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vervolg furocoumarine 3

vervolg furocoumarine 3

Dean S.W., Lane M., Dunmoor R.H., Ruddock S.P., Martin C.N., Kirkland D.J. & Loprieno N.
(1991) “Development of assays for the detection of photomutagenicity of chemicals during
exposure to UV light.” I. Assay development. Mutagenesis 6, 335-341. Abstract (first 250 words) Two complementary assay systems have been adapted for the detection of compounds which may form mutagenic photoproducts during exposure to UV light from an Osram Ultra-Vitalux sunlamp as used in the evaluation of the effectiveness of sun filters. The effects of UVA and of UVB were evaluated. A bacterial plate test using Escherichia coli strain WP2 allowed the
bacteria, co-plated with test chemical in soft agar, to be irradiated with various doses of UV light. Mutagenesis was assessed by scoring numbers of tryptophan-independent colonies. The chosen reference compound was 8-methoxypsoralen (8-MOP) which was non-mutagenic alone at the highest dose tested (1000 micrograms/plate). Following simultaneous exposure of bacteria to 8- MOP and doses of UV light which alone had little effect, large numbers of revertants were scored.
Numbers of mutants were dependent upon the doses of both 8-MOP and of UV light. The second test system involved the exposure of Chinese hamster ovary cells to UV light in the presence of test chemical to determine the clastogenic effects of photoproducts. Treatment with 8-MOP alone up to 50 micrograms/ml was not clastogenic but concomitant exposure to non-damaging doses of UV light caused large increases in the incidence of chromosome aberrations of all types. Damage was again dependent on the doses of both components. Two additional photoactive compounds, para-aminobenzoic acid and chlorpromazine both show photoclastogenic but not photomutagenic properties. These two complementary assay systems take advantage of using no-effect levels of UV light as a baseline against which photomutagenicity readily can be compared 

Gibbs N.K., Young A.R. & Magnus I.A. (1985) "Failure of UVR dose reciprosity for skin
tumorigenesis in hairless mice treated with 8-methoxypsoralen." Photochemistry & Photobiology
42(1), 39-42. Abstract. 8-Methoxypsoralen (8-MOP) phototumorigenesis was studied in hairless
albino mice irradiated with solar simulated radiation (SSR). Animals were exposed to three
different daily doses of SSR after application of an oily vehicle with or without 8-MOP. Tumor
production was dependent on daily SSR dose irrespective of topical treatment. The
phototumorigenic potency of SSR was increased by the vehicle and to a much greater extent by
inclusion of 8-MOP. Irrespective of topical treatment, a failure in dose reciprocity for
tumorigenesis was demonstrated; in terms of cumulative SSR dose, the lower daily doses were
more tumorigenic than the higher doses. This reciprocity failure in 8-MOP photosensitized mice is
similar to that previously observed for UV-B phototumorigenesis. The relevance of these findings
to therapeutic use of psoralens is discussed.

Kirkland D.J., Creed K.L. & Mannisto P. (1983) "Comparative bacterial mutagenicity studies with
8-methoxypsoralen and 4,5',8-trimethylpsoralen in the presence of near-ultraviolet light and in the dark." Mutat Res. 116(2), 73-82. Abstract. 2 strains of S. typhimurium, TA98 and TA100, and 2 strains of E. coli, WP2(pKM101) and WP2uvrA-(pKM101) were used to study mutagenesis by 8-methoxypsoralen (8-MOP) and 4,5',8-trimethylpsoralen (4,5',8-TMP) in the dark and in the
presence of near-ultraviolet (NUV) light both without metabolic activation and with rat-liver S9 at 3 levels (4, 10 and 30% in standard cofactors). The S9-independent base substitution mutagenic activity of 8-MOP plus NUV light was confirmed in WP2(pKM101), and a similar activity was seen for 4,5',8-TMP, although neither substance was active in TA100. The frameshift mutagenic activity of 8-MOP in the dark in TA98 was not confirmed despite histidine levels which would ensure DNA replication, but this may be due to the lower concentrations of 8-MOP achieved in the common solvent system adopted. Both 8-MOP and 4,5',8-TMP were mutagenic in WP2uvrA- (pKM101) after microsomal activation, and the responses were similar whether experiments were conducted in the dark or in NUV light. In view of the oral administration of 8-MOP to psoriasis patients, this finding may be of relevance in risk assessment, and tends to suggest that topical application of 4,5',8-TMP to psoriatic patients may present reduced risk of malignant disease.

