. For example in the case of the laboratory worker exposing the back of his right hand (area A,, rather than the whole sun exposed area A,, where A , = 0.01 m2 and A , = 0.12 m2) to a 1 W 308 nm laser beam for 10 s weekly would result in a relative risk of 1.89 rather than 1.23 at the age of 35 years. For indirect exposures this area effect may be small or even absent due to the usually diffuse nature of back scattered radiation.
Absolute risks Dosimetry As explained above, the exposure frequencies and durations were maximized to make a worst case estimate. In medical practice it should not be difficult to keep well below these values. Moreover, acute responses will occur in the skin areas receiving these exposures. For instance the single exposure to the XeCl laser (Table 2) occurring with a fiber of opening angle of 5" at a distance of 10 cm from the skin results in a dose of 2.3 times the MED (Skin type 11, Gange et al., 1986). The erythema1 response of such an exposure would most prqbably be noticed by the receiver. However, a single exposure to back scattered radiation represents a much lower dose and may not be noticed at all. For
To have an idea of absolute risks, i.e. chance of contracting a carcinoma of the skin, we use the skin cancer data of the south eastern part of The Netherlands (Coeberg et al., to be published). The chance for a Dutchman to develop a non-melanoma skin cancer (basal or squamous cell carcinoma) before 35 or 65 years of age are estimated at 0.0001 and 0.006, respectively. If we estimate that about 7.5% of the male working population has an outdoor profession (1983: Statistisch Zakboek 1985, Central Bureau of Statistics, The Netherlands), we calculate that the chances for indoor workers to get a squamous cell carcinoma before 35,65 or 75 years of age are 0.000006 and 0.0004 respectively and for basal cell carcinoma 0.00008 and 0.004.
Skin cancer risk of UV lasers CONCLUSIONS
A relative risk of 1.17 or less at an age of 35 years was estimated for the examples with medically used excimer lasers. For comparison, we calculated the increase in relative risk resulting from one additional day of sunbathing per year (1O:OO a.m. to 2:OO p.m., 21 July, clear sky). Using the model of Kelfkens et al. (1990) this represents an additional annual dose, ID,, of 7.4 kJ/m2, which results in a relative risk of 1.22 for squamous cell carcinomas at an age of 35 years. Hence, we can conclude that the use of excimer lasers mentioned in medicine represent a smaller occupational hazard than a day off in summer. For UV lasers in a laboratory environment listed in Table 4 a similar conclusion can be drawn. However, a dramatic increase in the relative risks results for the hypothetical laser at wavelength 302 nm. The calculations show a significant increase in the relative risk resulting from the back scattered radiation, i.e. a factor of 3.93 by the age of 35 and a factor of 11 by the age of 65. Although this increase is quite substantial, the relative risk is comparable to that of having an outdoor profession (5.3 for squamous cell carcinomas at the age of 35). Nevertheless, measures reducing the exposure by shielding back scattered radiation are indicated. This may be even more important in occupational situations other than those analyzed presently, for instance in industrial applications where the used laser powers usually exceed the values used in research applications. In most cases it should be possible to perform this shielding by placing a glass window between personnel and the scattering site. In more complicated geometries the use of gloves and application of a UV blocking sun screen on the exposed skin areas should be sufficient. APPENDIX
The Area Effect The relative risk is defined as a ratio of the tumor yields, i.e. the average number of tumors per person at risk: ye RR(a) = (A.1) y, where Y , stands for the tumor yield in the group receiving the regular plus the additional exposures and Y, for the yield in the group receiving the regular exposures only. The tumor yield, or the cumulative incidence, relate to age, a , and the accumulated dose, CD, as
Y-A,adCDc (A4 where d is a constant and A, is the exposed surface. When we assume the induction of tumors to be a local effect, so systemic effects are assumed to be numerically of minor importance, we can write Y , as a sum of two tumor yields YJa)
- (A, - A,) ad CD: + A, ad-'
(
CD,
+ CD,
7
(A.3) where the first term on the right side gives the tumor yield
779
