2. What are the health effects of solar UV radiation?
- 2.1 What are the benefits of solar UV radiation?
- 2.2 How can skin be damaged by solar UV radiation?
- 2.3 How can the eyes be damaged by solar UV radiation?
2.1 What are the benefits of solar UV radiation?
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Exposure to solar UVB initiates the synthesis of vitamin D, in the skin, that is vital for musculo- skeletal health (Vieth, 2005) and there is evidence that large numbers of people are vitamin D insufficient (Holick, 2005). Rickets, widespread in industrialized cities in 19th century Europe, is being increasingly diagnosed in ethnic minority populations in Northern and Southern Europe and can be attributed to vitamin D deficiency (Pedersen, 2003; Yeste and Carrascossa, 2003; Ladhani et al, 2004; Mallet et al, 2004). There is also emerging evidence, as yet mainly ecologic (i.e. by association), that vitamin D is important in other aspects of health such the prevention of autoimmune disorders (Ponsonby et al, 2005) and several internal malignancies (Berwick and Kesler, 2005; Giovannucci et al., 2006). There are also recent data suggesting that vitamin D may be important in improving outcome from cancer (Chen and Holick, 2003; Zhou et al, 2005). Exposure to the sun may therefore have widespread beneficial effects but it seems likely that these beneficial effects would also be produced by increased oral intake of vitamin D. However, the role of vitamin D in non-skeletal health, along with its association with UVR exposure remains a very controversial area and more data are needed for informed discussion.
2.2 How can skin be damaged by solar UV radiation?
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1. What are the general health and safety implications (negative and positive) relating to the exposure of persons to ultraviolet radiation (UVR)?
1.1 Negative Effects
Exposure of the skin to solar UVR (~ 295 – 400 nm) results in inflammation (erythema/sunburn) that is usually maximal about 24 hours later (Farr et al, 1988). This response is primarily induced by its UVB component (~295-315nm) (see section 2(b).1) and is associated with increased blood flow (Young et al, 1985), increased sensitivity to thermal and mechanical stimuli (Harrison et al, 2004), a dermal inflammatory infiltrate (Gilchrest et al, 1983; Hawk et al, 1988) and the presence of apoptotic keratinocytes know as sunburn cells (Sheehan and Young, 2002). Individual sensitivity to erythema can be assessed by determining the minimal erythema dose (MED) that increases with skin type as shown in Table 1 but MED is not predictive of skin type because there is considerable variation of MED within different white skin types (Harrison and Young, 2002). Within a few days of exposure to solar UVR delayed melanogenesis (tanning) occurs that is dependent on skin type and like erythema is primarily caused by UVB. This results from the synthesis of melanin in melanocytes: specialized pigment producing cells in the epidermis that transfer melanin to keratinocytes. Many people expose themselves to UVR, either from the sun or sunbeds, for the sole purpose of obtaining a tan that becomes more intense with repeated exposure. This repeated exposure also results in thickening of the epidermis, especially the stratum corneum, the outermost dead layer, which results in the skin feeling dry. The UVA content of solar UVR makes a relatively small contribution to erythema and tanning (see section 2(b).1). A UVB tan is photoprotective against erythema but the level of photoprotection is modest and equivalent to a sunscreen with a sun protection factor (SPF) of 2-3 (Agar and Young, 2005). However, tans primarily induced by UVA are not photoprotective against erythema (Gange et al, 1985). UVR exposure, in particular UVA, results in transient immediate pigment darkening (IPD) the function of which is not known (Routaboul et al, 1999).
Solar UVR exposure can aggravate certain skin diseases such as lupus erythematosus and pemphigus (Morison et al, 1999) and induce skin photosensitivity with commonly used UVR- absorbing systemic drugs and topically encountered chemicals (Ferguson et al, 1999). Furthermore, there is a wide range of acquired and genetic UVR and visible radiation photodermatoses that are beyond the scope of this document.
Exposure of the skin to UVR can suppress cell-mediated immunity when assessed with the sensitisation (Kelly et al, 2000) and the elicitation arms (Moyal and Fourtanier, 2003) of the contact hypersensitivity (CHS) response. A single sub-erythemal exposure of solar simulating radiation (SSR) suppresses the induction (sensitisation) arm of the CHS response in skin types I/II (Kelly et al, 2000) but erythemal exposure is necessary to suppress the elicitation arm (Moyal and Fourtanier, 2003). Suppression of cell-mediated immunity is thought to play a role in UVR-induced skin cancer and infectious diseases, e.g. Herpes simplex infections.
