UV Index - History · The 3rd International Conference on UV & Skin Cancer Prevention, Melbourne 7-11 December 2015 Global UV Index Pre-conference Workshop_Day 1 1

The 3rd International Conference on UV & Skin Cancer Prevention, Melbourne 7-11 December 2015 Global UV Index Pre-conference Workshop_Day 1

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UV Index 3 as a cut-off

Michael Kimlin

CRE Sun and Health

USC, AUSTRALIA

UV Index - History

The UV index was first introduced in Canada in 1992 in

response to growing concerns about the potential increase

of ultraviolet radiation due to ozone depletion(Fioletov et al., 2010).

In 1995, the World Health Organization (WHO) with the

World Meteorological Organization (WMO), the United

Nations Environment Program (UNEP), the International

Agency for Cancer Research (IARC) and the International

Commission on Non-Ionizing Radiation Protection (ICNIRP)

launched the Global Solar UV Index (UVI) as a vehicle to

visualize the amount of UV radiation reaching the Earth’s

surface (Italia and Rehfuess, 2012, Meves et al., 2003, Azooz and Jallo, 2015) .

UV Index

The UV Index is a simple and informative way of describing the daily danger of solar UV

radiation intensity (WHO, 2015).

The UV index range is expressed as a numeric value and as bands of color representing the

risk level of skin damage due to UV exposure from Low (0-2), Green, to Extreme (11+),

Purple. The higher the index value, the greater the potential for damage to the skin and eye,

and the less time it takes for harm to occur.

Low (0-2): Green

Moderate (3-5): Yellow

High (6-7): Orange

Very High (8-10): Red

Extreme (11+): Purple

In reporting the UVI, most emphasis is placed on the maximum UV level on a given day. This

occurs around solar noon. Depending on geographical location and whether daylight saving

time is applied, solar noon takes place between noon and 2 p.m.

Various Ultraviolet Exposure categories

UV Index Calculation

The calculation of UVI involves both

effect of different wavelengths, and

human susceptibility to them.

The calculations are weighted to those

UV wavelengths that human skin is most

sensitive to according to the McKinlay-

Diffey erythema action spectrum

curve (WHO, 2002). The UVI is a

unitless quantity defined by the

formula:

1.00E-04

1.00E-03

1.00E-02

1.00E-01

1.00E+00

250 270 290 310 330 350 370 390 410

Wavelength (nm)

Re

lativ

e R

esp

on

se

(W

n)


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The UV energy spectrum (radiation intensity) and the erythemal action spectrum

(skin sensitivity) across the range of UV wavelengths is shown below. The

multiplication of these two gives the erythemal UV spectrum, and the surface

below this graph (shown in yellow) is the UV index. The value of the UVI from this

measurement is 6.3.

Figure by Marc Allaart, KNMI, De Bilt (2012)

• Absorption by stratospheric

ozone is the main cause for the

decrease in UV intensity by

several orders of magnitude with

decreasing wavelength.

• The erythemal action spectrum

highlights that erythemal

potential increases with

decreasing wavelength.

• UV induced erythema is primarily

caused by UVB, with UVA being

200-300 times less effective than

UVB (Halliday and Lyons, 2008). Ultraviolet radiation measured from space and on the ground

at noon during the summer

(Fioletov et al., 2010)

Minimal Erythemal Dose (MED)

In order to measure the biological effects of UVR, the concept of ‘minimal

erythemal dose’ (MED) has been developed. The study of the erythemal influence

has been frequently based on the minimum dose of UV erythemal radiation that

will produce a noticeable reddening of human skin that has not been previously

exposed to solar radiation. This dose is known internationally as the MED and is

always related to a specific skin type.

If the UV irradiance is 1 MED/hour,

then it will take an hour for a person

exposed to this irradiance to receive

the minimum erythemal dosage. 1

MED corresponds to a total dose of

210 J/m². (Greinert et al., 2014).

Biological Evidence for “low

dose UV” (less than UVI 3)


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Low Dose UV and Skin

Cancer

Squamous Cell Carcinoma

Low dose UV has been shown to induce SCC in hairless mice with doses as low as

0.032 MED per day, although tumors arose more rapidly with increasing UV doses

(Rebel et al., 2005). Exposure to 8 mJ cm⁻² UV (about 0.08 of an MED) is sufficient to induce SCC and AK with a latency time of 234–238 days, with nearly all mice

developing multiple skin tumors .

UV-dose dependency of carcinogenesis in hairless mice. 0.032,

0.08 and 1 MED correspond to 32, 80 and 1000 J/m² of F40 lamps,

respectively. The tumour induction times at 0.08 MED/day

originate from (Rebel et al., 2005).