Kirkland D.J., Aardema M., Banduhn N., Carmichael P., Fautz R., Meunier J.R. & Pfuhler S.
(2007) "In vitro approaches to develop weight of evidence (WoE) and mode of action (MoA)
discussions with positive in vitro genotoxicity results." Mutagenesis. 22(3),161-75
Abstract. A recent analysis by Kirkland et al. [Kirkland, D., Aardema, M., Henderson, L. and Müller, L. (2005) Evaluation of the ability of a battery of 3 in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity. Mutat. Res.584, 1-256] demonstrated an extremely high false positive rate for in vitro genotoxicity tests when compared with carcinogenicity in rodents. In many industries, decisions have to be made on the safety of new substances, and health risk to humans, without rodent carcinogenicity data being available. In such cases, the usual way to determine whether a positive in vitro genotoxicity result is relevant (i.e. indicates a hazard) for humans is to develop weight of evidence (WoE) or mode of action (MoA) arguments. These are based partly on further in vitro investigations, but usually rely heavily on tests for genotoxicity in one or more in vivo assays. However, for certain product types in the European Union, the use of animals for genotoxicity testing (as well as for other endpoints) will be prohibited within the next few years. Many different examples have been described that indicate DNA damage and genotoxic responses in vitro can arise through non-relevant in vitro events that are a result of the test systems and conditions used. The majority of these nonrelevant in vitro events can be grouped under a category of 'overload of normal physiology' that would not be expected to occur in exposed humans. However, obtaining evidence in support of such MoAs is not easy, particularly for those industries prohibited from carrying out in vivo testing.
It will become necessary to focus on in vitro studies to provide evidence of non-DNA, threshold or in vitro-specific processes and to discuss the potential for such genotoxic effects to occur in
exposed humans. Toward this end, we surveyed the published literature for in vitro approaches
that may be followed to determine whether a genotoxic effect observed in vitro will occur in
humans. Unfortunately, many of the approaches we found are based on only a few published
examples and validated approaches with consensus recommendations often do not exist. This
analysis highlights the urgent need for developing consensus approaches that do not rely on
animal studies for dealing with in vitro genotoxins.

Kirkland D.J., Henderson L., Marzin D., Müller L., Parry J.M., Speit G., Tweats D.J. & Williams
G.M. (2005) "Testing strategies in mutagenicity and genetic toxicology: an appraisal of the
guidelines of the European Scientific Committee for Cosmetics and Non-Food Products for the
evaluation of hair dyes." Mutat Res. 588(2), 88-105.
Abstract. The European Scientific Committee on Cosmetics and Non-Food Products (SCCNFP) guideline for testing of hair dyes for genotoxic/mutagenic/carcinogenic potential has been reviewed. The battery of six in vitro tests recommended therein differs substantially from the batteries of two or three in vitro tests recommended in other guidelines. Our evaluation of the chemical types used in hair dyes and comparison with other guidelines for testing a wide range of chemical substances, lead to the conclusion that potential genotoxic activity may effectively be determined by the application of a limited number of well-validated test systems that are capable of detecting induced gene mutations and structural and numerical chromosomal changes. We conclude that highly effective screening for genotoxicity of hair dyes can be achieved by the use of three assays, namely the bacterial gene mutation assay, the mammalian cell gene mutation assay (mouse lymphoma tk assay preferred) and the in vitro micronucleus assay. These need to be combined with metabolic activation systems optimised for the individual chemical types. Recent published evidence [D. Kirkland, M. Aardema, L. Henderson, L. Müller, Evaluation of the ability of a battery of three in vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity, specificity and relative predictivity, Mutat. Res. 584 (2005) 1-256] suggests that our recommended three tests will detect all known genotoxic carcinogens, and that increasing the number of in vitro assays further would merely reduce specificity (increase false positives). Of course there may be occasions when standard tests need to be modified to take account of special situations such as a specific pathway of biotransformation, but this should be considered as part of routine testing. It is clear that individual dyes and any other novel ingredients should be tested in this three-test battery. However, new products are formed on the scalp by reaction between the chemicals present in hair-dye formulations. Ideally, these should also be tested for genotoxicity, but at present such experiences are very limited. There is also the possibility that one component could mask the genotoxicity of another (e.g. by being more toxic), and so it is not practical at this time to recommend routine testing of complete hair-dye formulations as well. The most sensible approach would be to establish whether any reaction products within the hair-dye formulation penetrate the skin under normal conditions of use and test only those that penetrate at toxicologically relevant levels in the three-test in vitro battery. Recently published data [D.
Kirkland, M. Aardema, L. Henderson, L. Müller, Evaluation of the ability of a battery of three in
vitro genotoxicity tests to discriminate rodent carcinogens and non-carcinogens. I. Sensitivity,
specificity and relative predictivity, Mutat. Res. 584 (2005) 1-256] suggest the three-test battery
will produce a significant number of false as well as real positives. Whilst we are aware of the
desire to reduce animal experiments, determining the relevance of positive results in any of the
three recommended in vitro assays will most likely have to be determined by use of in vivo
assays. The bone marrow micronucleus test using routes of administration such as oral or
intraperitoneal may be used where the objective is extended hazard identification. If negative
results are obtained in this test, then a second in vivo test should be conducted. This could be an in vivo UDS in rat liver or a Comet assay in a relevant tissue. However, for hazard
characterisation, tests using topical application with measurement of genotoxicity in the skin
would be more appropriate. Such specific site-of-contact in vivo tests would minimise animal
toxicity burden and invasiveness, and, especially for hair dyes, be more relevant to human routes of exposure, but there are not sufficient scientific data available to allow recommendations to be made. The generation of such data is encouraged.