in the area that receives the solar exposures only, and the second term gives the yield in the small area receiving the solar plus the additional exposures. Using Eq. (A.2) and introducing the factor E, the fraction of the sun exposed area that receives the additional exposures E =AJA, (A.4) Combining Eqs. (A.2)-(A.4), we can rewrite Eq. ( A . l ) as
Note that the doses CD, and CD, are given in Jim*. Therefore, if we have X Joules of UV radiation to add, . get evenly spread over area 4,we
For a constant X , RR* increases as e becomes smaller: with c -+ 0 we find
(A,CD,(a)
RR*(a) = 1 + I €E-I
~-
(A.7)
REFERENCES
Anderson, R. R . and J. A. Parrish (1980) The optics of human skin. The Science of Photomedicine (Edited by J . D. Regan and J. A. Parrish). Plenum Press, New York. Anderson, P., E . Kjellen, S. Montan, K. Svanberg and S. Svanberg (1987) Autofluorescence of various rodent tissues and human skin tumour samples. Lasers Med. Sci. 4, 41-49. Blum, H. F. (1943) Wavelength dependence of tumor induction caused by ultraviolet radiation. J . Nat. Cancer Inst. 1, 397-421. Blum, H. F. (1959) Carcinogenesis b j Ultraviolet Light. Princeton University Press, Princeton, NY, Cole, C. A., P. D. Forbes and R. E . Davies (1986) An action spectrum for photo carcinogenesis. Photochem. Photobiol. 43, 275-284. De Gruijl, F. R. (1989) Ozone change and melanoma. In Atmospheric Ozone Research and Its Policy Implications (Edited by T. Schneider et a l . ) , pp. 813-821. Elsevier, Amsterdam. De Gruijl, F. R. and J. C. van der Leun (1980) A doseresponse model for skin cancer induction by chronic UV exposure of a human population. J . Theor. Biol. 83, 487-504.
De Gruijl, F. R. and J. C. van der Leun (1991) Tumor development after discontinuation of UV radiation. Cancer Res. In press. De Gruijl, F. R., J. B. Van der Meer and J. C. van der Leun (1983) Dose-time dependency of tumor formation by chronic UV exposure. Photochem. Photobiol. 37, 53-62.
Fears, T. R. and J . Scotto (1985) Estimating increases in skin cancer morbidity due to increases in ultraviolet radiation exposure. Cancer Invest. 1, 119-126. Gange, R. W., Y-K. Park, M. Auletta, M. Kagetsu, A. D . Blackett and J. A. Parrish (1986) Action spectra for cutaneous responses to ultraviolet radiation. In The Biological Effects of UVA Radiation (Edited by F. Urbach and R. W. Gange). Praeger Publishers, NY. Green et al. (1976) The ultraviolet dose dependence of non-melanoma skin cancer incidence. Photochem. Photobiol. 24, 353-362. Green, H., J. Boll, J. A. Parrish, I. E Kochevar and A. R. Oseroff (1987) Cytotoxicity and mutagenicity of low intensity 248 and 193 nm excimer laser radiation in
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H. J. C. M. STERENBORG et a1
mammalian cells. Cancer Res. 47, 410-413. Kelfkens, G., F. R. De Gruijl and J. C. van der Leun (1990) Ozone depletion and increase in annual carcinogenic ultraviolet dose. Photochem. Photobiol. 52, 819-823. Leach, J. F., V. E. McLeod, A. R. Pingstone, A. Davies and G. H. W. Deane (1978) Measurements of ultraviolet doses received by office workers. Clin. Exp. Dermatol. 3, 77-79. Ley, R. D . , L. A. Applegate, R. S. Padilla and T. D. Stewart (1989) Ultraviolet radiation-induced malignant melanoma. Photochem. Photobiol. 50, 1-5. Schothorst, A. A., H. Slaper, R. Schouten and D. Suurmond (1985) UVB doses in maintenance psoriasis phototherapy versus solar UVB exposure. Photodermatology 2 , 213-220. Slaper, H., A. A. Schothorst and J. C. van der Leun (1985) Risk evaluation of UVB therapy for psoriasis: comparison of calculated risk for UVB therapy and
observed risk in PUVA treated patients. PhotodermatolOgy 3 , 271-283. Sterenborg, H. J. C. M. and J. C. van der Leun (1987) Action spectra for tumorigenesis by ultraviolet radiation. In Human Exposure to Ultraviolet Radiation: Risks and Regulations (Edited by W. F. Passchier and B. F. M. Bosnjacovic). Excerpta Medica, Amsterdam. Sterenborg, H. J. C. M., S. J. C. van der Putte and J. C. van der Leun (1988) The dose-response relationship of tumorigenesis by ultraviolet radiation of 254 nm. Photochem. Photobiol. 47, 245-253. Stern, R. S . , M. C. Weinstein and S. G. Baker (1986) Risk reduction for non-melanoma skin cancer with childhood sunscreen use. Arch. Dermatol. 122, 537-545. Van Weelden, H., F. R. De Gruijl and J. C. van der Leun (1986) Carcinogenesis by UVA, with an attempt to assess the carcinogenic risk of tanning with UVA and UVB. In The Biological Effects of UVA Radiation, pp. 147-152. Praeger, NY.