Exposure of opossums (Monodelphis domestica) to 25mJcm⁻² UV from FS40

sunlamps three times per week for 81 weeks has also been shown to induce non-

melanoma skin tumours in about 75% of animals. This dose is about half an MED in

the opossums, again showing that subinflammatory doses of UV are able to induce

skin cancers in this animal.

Weeks from first exposure

Kaplan-meier plots of the prevalence of NMSTs as a function of weeks

from first exposure to UVB (▪) OR UVA (∆). Treatment groups were

exposed to 250J/m² of UVR (˷150J/m² of UVB) from the FS40 sunlamps or 2.5×10⁴ J/m² of UVA from the filtered F40BLB lamps three times per

week for 81 weeks (Ley, 1997).


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While the UVB component is largely responsible for erythema, there is about 20-fold more UVA than UVB within sunlight. Sub-erythemal UVA (24 500 mJ cm⁻² day⁻¹) has also been shown to cause SCC in mice (Berking et al., 2002). UVA (2500

mJ cm⁻²) has also been shown to induce a single non-melanoma skin cancer in 30

irradiated opossums. Thus, experiments on UVA photocarcinogenesis indicate that

skin cancer may be induced in the absence of UV-induced erythema. Inflammation

from another cause may however be required for skin cancer development.

Probability of tumor development vs.

weeks of irradiation. Sencar mice were

exposed to UVB/UVA radiation (triangles),

UVA radiation (circles), or no radiation

(squares). Skin tumors (ear and dorsum)

are indicated by closed symbols,

mammary tumors are indicated by open

symbols (Berking et al., 2002)

In order to get information on the dose of UV that can cause skin cancer in

humans, skin obtained from white skinned human donors who underwent cosmetic

surgery was grafted onto immunodeficient (SCID or Rag-1) knockout mice, and exposed two to three times per week for up to 10 months with 40 mJ cm⁻² UVB or

solar-simulated UV consisting of 30 mJ cm⁻² UVB and 3–6000 mJ cm⁻² UVA. The UVB

was filtered to remove wavelengths below 295 nm. UVB induced AK in 10% of

grafts, and solar-simulated UV in 18% of grafts (Berking et al., 2002).

The study showed that at least in the absence of an immune system, UV can

induce skin cancers in human skin with very low doses, within the order of 10–20%

of an average human MED. Also, UVA contributes to the formation of tumors, as

there was an increased incidence when UVA was included. Hence this suggests

that human skin tumors may be induced with subinflammatory doses of UV.

Histological analysis of human adult skin grafts treated with MBA, UV or a combination of bothᵃ (Berking et al., 2002)

Pigmentation-related changes in human skin xenografts

after one exposure of DMBA followed by UVB three times

per week over 5 to 9 months. A: Dark pigmentation of skin

grafted to SCID mouse after 9 months. B: Irregular

pigmentation pattern with epidermal thickening of graft

after 8 months. C: Solar lentigo; pigmented macule in center

of skin graft after 5 months (Atillasoy et al., 1998).

Irradiation of human skin grafted onto Rag-1 mice three times per week for 12

months with 50 mJ cm⁻² UVB (290– 320 nm, peak 314 nm) caused the development

of solar lentigo in 23%, and melanocytic hyperplasia in 68% of human skin grafts.

The changes in melanocytes are associated with early malignancy. The induction of

these lesions with such a low dose of UV is consistent with subinflammatory UVB

being able to induce melanoma in human skin (Atillasoy et al., 1998).

Melanoma

UVA (2500 mJ cm⁻²) and UVB (25 mJ cm⁻², about 0.5 MED) have been shown to

induce melanocytic hyperplasia in opossums (Ley, 1997).

Weeks from first

exposure

Kaplan-meier plots of the

prevalence of MH (B) as a function

of weeks from first exposure to

UVB (▪) OR UVA (∆). Treatment

groups were exposed to 250J/m²

of UVR (˷150J/m² of UVB) from the FS40 sunlamps or 2.5×10⁴ J/m² of UVA from the filtered

F40BLB lamps three times per

week for 81 weeks (Ley, 1997).


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Summary – Animal Models

Doses of UVB more than 10-fold lower to produce erythema can induce SCC in

animal models.

UVA at doses several hundred fold lower to produce erythema can induce skin

cancers in animal models and at least contribute to photocarcinogenesis in

human skin grafted onto immunodeficient mice.

Therefore, it can be suggested that sub-erythemal UVB or UVA may cause

melanocytic lesions in a variety of animal models and in human skin grafted onto

immunoincompetent mice.

This shows that it is possible for sub-erythemal doses of UV to cause skin cancer.

However, the relative importance of subinflammatory compared to erythemal

doses of sunlight in causing skin cancer in humans remains unknown.

Low Dose UV and

immunosuppression

It is now known that in order for skin cancers to develop, both

genetic damage and immunosuppression is required.