Koch K.W. (1986) "Psoralen photomutagenic specificity in Salmonella typhimurium." Mutat Res.
160(3), 195-205. Abstract. The cytotoxic and mutagenic specificity of two therapeutically
employed psoralens was examined in several Ames Salmonella typhimurium strains with near
ultraviolet light (UVA, 320-400 nm) activation. Photomutagenic activity of 8-methoxypsoralen
(8MOP) and 4,5',8-trimethylpsoralen (TMP) was found to be sequence-specific, and additionally
was dependent on the level of DNA-repair proficiency. Base-pair substitution photomutagenesis
in hisG46 appeared to require plasmid pKM101-mediated "error-prone" repair. Frameshift
photomutagenesis was observed in all hisC3076 strains but not in hisD3052 strains. Frameshift
mutagenic activity in hisC3076 was enhanced in the absence of uvrB excision repair and
increased further by plasmid pKM101. Phototoxicity was essentially identical in hisC3076,
hisD3052 and hisG46 strains; uvrB- excision-repair-deficient bacteria were considerably more
susceptible to lethal effects than wild-type parental strains, while the presence of pKM101 had no apparent effect on survival. Finally, the data show that psoralens are potent frameshift
photomutagens in Salmonella hisC3076 strains and demonstrate the potential utility of these
strains in evaluating photomutagenic and phototoxic activity of new furocoumarin derivatives.

Moysan A., Vigny P., Dardalhon M., Averbeck D., Voituriez L. & Cadet J. (1988) "3-
Carbethoxypsoralen-DNA photolesions: Identification and quantitative detection in yeast and
mammalian cells of the two cis-syn diastereoisomers formed with thymidine." Photochem
Photobiol 47, 803-808.

Nakagawa Y, Wakuri S, Sakamoto K, & Tanaka N. (1997) "The photogenotoxicity of titanium
dioxide particles." Mutat Res. 394(1-3), 125-32. Abstract. We employed a series of in vitro
genotoxicity assays--a single cell gel (SCG) assay with mouse lymphoma L5178Y cells, a
microbial mutation assay with Salmonella typhimurium, a mammalian cell mutation assay with
L5178Y cells, and a chromosomal aberration assay with Chinese hamster CHL/IU cells--to
evaluate the photogenotoxicity of titanium dioxide (TiO2) particles. Without UV/visible light
irradiation, TiO2 particles exhibited no or weak genotoxicity. With irradiation, however, TiO2
particles exhibited significant genotoxicity in the SCG and chromosomal aberration assays.
Therefore, we concluded that TiO2 particles are photogenotoxic.

Acute photoirritation is an undesirable effect resulting from the interaction of long
wavength UVA- light with exogenous chemicals, including furanocoumarins.