Phorochemi.stry and Photobiology Vol. 54, No. 5 . pp. 775-780, 1991 Printed in Great Britain. All rights reserved
Copyright
0 1991 Pergamon Press plc
EVALUATION OF SKIN CANCER RISK RESULTING FROM LONG TERM OCCUPATIONAL EXPOSURE TO RADIATION FROM ULTRAVIOLET LASERS IN THE RANGE FROM 190 TO 400 nm H. J. C. M. STERENBORG'*, F. R.
DE
G R U I J LG. ~ , KELFKENS~ and J. C.
VAN DER
LEUN'
ILaser Center, Academic Hospital of the University of Amsterdam, Meibergdreef 9, NL-1105 A Z Amsterdam zuidoost, The Netherlands and *Institute of Dermatology, State University of Utrecht, Heidelberglaan 100, NL-3584 CX Utrecht, The Netherlands
(Received 11 January 1991; accepted 16 April 1991) Abstract-The relative risk of occupational exposure to radiation from UV lasers was estimated using a mathematical model based on both epidemiological data and animal experiments. Calculations were performed for the 193 nm ArF excimer laser cornea shaping, the 308 nm XeCI excimer laser for coronary angioplasty, and other UV lasers in a laboratory environment. The model included the effects of direct exposure and exposure to scattered radiation. The results show that for the two medical applications the increase in the relative risk is comparable to that of one additional day of sunbathing per year. For subjects exposed to UV lasers in a laboratory setting, the relative risk may increase to a value comparable to that of people with an outdoor profession.
same time sophisticated mathematical models have been developed to describe the experimental results in detail. The experiments mentioned mainly concerned squamous cell carcinoma. In fact, the relation between melanoma induction and UVR is still somewhat obscure (De Gruijl, 1989). Only recently there have been reports of reproducible induction of melanoma by UV-irradiation of fish (Woodhead, 1989) and opossums (Ley et al., 1989).
INTRODUCTION
During the last decade the laser has gained widespread use in medicine as a new modality for the treatment of a variety of diseases. With the introduction of lasers that emit ultraviolet radiation (UVR), both patients and medical personnel are exposed to a carcinogenic hazard; UVR can induce cancer of the skin. In the present paper we will evaluate the long term cancer risk of occupational exposure of the skin to radiation from UV lasers. Two exposure geometries will be investigated: direct exposure of the skin to the laser beam and exposure to diffuse reflections from the irradiated surface. Also, the effects of exposure to UV produced by fluorescence inside the tissue will be evaluated.
Long term risk estimation
Skin cancer Skin cancer induced by UVR has been investigated for many decades. The first systematic studies were done by Blum and co-workers (Blum, 1943, Blum, 1959). These studies were performed on the ears of Swiss mice and revealed many interesting aspects of UV-carcinogenesis. Some 20 years ago a new, more suitable animal model became available; the hairless mouse (albino: Skh-hrl and pigmented: Skh-hr2). Since then a series of detailed investigations on the time and dose dependence (De Gruijl et al., 1983; Sterenborg et al., 1988; Van Weelden et al., 1986) and of the action spectrum of skin tumor formation, have been performed (Cole et al., 1986; Sterenborg and van der Leun, 1987). At the *To whom correspondence should be addressed. tAbbreviations: MED, minimal erythema dose; RR, relative risk.