The clinical effects of UVR exposure, whether acute or long-term, are underpinned by many molecular and cellular events (Matsumura and Ananthaswamy, 2002). UVR-induced damage to epidermal DNA, especially cyclobutane pyrimidine dimers (CPD), is thought to be responsible for many adverse effects of solar UVR, including immunosuppression, and can be demonstrated in the skin immediately after exposure to erythemal and sub-erythemal UVR (Young et al, 1998). DNA integrity is maintained by complex repair processes and the p53 mediated elimination of damaged cells by apoptosis (sunburn cell formation). Failure of these processes is though to result in skin cancer (Matsumura and Ananthaswamy, 2002). Membrane as well as DNA effects also contribute to UVR-induced skin damage. The relevant cell surface or cytoplasmic chromophores are currently unknown. There is considerable evidence that the photoisomerization of stratum corneum trans-urocanic acid (UCA) to the cis-form also plays an important role in immunosuppression. Exposure to erythemal UVR or repeated sub-erythemal UVR results in a loss of epidermal antigen presenting Langerhans cells (Novakovic et al, 2001).
An IARC monograph on solar and ultraviolet radiation classified solar radiation as “carcinogenic” to humans (Group 1) and UVA and UVB and the use of sunbeds as “probably carcinogenic” to humans (Group 2A )(IARC, 1992).
Solar exposure is recognized as the main environmental factor in the development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) that form the great majority of skin cancers (IARC, 1992). These lesions result in a high level of morbidity with only occasional mortality from infrequent metastatic SCC. UVR is also associated with actinic keratoses (AK) that may be regarded as precancerous lesions for SCC.
The evidence for UVR in these lesions has been primarily ecologic (reviewed by Armstrong and Kricker, 2001), supported by mouse studies in the case of SCC (de Gruijl, 1995). More recently, a role for UVR has been supported by the presence of UVR “signature mutations” in tumours (Brash et al, 1996). Skin type is an important determinant of BCC and SCC risk with skin types I and II at greater risk than skin types III and IV, with the lowest risk being in skin types V and VI. SCC is associated with chronic UVR exposure and is more common in people with outdoor occupations. There is evidence that BCC is associated with intermittent exposure (Kricker et al,1995). Many cancer registers do not record BCC and SCC. Melanoma has been registered for many years and there is evidence that the incidence rate is increasing substantially in Europe (Boyle et al, 2004). Data from the skin cancer registry in Trentino, Italy showed incidence rates of 88 per 100,000 for BCC and 29 per 100,000 for SCC in the period 1993-1998 in comparison to 14 per 100,000 for melanoma (Boi et al, 2003).
Though much less common than BCC and SCC, melanoma is the main cause of death from skin cancer. There were an estimated 35,000 cases of melanoma diagnosed in Europe in 2000 with 9000 deaths (Boyle et al, 2004). Sun exposure is established as the major environmental determinant of melanoma (IARC, 1992; Donawho et al, 1994; Armstrong and Kricker, 1993) and the risk of melanoma depends on the interaction between environmental exposures and the genes which determine susceptibility. Melanoma is rare in black skinned peoples (Parkin et al, 1997).
There is no doubt that skin colour and sun exposure are potent determinants of risk of melanoma. World incidence figures show that the risk to individuals is greatest where pale skinned peoples live at low latitudes such as Australia and New Zealand (Parkin et al, 1997; Bulliard, 2000). In areas of the world where dark and pale skinned peoples live at high UV exposure levels, such as Hawaii, then the risk to pale skinned people is much greater than for their darker skinned neighbours (Chuang et al, 1999). Within Europe there is variation in incidence which reflects the interaction between skin colour and latitude as the peak incidence is in the north, in countries such as Sweden, where fair skinned peoples live an outdoor life and have access to sunny holidays in the south, or Switzerland where fair skinned peoples live at high altitude (Parkin et al, 1997). So, in the period 1996-8 the incidence rates (European Standardised Rates) in women were reported to be 17 per 100,000 in Switzerland, 6 per 100,000 in Spain and 16 per 100,000 in Sweden (de Vries and Coebergh, 2004).