Deleo V.A. (2004) "Photocontact dermatitis." Dermatol Ther. 17(4), 279-88.
Photocontact dermatitis is not a common condition, but neither is it rare. Both photo-irritant
contact dermatitis (PICD) and photoallergic contact dermatitis (PACD) are seen by most
dermatologists in general practice. PICD is diagnosed on clinical grounds and is usually caused
by furocoumarins in plants like limes and celery. PACD is caused primarily by sunscreens but can
also be the result of fragrances and antibacterial agents. PACD can only be diagnosed by photopatch testing that most dermatologists, even those who patch test and give phototherapy in their office, do not perform. The procedure as outlined in this manuscript is relatively simple and can easily be accomplished in the dermatologist's office.

Kligman L.H., Zheng P. & Kligman A.M. (1995) "Photoirritation: a new photobiologic phenomenon induced by long wavelength UVA radiation in hairless mice treated with broad-spectrum sunscreens." Acta Derm Venereol. 5(3), 205-11.
While assessing the protective effect of broad-spectrum sunscreens against chronic UVA radiation, we observed a paradoxical worsening of skin damage with one product. To further examine this finding, five proprietory broad-spectrum sunscreens were applied to albino hairless mice irradiated thrice weekly for 32 weeks with a UVASUN lamp (> 340 nm). Appropriate age-matched controls were included. After approximately 12 weeks, two sunscreens induced a marked dermatitis. Biopsies showed damage greatly exceeding that found in UVA-irradiated, unprotected controls. Histologically, elastic fibers were hyperplastic, coalescing into elastotic clumps. Glycosaminoglycans also increased. Collagen damage was notable since UVA alone does not induce a histologic change. Electron microscopy confirmed these findings. Two other sunscreens provided nearly complete protection. Against chronic UVB radiation, the two UVA photoirritating sunscreens provided substantial protection. Since the UVA sunfilter, oxybenzone, was the same in all sunscreens, we postulate that an irritating component of the vehicle was responsible for the UVA-induced photoirritation. The fifth sunscreen produced severe damage with UVB and UVA.

Pape WJ. (1997) "Validation of in vitro methods to single out photoirritants using mechanistically
based tests." Arch Toxicol Suppl. 19, 239-47. Abstract. In the recent OECD draft proposal for a
new guideline on acute dermal photoirritation testing, in vitro screening tests have been included as part of the sequential test strategy. These screening tests were placed directly prior to animal tests proposed. In Europe some in vitro techniques - cell culture and mechanistic tests - are under validation in a joint project of the European Center for the Validation of Alternative Methods (ECVAM) and the European Cosmetic, Toiletry, and Perfumery Association (COLIPA). Two promising cellular in vitro tests are presented and discussed as tool for the screening of
photoirritancy. The first one as a general core test performed in each participating laboratory is
the 3T3 mouse fibroblast Neutral Red Uptake Phototoxicity test determining the cell viability by
uptake of Neutral Red as end point, whereas the second performed only by three participating
laboratories was the the Red Blood Cell phototoxicity test comprising a combination of two end
points, the photohaemolysis and the oxyhaemoglobin oxidation. Besides this, other mechanistic
tests can be used as additional support. Identification of photoirritation is generally considered to be one area for the successful research and validation of in vitro techniques.

Quinto I, Averbeck D, Moustacchi E, Hrisoho Z, Moron J. (1984) "Frameshift mutagenicity in
Salmonella typhimurium of furocoumarins in the dark.” Mutat Res. 136(1), 49-54. Abstract. The
dark mutagenicity of 4,5',8-trimethylpsoralen (4,5',8-TMP), 5-methoxypsoralen (5-MOP), 8-
methoxypsoralen (8-MOP), 3-carbethoxypsoralen (3-CPs) and two new pyridopsoralens (PyPs
and MePyPs) was tested using the Ames Salmonella plating assay in the absence of metabolic
activation. 4,5',8-TMP, 8-MOP and the two pyridopsoralens were found to be weak frameshift
mutagens in strain TA1537 whereas 5-MOP and 3-CPs did not demonstrate any significant
mutagenic activity. These findings support the notion that the genetic risks of these psoralens in the dark may be considered to be negligible.