Epidemiological data on human skin cancer show a positive correlation between cumulative UV dose and skin tumor incidence (Fears and Scotto, 1985). De Gruijl and van der Leun (1980) developed a mathematical model, linking epidemiological data and experimental carcinogenesis. Such models are used to estimate the risks of altered UV exposures of humans, e.g. due to stratospheric ozone depletion (De Gruijl et al., 1983; De Gruijl and van der Leun, 1980), protection by sunscreens (Stern et al., 1986) and UV therapy of skin diseases (Slaper et al., 1986). A model similar to the one used by Stern et al. (1986) and Slaper et al. (1985) will be employed here. This model is in line with experimental results found after discontinuation of UV irradiation (De Gruijl and van der Leun, 1991). Action spectrum In epidemiological data, the yearly effective doses are generally expressed in MEDt (Minimal Erythema Dose) per year, or in units approximating the MED. In other words, the carcinogenic effectiveness of the radiation is estimated by its ery-
775
776
H. J . C. M . STERENBORG et al.
themal effectiveness. This is only true when the action spectra for skin cancer and erythema are identical. This assumption was made because at the time of the earlier risk estimations, an action spectrum for photocarcinogenesis was not available. In order to be able to estimate the carcinogenic risk of skin exposure to UV radiation sources, it is better to incorporate an actual carcinogenesis action spectrum into the risk estimation model. The carcinogenic action spectrum used for our calculations was derived by Sterenborg and van der Leun (1987). This action spectrum is based on a series of experiments performed on the skins of hairless mice (SkhHrl). Aim
Besides risks due to unintentional exposure of the skin, there is the risk of the induction of cancer in the treated area. For instance the (hypothetical) induction of tumors in the coronary artery wall as a result of coronary angioplasty using an excimer laser. Presently, it is impossible to evaluate these risks, as neither experimental nor epidemiological data on such types of cancer are available. For this reason the aim of the present paper is limited to an analysis of the long term effects on the skin of those who work with UV lasers. The present analysis should be regarded as a worst case study. The number of exposures chosen and the energies involved are such that it should not be difficult to keep below these figures in a normal situation. Hence, the risk estimations presented represent an upper limit.
Table 1. The action spectrum for skin cancer used for the present analysis (normalized at 296 nm) and the original, derived by Sterenborg and van der Leun (1987) (normalized at 302 nm). The value of the carcinogenic effectiveness at other wavelengths must be calculated using logarithmic interpolation. The value at 296 nm in the latter spectrum (marked with an asterisk) was not in the original publication, but was calculated. It was added here for illustration only
Wavelength
Action spectrum used here
< 190 190 254 293 296 302 313
Action spectrum by Sterenborg and van der Leun
0.0 0.156
Not defined Not defined 0.0915 0.4495 0.5867* 1.0000 0.0216 0.00022 Not defined Not defined
0.156 0.766 1.OO 1.70
0.037 0.00029 0.00037 0.0
365
400
> 400
D=
I
Ery(X) S ( h ) dh
(2)
where S ( h ) stands for the annual spectral energy distribution of the incident radiation (J m-z nm-' y-') and Ery(h) for the (dimensionless) action spectrum of erythema, as approximated by the spectral response of a Robertson-Berger meter. This action spectrum is defined as the M E D at 296 nm, divided by the M E D at wavelength A. For our calculations we shall not use this erythema spectrum, but an action spectrum for skin cancer u ( h ) . This action spectrum is given in Table 1 and Fig. 1. The quantity a ( h ) is also dimensionless and gives the carcinogenic effectiveness at wavelength A , relative to that at 296 nm. A n annual Carcinogenic Effective Dose ID is defined as
MATERIALS AND METHODS
Risk estimution. The model used predicts the relative risk, R R , as the ratio of the expected number of skin cancer cases with and without the additional U V exposures. The model assumes that the regular (annual) U V dose due to sun exposures, D,, is delivered mainly to a limited part of the body, i.e. head, neck, and hands, which is the usual location for skin cancers in Caucasians. In case the extra (annual) dose of UV, D,, is delivered to the same skin area as the sun exposure, then the model simplifies to
where a stands for age, CD, and CD, for the accumulated doses due to the additional U V exposures and the regular exposure to solar U V , respectively, and c is a constant. Obviously, the relative risk is equal to 1 as long as no additional exposure has taken place (D,= 0). The parameter c is a constant that depends on the type of cancer and is different in animals and man. Slaper et al. (1986) derived values for c from human epidemiological data of 2.9 for squamous cell carcinomas and 1.7 for basal cell carcinomas. His calculations were based on effective U V doses measured with a Robertson-Berger meter, a device with a spectral sensitivity roughly matching the human erythema action spectrum. Action spectrum. The annual U V dose as used in epidemiological studies (Fears and Scotto, 1985) can be represented as
ID = [ a ( h ) S ( X ) dh
(3)
For our risk estimations we modify E q . (1) by replacing
Action spectra relative effectiveness
0.0 100
1
IF-:
9
~00100
00010
*XlB"*I0"8
Skin Cancer
Erythema (Gange 861
O 00001 Ool O
~L
A
'\ -
0 0001
180 200 220 240 260 260 300 320 340 360 380 400
Wavelength in nanometers
Figure 1. The action spectra for skin cancer derived by Sterenborg and van der Leun (1987) and the action spectrum used for the present calculations The latter was derived by extrapolation (broken line) to cover the desired range.