Broadly, it would be reasonable to conclude that the risks of melanoma are so low in black- skinned peoples that sun protection advice should be directed only towards white-skinned peoples. The difficulty here is that skin colour is a continuous rather than a discontinuous variable. Some Asian peoples have quite a high tendency to burn and within white skinned peoples there is variation in susceptibility to sunburn and to melanoma which is related to skin colour and whether there are freckles or not. Data from many case control studies have established that phenotypic characteristics associated with vulnerability to the sun are risk factors for melanoma. Gandini et al (2005a) recently summarized these in a meta-analysis of 60 such studies. Her overall conclusions were that skin type I (versus IV) was associated with a relative risk (RR) of 2.1 for melanoma (95% CI 1.7-2.6), where skin type I, is skin which always burns and never tans and skin type IV is skin which never burns. A high density of freckles was associated with a RR=2.1 (95% CI 1.8-2.5), eye colour (Blue vs. Dark: RR=1.5, 1.3-1.7) and hair colour (Red vs. Dark: RR=3.6, 2.6-5.4). Hence, whatever the ethnic origin of Europeans, in terms of skin type, health advice about skin cancer should be directed to those individuals with a tendency to burn rather than to tan, those who have freckles and those with fair (particularly red) hair. It is clear from the level of these risk factors that the relative risk is significant but the absolute risk associated with these phenotypic characteristics is relatively small in European countries with incidence rates of between 5 and 17 per 100,000 per annum (European Standardised Rates) (de Vries and Coebergh, 2004). The prevalence of individuals with these risk factors will vary considerably between populations. In a study of healthy women in the UK, 8% had red hair and 6% had very high freckle scores on the back (Bertram et al, 2002).
Risk of melanoma is also greater in patients with larger numbers of melanocytic naevi whether banal or clinically atypical, where an atypical naevus is defined as a mole 5mm or greater in diameter, with an irregular or ill-defined edge and variable pigmentation. Numerous case-control studies have addressed this, and a second meta-analysis by Gandini et al (2005b) showed that the number of common naevi was confirmed as an important risk factor for melanoma with a substantially increased risk associated with the presence of 101-120 naevi compared with < 15 (pooled Relative Risk (RR) = 6.9; 95% Confidential Interval (CI): 4.6, 10.3) as was the number of atypical naevi (RR = 6.4 95%; CI: 3.8, 10.3; for 5 versus 0). Twin studies have provided strong evidence that naevus number is genetically determined (Wachsmuth et al, 2001; Zhu et al, 1999; Easton et al, 1991) and the association of the phenotype with melanoma risk therefore implies the presence of naevus genes, which are also low penetrance melanoma susceptibility genes. Thus, persons with this atypical naevus phenotype have an increased risk of melanoma, which is significantly higher than that associated with red hair or freckles. The prevalence of this phenotype also varies between populations but was reported in 2% of individuals in the UK (Bataille et al, 1996).
The phenotypes described above are genetically determined and therefore it is not surprising that family history is a risk factor for melanoma. Familial melanoma was reported in the 19th century in the UK (Norris, 1820), and a strong family history of melanoma is the most potent risk factor for melanoma (Kefford et al, 1999). Any family history of melanoma is associated with a doubling of risk for close relatives. A study from the Utah population database estimates risk to first-degree relatives of melanoma cases to be 2.1 (95% CI 1.4-2.9). A similar study from the Swedish Cancer Registry estimated the standardized incidence ratio for melanoma to be 2.4 (95% CI 2.1-2.7) for offspring if one parent had a melanoma, 3.0 (95% CI 2.5-3.5) for an affected sibling and 8.9 (95% CI 4.3-15.3) if a parent and a sibling were both affected. The highest ratio was 61.8 (95% CI 5.8-227.2) for offspring when a parent had multiple melanomas (Hemminki et al, 2003). Such patterns of risk are indicative of a significant hereditary component, which is most probably inherited as an autosomal dominant trait with incomplete penetrance. The risk of melanoma increases with age although in Europe the age distribution curve is relatively flat and in Europe the incidence is commonly higher in women than in men (Parkin et al, 1997).
Sun exposure is clearly the major environmental risk factor for melanoma as discussed above. A third meta-analysis reported by Gandini et al (2005c) has supported the conclusions of many individual case-control studies that intermittent sun exposure remains the most predictive environmental risk factor for melanoma (random effects model RR=1.6 (95% CI 1.3-2.0) and that sunburn, especially in childhood is a significant risk factor, although there was much heterogeneity between studies. A random effects model suggested a highly significant effect for sunburn at any age (RR=2.0 95% CI 1.7-2.4). The pooled analysis provided no evidence for a causal effect of chronic sun exposure on melanoma risk, RR=1.0 (95% CI 0.9-1.0). Further evidence for a role of sun exposure in melanoma comes from penetrance studies for the melanoma susceptibility gene CDKN2A in which there was evidence for an interaction between susceptibility genes and latitude of residence so that penetrance was highest in families with germline CDKN2A mutations living in Australia when compared with those in Europe (Bishop et al, 2002).