While it cannot be directly experimentally determined

whether or not erythemal doses of UV are required for

photocarcinogenesis in humans, photoimmunosuppression and

gene mutations can be studied as surrogate markers because

these two biologic events are essential for skin cancer

induction.

Low Dose UV and Immunosuppression Sub-erythemal Doses of UV are Immunosuppressive in

Humans

Ultraviolet-induced immunosuppression is a key contributor to the development of

skin cancer. There are different lab models to describe UV-induced

immunosuppression:

The local model is when the antigen is applied to UV-irradiated skin of

unimmunized individuals.

Systemic immunosuppression is when the antigen is applied to an unirradiated

skin site of an unimmunized individual who has been exposed to UV at a

different skin site.

An established or memory immune response can also be suppressed by UV

irradiation.


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Daily irradiations with a suberythemal UV dose of 144 mJ cm⁻² UVB can cause

increasing levels of immunosuppression (local immunosuppression) with

increasing numbers of daily irradiations (Halliday and Lyons, 2008).

Increasing doses of single exposures to UVB also cause greater levels of

immunosuppression in humans with the suppression being discernible within 48h

of irradiation with 300 mJ cm⁻² UVB, which is subinflammatory (Poon et al.,

2005).

Single-exposure ultraviolet (UV) immunosuppression

time course and dose response (Poon et al., 2005)

UVB and Immunosuppression UVA and Immunosuppression

UVA is immunosuppressive at doses much lower than are required for this waveband

to cause erythema (Poon et al., 2005).

Irradiation with UVA suppresses reactivation of memory immunity to nickel in

humans. UVA also causes systemic suppression of recall immunity in humans

(Fourtanier et al., 2005).

In mice, UVA suppresses the induction of local immunosuppression and the

reactivation of memory immunity. Systemic suppression of the induction of primary

CHS can occur with three daily exposures to the relatively low UVA dose of 1680 mJ cm⁻² (Byrne et al., 2002).

• It has to be noted that unlike UVB, UVA is

immunosuppression but not until 48h following

exposure.

Single-exposure ultraviolet (UV)

immunosuppression time course

and dose response (Poon et al.,

2005)

UV and Immunosuppression

Humans are not exposed to pure UVB or UVA, but to sunlight, which consists of a

mixture of these two wavebands.

A single exposure to solar-simulated UV, less than half of what is required to cause

erythema has been shown to suppress the reactivation of memory immunity to

nickel in humans (Poon et al., 2005)

In mice a dose of 1820 mJ cm⁻² solar-simulated UV which is only half that required

to cause barely detectable inflammation can cause systemic immunosuppression

(Byrne et al., 2002).

Single-exposure ultraviolet (UV) immunosuppression time course and

dose response (Poon et al., 2005)

Summary

• Sub-erythemal doses of UVB can cause local immunosuppression.

• Erythemal doses + may be required for systemic immunosuppression in humans

• UV dose as low as 12.5% of an erythemal dose can cause systemic

immunosuppression in mice (Byrne et al., 2002)

• UVA at doses far too low to be inflammatory can cause local and systemic

immunosuppression in humans and mice.

• UV that mimics the UV portion of the solar spectrum is immunosuppressive in

humans and mice at subinflammatory doses.


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Low Dose UV and genetic

mutations

Low Dose (sub –erythemal) of UV are Mutagenic

Melanomas have been shown to contain significantly elevated numbers of UVR

signature mutations compared with internal cancers;

Mutations that give cells a growth advantage—inhibit cell death by apoptosis or

other mechanisms, establish genomic instability or overcome senescence—can all

contribute to the development of cancer. Such mutations are an essential step in

the formation of skin cancer;

UV can cause gene mutations in normal keratinocytes that result in the formation

of benign skin lesions, while inflammatory responses, developing for unknown

reasons as a post-UV exposure event, drive progression beyond an initial lesion;

UV induced mutations can cause epidermal cells to make pro-inflammatory

factors or to induce them in the surrounding stroma, creating an oxidizing

environment in which additional oncogenic mutations are likely to take place,

even in the absence of UV.

The high level of mutations in melanomas that have the signature of UVR-induced

damage indicates that the normal mechanisms that detect and repair this damage

must be defective in this system.

UVR causes DNA damage in the form of cyclobutane pyrimidine dimers (CPD) and

6-4 photoproducts (6-4PP), which are repaired by nucleotide excision repair

(NER) and if it not repaired, can lead to mutation. The 6–4PP are less abundant and

efficiently repaired, whereas the more abundant CPDs repair is slower and

misrepair of these lesions produce the UVR signature C>T and CC>TT mutations.

(A) Different forms of DNA damage are repaired by specific

repair mechanisms. (B) The extent of damage and success of

repair determine the outcome, either cell cycle checkpoint

arrest to allow for repair and return to proliferation or

where damage is too extensive for successful repair,

senescence, or death (Pavey et al., 2013).