Spielmann H., Liebsch M., Döring B. & Moldenhauer F. (1994) "First results of an EC/COLIPA
validation project of in vitro phototoxicity testing methods." ALTEX. 11(1), 22-31. Abstract. In a
joint project six laboratories from the European cosmetics industry (COLIPA) as well as from
FRAME (England) and ZEBET (Germany) are validating in vitro methods to be incorporated into
new international guidelines for photoirritancy testing. During the first stage of the study it was
attempted to select the most promising in vitro photoirritancy tests for further validation. Twenty chemicals with known photoirritation properties (12 phototoxins (PT), 4 non-PTs and 4 UV absorbing non-PTs) were tested under identical UV exposure conditions (5 J/cm2, UV-A sun
simulator) in a standardized cytotoxicty assay using 3T3 fibroblasts (endpoint): Neutral red
uptake, NRU). The chemicals were also tested with in vitro phototoxicity assays established in
industrial laboratories, e.g. the photohaemolyses (Pape et al, 1993), histine oxidation, candida
albicans (Johnson et al, 1986), and, furthermore two commercial tests (SOLATEX PItrade mark
and Skin2trade mark). Data from the 3T3 NRU photoirritancy test, the red blood cell
photohaemolysis test and the Skin2trade mark assay showed a better overall correlation to
human in vivo data than results from the other tests. These simple assays therefore, seem very
promising for further validation under blind conditions. The protocols of the other tests have to be improved and standardized to permit better interlaboratory comparison.

Vohr H.W., Blümel J., Blotz A., Homey B. & Ahr H.J.(2000) " An intra-laboratory validation of the
Integrated Model for the Differentiation of Skin Reactions (IMDS): discrimination between
(photo)allergic and (photo)irritant skin reactions in mice." Arch Toxicol. 73(10-11), 501-9.
Abstract. We recently presented a modified local lymph node test which made it possible to
quickly and reliably differentiate between irritative and allergic skin reactions with extremely
simple parameters. The Integrated Model for the Differentiation of Skin Reactions (IMDS) test
combines measurement of cell proliferation in draining lymph nodes with measurement of primary ear swelling after topical application of the test substance on three consecutive days. In contrast to the 'classic' skin sensitisation test in guinea-pigs the IMDS test is considerably faster and is based on objective measured data, not subjective skin evaluations. Like the Local Lymph Node Assay (LLNA), measurement of allergic potential in the IMDS test is based on the underlying immunological mechanisms, but also considers the behaviour of immune competent cells following non-specific activation by irritants. In addition, the IMDS test can employ UV radiation after application of the substance and, therefore, make differentiation possible between different types of skin photoreaction (photoallergy and photoirritation) after both topical and systemic administration. Attempts to achieve this kind of discrimination with the LLNA necessitate considerably greater expenditure, as proliferation in the draining lymph nodes can also be induced by moderate to extreme (photo)irritants. In a previous paper in which we presented the IMDS test, we examined each type of reaction in reference to one single standard; the next logical step was therefore a broad-based intra-laboratory validation. An important factor in the validation was the use of standards that had been thoroughly examined in both guinea pig and mouse systems and were also relevant with regard to estimation of the risk for humans. The data presented here show that the IMDS is a simple and reliable tool for obtaining fast and reproducible assessments of potential (photo)allergic and (photo)irritant skin reactions to substances.
Studies by Young et al. (1987) are claimed to show that on hairless albino mice, the carcinogenicity shown by 25 & 50 ppm 5-MOP plus solar radiation is prevented by application of octyl cinnamate sunscreen or by 1,7,7-trimethyl-3- benzylidene-bicycl-[2.2.1]-heptanone. This is seemingly in contrast to the findings of an alternative study (Dubretet et al. 1990 - the team even included the same author - Young A.R.!), which concluded that “despite their promising protective effect in vitro, UVB and UVA sunscreens at low concentration (0.5%–1%) in perfumes cannot suppress the phototoxicity of bergamot oil on human skin.”
IFRA (2007) cite the study by Young et al. (1990) concluding “These data show that low concentrations of sunscreens can completely inhibit 5-MOP enhanced tumorigenesis.” However some studies show that not all sunscreens are beneficial - some sunscreens can actually cause more skin damage than controls with no sunscreen.

Dubertret L., Serraf-Tircazes D., Jeanmougin M., Morliere P., Averbeck D., & Young A.R. (1990)
“Phototoxic properties of perfumes containing bergamot oil on human skin: Photoprotective effect of UVA and UVB sunscreens.” Journal of Photochemistry and Photobiology B: Biology 7, 251- 259.
Abstract. As part of an international cooperative study of the photophysical, photomutagenic
and photocarcinogenic properties of bergamot oil and the effect of UVA and UVB sunscreens, the phototoxic properties of model perfumes containing 5, 15 and 50 ppm 5-methoxypsoralen (5- MOP) in bergamot oil with and without a suncreen have been investigated on human skin. It has been confirmed that the photosensitivity of human skin is maximal 2 h after perfume application.
Interestingly the addition of a UVA sunscreen is more efficient for decreasing the phototoxic
properties of bergamot oil than is a UVB suncreen. The addition of sunscreens in a model
perfume containing 50 ppm 5-MOP in bergamot oil can reduce the phototoxic properties of this
perfume to a toxicity equivalent to that produced by the application of a model perfume containing 15 ppm 5-MOP without sunscreens. However, despite their promising protective effect in vitro, UVB and UVA sunscreens at low concentration (0.5%–1%) in perfumes cannot suppress the phototoxicity of bergamot oil on human skin.