Skin cancer risk of UV lasers the ratio of the accumulated erythema1 doses CDJCD, by the ratio of the accumulated carcinogenic doses CD,/CD,. According to Green et al. (1976) the relation between an annual RB (Robertson-Berger) dose and another kind of annual UV dose (e.g. spectrally weighted according to the DNA absorption) at various latitudes is given by
D=KV (4) where K and p are constants. For the present analysis only the constant p is of importance (see Eq. 1). Calculations using the solar spectrum according to Kelfkens et al. (1990) yielded a value for p of 0.98. Hence, Eq. (1) changes into (5) Dosimetry. For clear sky conditions in The Netherlands (52”N latitude) we calculated using the solar spectrum according to Kelfkens et al. (1990) and the action spectrum from Table 1, an annual carcinogenic effective dose, ID,, of 1.71 x lo6 Jim2. Estimating an average cloud cover, fc, of 55% and using the formula proposed by Green et al. (1976) we find a dose reduction factor F F=1-0.56fc (6) where F is the dose-correction factor. This yields a dose reduction factor, F, of 0.69. Hence we find an ambient annual carcinogenic dose of 1.18 lo6 J/m2. According to Schothorst et ul. (1985) and Leach et al. (1978) indoor workers receive approx. 2.5% of the ambient dose, and outdoor workers 7%. We shall assume that users of UV lasers behave like indoor workers. Hence, we come to an annual carcinogenic effective dose, ID,, of 29.5 lo3 Jimz. For the calculation of the annual extra doses, ID,, we shall use the average output power of the laser, P. In the case of pulsed lasers, P equals the energy per pulse, multiplied by the repetition frequency. The spots where the laser light hits the skin directly are assumed to be randomly distributed over the area regularly exposed to sunlight, i.e. head, neck, and hands. The long term effect is assumed to be independent of the local peak power, but determined by the accumulated effective dose only. Two exposure geometries will be considered: direct exposure of the skin to t h e laser output, IDc,l, and skin exposure to back scattered radiation, IDc,*. The annual carcinogenic effective dose per unit area due to direct exposure, IDc,,, will be calculated as
where N stands for the number of exposures per year, T for the average duration (seconds) per exposure and A for the total area submitted to the accidental UV exposures. I n the case of back scattered radiation the effective annual dose follows from
777
Table 2. The laser and exposure paramctcrs used for the calculations for the Carcinogenic risk resulting from laboratory work using various UV lasers Output power: 1 W Direct exposure Maximum exposure time: Number of exposures:
SO per year
Buck scattered Maximum exposure time: Numbcr of exposures:
900 s 250 pcr ycar
Reflection coefficient: Working distance:
10 s
5 Yo 0.5 m
one of the bystanders with the laser beam. For back scattered radiation this may be different. We shall assume a diffuse reflection coefficient of the laser target area (the patient’s eye) at 193 nm of 5% and a working distance of 50 cm. The value of the diffuse reflection coefficient was based on an extrapolation of the data reported by Anderson and Parrish (1980). The attenuation of the radiation in air will be neglected. We assume 5 exposures per week, lasting each 15 min. A relatively new field in which a UV laser is used is coronary laser angioplasty. In this application the UV light of 308 nm from a XeCl excimer laser is transported through a fiber into the patient. Thus, no back scattered light reaches the attending personnel, in a normal situation. However, the laser may be fired accidentally while the fiber is not yet in position. Also, a fiber catheter may break. In such cases the bystanders may be exposed to the full output of the laser. For the calculations we assumed a weekly occurrence of such an event and an exposure equal to the clinically used pulse train (3 s) at maximum output power (2 W). With the development of powerful UV emitting lasers (Ar-ion, nitrogen, excimers) a new research tool has become available. We will analyze the possible adverse effects on laboratory personnel. In our calculations we assume a laser emitting 1 W CW. Both direct exposures and indirect exposures may occur on a regular basis. For the diffuse reflection coefficient again a value of 5% was used throughout the UV range. Most materials with a higher reflection coefficient, like metals, do not reflect in a diffuse manner. The case of a collimated reflection can be treated as a direct exposure. The exposure parameters used are listed in Table 2 . For all calculations the exposure to laser light was started at an age of 25. RESULTS AND DISCUSSION
The results of the calculations are shown in Tables 3 and 4. where R(h) stands for the diffuse reflection coefficient of the reflecting material and r for the distance between exposed subject and the surface reflecting the laser beam. The total carcinogenic effective dose is assumed to be the sum of the two (9)
Applications. The risks of three laser applications will be worked out in detail: cornea surgery with an ArF excimer laser, angioplasty with a XeCl excimer laser and laboratory work with various UV lasers. A promising new application of UV lasers at the moment is cornea surgery using an ArF excimer laser. The construction of the delivery system is such that it is not possible to directly “hit”
Action spectrum
In experiments with cell cultures, the mutagenicity of 193 nm radiation was found to be very small (Green et al., 1987). Hence, we might expect the horizontal extension of the carcinogenesis action spectrum to grossly overestimate the effectiveness in this wavelength region. However, when biologic tissue is exposed to UV, radiation of longer wavelengths will be produced in a broad spectrum due to autofluorescence ( A n d e r s o n et al., 1987). For
H. J. C . M. STERENBORG et a1
778
Table 3. The relative risk calculated for medical use of the ArF and the XeCl excimer lasers Type of exposure
Age
Basal
Squamous
ArF, back scattered (cornea shaping)
35 65
1.096 1.21
1.17 1.39
XeCl direct exposure (laser angioplasty)
35 65
1.0010 1.0022
1.0017 1.0037
Table 4. Relative risks for basal and squamous cell carcinomas at an age of (a) 35 years and (b) 65 years. The exposures were started at an age of 25 years. The calculations were performed for 4 commonly used laser wavelengths: ArF, XeCl excimer lasers, the nitrogen laser and a UV emitting Ar ion laser
the case of the laboratory workers this will be much the same. Moreover, exposures of this type are expected to last a few years at maximum, as scientists move on to new experiments continuously. Exposures of much longer duration caused by lasers of much higher output power can be expected in industrial applications of UV lasers. The present analysis suggests that in these cases high relative risks are possible. A more precise analysis than presented here must be performed, in order to obtain an accurate estimation of the actual relative risks occurring. Such an analysis would need precise data on the amount of back scattered light, the working distance and the exposure duration.
~
basal Laqer wavelength backsc.
squamous
direct (a) Age
=
backsc.
direct
35 years
193 308 335 35 1
1.096 1.13 1.0032 1.00077
1.0013 1.0017 1.000041 1.000010
1.17 1.23 1.0054 1.0013
1.0022 1.0029 1.000072 1.0OOO18
302
2.23
1.014
3.93
1.024
193 308 335 351
1.21 1.29 1.0069 1.0017
1.0027 1.0037 1.00009 1.000022
1.39 1.54 1.012 1.0028
1.0046 1.0062 1.00016 1.00004
302
4.10
1.030
11.10
1.051
(b) Age
=
65 years
wavelengths between 190 and 250 nm, the direct carcinogenic effectiveness may be small, but a part of the autofluorescence will be in the 300 nm wavelength range where the carcinogenic effectiveness is maximum. Autofluorescence may thus contribute to the carcinogenic effectiveness. To account for this effect in a worst case manner, the action spectrum of Sterenborg and van der Leun (1987) was extended horizontally towards the smaller wavelengths.