Defects in checkpoint mechanisms have been identified in melanomas and are

likely to be responsible for increased mutation load in melanoma.

UVR causes both G1 and G2 phase checkpoint arrest in vitro cultured cells:

• The G1 arrest appears to be through a p53-dependent mechanism

• The G2 arrest is independent of p53, and involves a block in the cdc25-

dependent activation of the mitotic cyclin dependent kinase (CDK) complexes

(p16/CDKN2A)

Cell cycle checkpoints: Cell cycle checkpoints are

triggered in response to specific stresses and utilize

different signaling mechanisms to arrest the cells at

specific points in the cell cycle until the stress has been

resolved. (Pavey et al., 2013)


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Sub-erythemal UV doses are able to induce mutations (Mouret et al., 2006).

Chronic irradiation with 0.5 MED UV for 59 or 75 days has been shown to cause the

formation of p53 patches in hairless mice. The majority of these patches contained

mutant p53 (Rebel et al., 2005).

UVB and Mutation

Average numbers of mutant p53 patches

in Xpc-deficient mice (open diamonds)

and wild-type littermates (closed

diamonds) (n=4) at 1.0 of a wild-type

MED/day. Wild-type SKH1 data at 1.0

MED (closed circles and regression line)

are derived from (Rebel et al., 2005).

The melanoma susceptibility gene CDKN2A which encodes the cell cycle inhibitor

p16INK4A (p16) is commonly defective in melanoma.

Mutations of p16/CDKN2A have also been identified in non-melanoma skin cancers

(Pavey and Gabrielli, 2002).

P16/CDKN2A, which is functionally inactivated in a high proportion of melanoma

cell lines and in 10 - 30% of tumors, is a direct effectors of cell cycle progression

(Pavey et al., 2001).

Melanoma associated mutations of p16 disrupt its ability to promote senescence

arrest. In addition to this role, increased p16 expression has been correlated with

the G2 phase checkpoint arrest in response to suberythemal UVR (Pavey et al., 2013).

Checkpoint Defects (G2 – p16)

G2 phase checkpoint and repair response to UV lesions detected in S phase (Pavey et al.,

2013)

The studies show that in response to suberythemal dose of UVB, basal and

suprabasal layer cells (keratinocytes and melanocytes 24 - 48 h after exposure ) in

human skin arrest in G2 phase, and this is associated with increased levels of p16

(Pavey et al., 2001).

p16 expression is a delayed response, peaking at 24h after UV exposure. The

proportion of cells expressing p16 dramatically increased at 16h post-irradiation with 250 Jm⁻² UVB, peaked at 24h, and substantially diminished by 72h post-

irradiation. Similar data were obtained with 150 and 875 Jm⁻² UVB.

• Several studies identified p53 mutations in a majority of human non-melanoma

skin cancers (NMSC) and the commonest preneoplastic lesion, actinic keratosis,

from sun-exposed body sites (Roshan and Jones, 2012). Clusters of p53-positive

epidermal keratinocytes (p53 patches) are clonal outgrowths of keratinocytes

that contain mutations in p53 and are related to the formation of carcinomas

(Nicolien et al., 2005).

• Loss of p16 function may not only provide a growth advantage by disabling the

senescence mechanism, thus extending the proliferative capacity of the cells,

but may also result in cells undergoing mitosis with an increased burden of UV-

induced DNA mutations, the result of an inability to delay in G2 phase to permit

complete repair of the UV-induced lesions(Pavey and Gabrielli, 2002)

• It is therefore suggests that low dose UV is able to induce signature UV

mutations.

• Photocarcinogenesis in humans could only occur in response to UV doses too low

to cause erythema if these low doses are able to suppress immunity and mutate

genes in humans

Summary


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Summary

Skin Cancer may be induced with Sub-erythemal Doses of UV

With low dose UV (less than an MED):

Studies have indicated that sub-erythemal doses of UV

may cause benign skin tumors.

UV induced immunosuppression and gene mutations

may be sufficient to cause skin carcinogenesis.

Other considerations:

Most studies in this area (low dose UV) have been conducted in animal models – large area of research;

Limited human studies and epidemiological data

Dose rate of UV

UVI based on erythema as an end point

Other possible factors to consider – eye, Vitamin D

(Prof Lucas this afternoon will discuss balance)

Skin cancer may occur in response to lower doses of UV than are required to cause

erythema. Skin cancer, immunosuppression and gene mutations can all occur in

response to lower doses of UV radiation than are required to cause erythema (Halliday and Lyons, 2008).

MED

Thank you


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References

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UV Index - History · The 3rd International Conference on UV & Skin Cancer Prevention, Melbourne 7-11 December 2015 Global UV Index Pre-conference Workshop_Day 1 1