Folsom J., Gange R.W. & Mendelson I.R. (1983) "Ornithine decarboxylase induction in psoralentreated mouse epidermis used as a test of UV-A sunscreen potency." Br J Dermatol. 108(1), 17- 23. Abstract. Inhibition by sunscreens of UV-A-induced epidermal ornithine decarboxylase (ODC) activity in 8-methoxypsoralen-treated mice was used to examine the UV-A sunscreen activity of two commercial preparations, Uval (para-aminobenzoic acid) and PreSun (a benzophenone derivative). Both gave significant protection against UV-A doses of up to 3 J/cm2 and Uval was more effective that PreSun in the UV-A range. At intermediate doses (5-15 J/cm2) neither Uval nor PreSun significantly altered the ODC response to UV-A. At doses of 20-40 J/cm2 UV-A, control and PreSun-treated animals showed a decline in ODC activity which histological studies suggested was due to severe epidermal damage. This decline in ODC activity and severe epidermal damage was not seen in Uval-treated animals. Topical zinc oxide was highly effective in preventing induction of ODC by UV-A irradiation at doses up to 40 J/cm2, and was significantly more effective than either PreSun or Uval.

Kaidbey K.H., Agin P.P., Sayre R.M. & Kligman A.M. (1979) "Photoprotection by melanin--a
comparison of black and Caucasian skin.” J Am Acad Dermatol. 1(3), 249-60. Abstract. The
photoprotective role of melanin was evaluated by comparing the transmission of ultraviolet (UV)
radiation through skin samples of blacks and Caucasians, using both biologic and spectroscopic
techniques. UVA transmission was measured using fluoranthene, which causes a phototoxic
response to UVA wavelength. UVB was measured by monitoring erythema produced by either a
150-watt xenon arc or FS-20 sunlamps. It was found that on the average, five times as much
ultraviolet light (UVB and UVA) reaches the upper dermis of Caucasians as reaches that of
blacks. Differences in transmission between the stratum corneum of blacks and of Caucasians
were far less striking. The main site of UV filtration in Caucasians is the stratum corneum,
whereas in blacks it is the malpighian layers. Melanin acts as a neutral density filter, reducing all
wavelengths of light equally. The superior photoprotection of black epidermis is due not only to
increased melanin content but also to other factors related to packaging and distribution of
melanosomes. Not only are these data consistent with epidemiologic evidence, but they also may indicate why blacks are less disposed to phototoxic drug responses as well as less susceptible to acute and chronic actinic damage.

Kligman A.M & Forlot P. (1989) “Comparative photoprotection in humans by tans induced either
by solar stimulating radiation or after a psoralen-containing sunscreen.” In Fitzpatrick T.B., Forlot P., Pathak M.A. et al. (eds) Psoralens: past & present & the future of photochemoprotection & other biological activites. John Libby Eurotext, Paris, 1989.

Morliere P., Hilppe G., Averbeck D., Young A.R., Santus R. & Dubertret L. (1990) "In vitro
photostability and photosensitisng properties of bergamot oil. Effects of a cinnamate sunscreen." J. Photochem Photobiol, B: Biol. 7, 119-208.
Abstract. Bergamottin, which accounts for about two-thirds of the absorption of UVA and UVB light by bergamot oil, is shown to be fairly unstable on UV irradiation of solutions of bergamot oil (in ethanol-water, 80:20 (w/w)). Bergamottin photodegradation is partly inhibited by molecular oxygen and also by a cinnamate sunscreen acting as a triplet excited state quencher. On UV irradiation of bergamot oil, type II photodynamic properties, i.e. singlet oxygen production, are observed, which can be mainly attributed to the excitation of bergamottin by light. Therefore bergamottin can be considered as a potential photosensitizer in the photobiological activity of bergamot oil.