Exposed area
For the derivation of Eq. (1) it was assumed that only a part of the skin, i.e. head, neck, and hands, receives the UV exposures, ID,, and that the additional exposures, D,, are evenly distributed over the same skin area, A,. Especially in the case of direct exposure to laser beams, these local exposures may be limited to an area A,, much smaller than A,. Equation (1) is a special case of the more general relation between relative risk and exposures given in the Appendix. Exposing a smaller area to a higher dose increases the risk, because the risk is assumed to be directly proportional to the exposed area and directly proportional to the UV-dose per unit area to a certain power, c. For example in the case of the laboratory worker exposing the back of his right hand (area A,, rather than the whole sun exposed area A,, where A , = 0.01 m2 and A , = 0.12 m2) to a 1 W 308 nm laser beam for 10 s weekly would result in a relative risk of 1.89 rather than 1.23 at the age of 35 years. For indirect exposures this area effect may be small or even absent due to the usually diffuse nature of back scattered radiation.
Absolute risks Dosimetry As explained above, the exposure frequencies and durations were maximized to make a worst case estimate. In medical practice it should not be difficult to keep well below these values. Moreover, acute responses will occur in the skin areas receiving these exposures. For instance the single exposure to the XeCl laser (Table 2) occurring with a fiber of opening angle of 5" at a distance of 10 cm from the skin results in a dose of 2.3 times the MED (Skin type 11, Gange et al., 1986). The erythema1 response of such an exposure would most prqbably be noticed by the receiver. However, a single exposure to back scattered radiation represents a much lower dose and may not be noticed at all. For
To have an idea of absolute risks, i.e. chance of contracting a carcinoma of the skin, we use the skin cancer data of the south eastern part of The Netherlands (Coeberg et al., to be published). The chance for a Dutchman to develop a non-melanoma skin cancer (basal or squamous cell carcinoma) before 35 or 65 years of age are estimated at 0.0001 and 0.006, respectively. If we estimate that about 7.5% of the male working population has an outdoor profession (1983: Statistisch Zakboek 1985, Central Bureau of Statistics, The Netherlands), we calculate that the chances for indoor workers to get a squamous cell carcinoma before 35,65 or 75 years of age are 0.000006 and 0.0004 respectively and for basal cell carcinoma 0.00008 and 0.004.
Skin cancer risk of UV lasers CONCLUSIONS
A relative risk of 1.17 or less at an age of 35 years was estimated for the examples with medically used excimer lasers. For comparison, we calculated the increase in relative risk resulting from one additional day of sunbathing per year (1O:OO a.m. to 2:OO p.m., 21 July, clear sky). Using the model of Kelfkens et al. (1990) this represents an additional annual dose, ID,, of 7.4 kJ/m2, which results in a relative risk of 1.22 for squamous cell carcinomas at an age of 35 years. Hence, we can conclude that the use of excimer lasers mentioned in medicine represent a smaller occupational hazard than a day off in summer. For UV lasers in a laboratory environment listed in Table 4 a similar conclusion can be drawn. However, a dramatic increase in the relative risks results for the hypothetical laser at wavelength 302 nm. The calculations show a significant increase in the relative risk resulting from the back scattered radiation, i.e. a factor of 3.93 by the age of 35 and a factor of 11 by the age of 65. Although this increase is quite substantial, the relative risk is comparable to that of having an outdoor profession (5.3 for squamous cell carcinomas at the age of 35). Nevertheless, measures reducing the exposure by shielding back scattered radiation are indicated. This may be even more important in occupational situations other than those analyzed presently, for instance in industrial applications where the used laser powers usually exceed the values used in research applications. In most cases it should be possible to perform this shielding by placing a glass window between personnel and the scattering site. In more complicated geometries the use of gloves and application of a UV blocking sun screen on the exposed skin areas should be sufficient. APPENDIX