A meta-analysis, incorporating latitude, showed that phenotypic indicators of excessive sun exposure (representing gene/environment interaction) in fair-skinned individuals are risk factors for melanoma (Gandini et al, 2005a). Pre-malignant and malignant lesions were associated with a RR=4.3 (2.8-6.6) and actinic damage indicators with a RR=2.0 (1.2-3.3). This is of note despite the lack of epidemiological evidence from case-control studies for chronic sun exposure as a risk factor for melanoma.
In summary, there is strong evidence that excessive sun exposure is causal for melanoma. Evidence persists that the exposure pattern is important, e.g. intermittent, although the observation in some studies that actinic skin damage is a risk factor provides some evidence that chronic over-exposure is also causal in some patients. The evidence is also strong that excessive sun exposure increases the risk of melanoma in those with a strong family history. There is an emerging view, based upon epidemiological and biological studies that there may be more than one route to melanoma: one associated with low or intermittent sun exposure and for which numerous naevi is a risk factor and another with chronic over exposure (Whiteman et al, 2003). All of the risk factors quoted above are independent risk factors in individual case control studies and therefore the presence of multiple risk factors in an individual increases the relative risk of melanoma.
Health education is postulated to be most effective when targeted at those at greatest risk. Thus, UVR risk communication to European citizens is probably best directed at those with established risk factors (e.g. family history, fair skin and multiple naevi). There is a need to communicate these complex issues to the European citizen in a way that is easily understood.
Exposure of the skin to UVR results in UVR-induced skin ageing known as photoageing, which is very evident, when one compares normally sun-exposed (face) and sun-protected (buttock) sites. Clinical symptoms of photoageing include wrinkling, laxity and disturbances of the distribution of pigmentation (Glogau, 1996). Photoageing is thought to at least partially arise from the induction of matrix metalloproteinases (MMPs) that degrade collagen, the major structural protein of the dermis (Fisher et al, 2002). Photoageing, assessed by elastosis, is an indicator of non-melanoma skin cancer risk (Kricker et al, 1991).
2.3 How can the eyes be damaged by solar UV radiation?
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The eye is a complex multi-layered organ that receives visible radiation on its retina. The intermediate layers attenuate UVR to different degrees and thereby protect the retina from UV photodamage. The outermost cornea absorbs UVC and a substantial amount of UVB, which is further attenuated by the lens and the vitreous humor in front of the retina. UVA is less well attenuated by the cornea but is attenuated by the internal structures so it does not reach the retina (Sliney, 2001; Roberts, 2001; Johnson, 2004). The only acute clinical effect of UVR on the eye is photokeratitis that is also known as snow blindness or welder’s flash (Sliney, 2001; Roberts, 2001; Johnson, 2004). This is a painful transient inflammatory condition caused by UVC and UVB-induced damage to the corneal epithelium. Typically it appears 6-12 hours after exposure and resolves, within 48 hours. In some ways it can be regarded as sunburn of the eye.
Effects on the Eye
There is epidemiological evidence that solar UVR exposure increases the risk of cataracts of the lens, anterior lens capsular change and pterygium (Johnson, 2004). In vivo and ex vivo acute studies on mammalian lens (Pitts et al, 1977; Merriam et al, 2000; Oriowo et al, 2001) and a chronic in vivo study (Jose and Pitts, 1985) have indicated that the UVB part of the solar spectrum is most likely to be responsible for any long term effects that solar UVR has on the lens. There is also epidemiological evidence that solar UVR exposure results in ocular melanoma, especially from a study in Australia (Vajdic et al, 2002) that showed that choroid and ciliary body melanoma were positively associated with time outdoors on weekdays with OR up to 1.8 (95% CI 1.1 – 2.8) and p = 0.01 for trend. Unlike melanoma of the skin there is no latitude gradient for ocular melanoma (Vajdic et al, 2003), which may be because UVR dose to the eye is probably determined by UVR exposure from horizon sky that is less affected by latitude.