The Area Effect The relative risk is defined as a ratio of the tumor yields, i.e. the average number of tumors per person at risk: ye RR(a) = (A.1) y, where Y , stands for the tumor yield in the group receiving the regular plus the additional exposures and Y, for the yield in the group receiving the regular exposures only. The tumor yield, or the cumulative incidence, relate to age, a , and the accumulated dose, CD, as
Y-A,adCDc (A4 where d is a constant and A, is the exposed surface. When we assume the induction of tumors to be a local effect, so systemic effects are assumed to be numerically of minor importance, we can write Y , as a sum of two tumor yields YJa)
- (A, - A,) ad CD: + A, ad-'
(
CD,
+ CD,
7
(A.3) where the first term on the right side gives the tumor yield
779
in the area that receives the solar exposures only, and the second term gives the yield in the small area receiving the solar plus the additional exposures. Using Eq. (A.2) and introducing the factor E, the fraction of the sun exposed area that receives the additional exposures E =AJA, (A.4) Combining Eqs. (A.2)-(A.4), we can rewrite Eq. ( A . l ) as
Note that the doses CD, and CD, are given in Jim*. Therefore, if we have X Joules of UV radiation to add, . get evenly spread over area 4,we
For a constant X , RR* increases as e becomes smaller: with c -+ 0 we find
(A,CD,(a)
RR*(a) = 1 + I €E-I
~-
(A.7)
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Anderson, R. R . and J. A. Parrish (1980) The optics of human skin. The Science of Photomedicine (Edited by J . D. Regan and J. A. Parrish). Plenum Press, New York. Anderson, P., E . Kjellen, S. Montan, K. Svanberg and S. Svanberg (1987) Autofluorescence of various rodent tissues and human skin tumour samples. Lasers Med. Sci. 4, 41-49. Blum, H. F. (1943) Wavelength dependence of tumor induction caused by ultraviolet radiation. J . Nat. Cancer Inst. 1, 397-421. Blum, H. F. (1959) Carcinogenesis b j Ultraviolet Light. Princeton University Press, Princeton, NY, Cole, C. A., P. D. Forbes and R. E . Davies (1986) An action spectrum for photo carcinogenesis. Photochem. Photobiol. 43, 275-284. De Gruijl, F. R. (1989) Ozone change and melanoma. In Atmospheric Ozone Research and Its Policy Implications (Edited by T. Schneider et a l . ) , pp. 813-821. Elsevier, Amsterdam. De Gruijl, F. R. and J. C. van der Leun (1980) A doseresponse model for skin cancer induction by chronic UV exposure of a human population. J . Theor. Biol. 83, 487-504.
De Gruijl, F. R. and J. C. van der Leun (1991) Tumor development after discontinuation of UV radiation. Cancer Res. In press. De Gruijl, F. R., J. B. Van der Meer and J. C. van der Leun (1983) Dose-time dependency of tumor formation by chronic UV exposure. Photochem. Photobiol. 37, 53-62.
Fears, T. R. and J . Scotto (1985) Estimating increases in skin cancer morbidity due to increases in ultraviolet radiation exposure. Cancer Invest. 1, 119-126. Gange, R. W., Y-K. Park, M. Auletta, M. Kagetsu, A. D . Blackett and J. A. Parrish (1986) Action spectra for cutaneous responses to ultraviolet radiation. In The Biological Effects of UVA Radiation (Edited by F. Urbach and R. W. Gange). Praeger Publishers, NY. Green et al. (1976) The ultraviolet dose dependence of non-melanoma skin cancer incidence. Photochem. Photobiol. 24, 353-362. Green, H., J. Boll, J. A. Parrish, I. E Kochevar and A. R. Oseroff (1987) Cytotoxicity and mutagenicity of low intensity 248 and 193 nm excimer laser radiation in
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observed risk in PUVA treated patients. PhotodermatolOgy 3 , 271-283. Sterenborg, H. J. C. M. and J. C. van der Leun (1987) Action spectra for tumorigenesis by ultraviolet radiation. In Human Exposure to Ultraviolet Radiation: Risks and Regulations (Edited by W. F. Passchier and B. F. M. Bosnjacovic). Excerpta Medica, Amsterdam. Sterenborg, H. J. C. M., S. J. C. van der Putte and J. C. van der Leun (1988) The dose-response relationship of tumorigenesis by ultraviolet radiation of 254 nm. Photochem. Photobiol. 47, 245-253. Stern, R. S . , M. C. Weinstein and S. G. Baker (1986) Risk reduction for non-melanoma skin cancer with childhood sunscreen use. Arch. Dermatol. 122, 537-545. Van Weelden, H., F. R. De Gruijl and J. C. van der Leun (1986) Carcinogenesis by UVA, with an attempt to assess the carcinogenic risk of tanning with UVA and UVB. In The Biological Effects of UVA Radiation, pp. 147-152. Praeger, NY.