Séite S, Moyal D, Richard S, de Rigal J, Lévêque JL, Hourseau C, Fourtanier A.(1998) "Mexoryl
SX: a broad absorption UVA filter protects human skin from the effects of repeated suberythemal doses of UVA." J Photochem Photobiol B. 44(1), 69-76. Abstract. There is now considerable evidence that chronic UVA exposure induces damage in animal and human skin; however, little is known about UVA protection of human skin. The aim of this study is to evaluate the efficacy of Mexoryl SX, a broad UVA absorber (lamada max = 345 nm) against UVA-induced changes in human skin. The regimen of UVA exposure (13 weeks with increasing suberythemal doses) induces intense pigmentation with no erythema. Skin hydration and elasticity decrease, whereas otal skin thickness, assessed by echography, remains unchanged. Irradiated epidermis reveals a significant thickening of the stratum corneum, an absence of hyperplasia and an increase in the expression of the protective iron-storage protein ferritin. No significant alterations are seen using antisera against type IV collagen or laminin, suggesting that the dermal-epidermal junction (DEJ)is mainly preserved. In dermis, enhanced expression of tenascin is seen just below the DEJ but type I procollagen, which is localized at the same site, is unaltered. Although we are unable to visualize any changes in elastic network organization using Luna staining or specific antiserum directed against human elastin, we notice an increased deposition of lysozyme or alpha-1 antitrypsin on elastin fibres. Mexoryl SX (5%) efficiently prevents these alterations. Thus, these results suggest that UVA photoprotection can prevent early putative alterations leading to photoageing.

Wolf P., Donawho C.K. & Kripke ML. (1994) "Effect of sunscreens on UV radiation-induced
enhancement of melanoma growth in mice." J Natl Cancer Inst. 86(2), 99-105. Abstract.
BACKGROUND: Epidemiologic evidence suggests that exposure to UV radiation plays a
significant role in the development of melanoma skin cancers. As early surgical removal of the
melanoma is the only effective therapy, current strategies for reducing mortality from melanoma
focus on prevention of the disease. Chemical sunscreens protect mice from development of skin
cancers that resemble sunlight-induced human squamous cell cancers, but there appears to be a complex relationship between UV radiation exposure and development of melanoma. PURPOSE: We asked whether common sunscreens would protect mice against UV radiation-induced enhancement of melanoma incidence. METHODS: C3H mice were exposed to 4.8 kJ/m2 UVB from FS40 sunlamps twice a week for 3 weeks. Sunscreens containing 7.5% 2-ethylhexyl-pmethoxycinnamate, 8% octyl-N-dimethyl-p-aminobenzoate, 6% benzophenone-3, or the oil-inwater vehicle alone were applied to the ears and tails of the mice 20 minutes before irradiation. At various times during and after exposure, we determined UV radiation-induced inflammation by measuring ear swelling. We also examined the ears histologically for UV radiation-induced alterations. One day after the final irradiation, 2.5 x 10(4) syngeneic K1735 melanoma cells were injected into the external ears. Mice were examined weekly for tumor growth for 5-8 weeks after tumor cell injection. Control mice were treated in the identical way except for exposure to UV radiation. RESULTS: The incidence of melanomas was significantly higher in the UV-irradiated mice. All three sunscreens protected against UV radiation-induced ear swelling and clearly diminished histopathologic alterations, including sunburn cell formation, epidermal hyperplasia, and mononuclear cell infiltrate in the dermis. However, the sunscreens failed to protect against UV radiation-induced increase in melanoma incidence. The sunscreens or vehicle alone did not significantly alter tumor growth. CONCLUSIONS: Protection against sunburn does not necessarily imply protection against other possible UV radiation effects, such as enhanced melanoma growth. IMPLICATIONS: Sunscreen protection against UV radiation-induced inflammation may encourage prolonged exposure to UV radiation and thus may actually increase the risk of melanoma development. These findings suggest that further research on the ability of sunscreens to prevent melanoma is urgently needed.

Wolf P, Cox P, Yarosh DB, Kripke ML. (1995) “Sunscreens and T4N5 liposomes differ in their
ability to protect against ultraviolet-induced sunburn cell formation, alterations of dendritic
epidermal cells, and local suppression of contact hypersensitivity.” J Invest Dermatol. 104(2),
287-92. Abstract. Exposure of skin to ultraviolet (UV) radiation can lead to diverse biologic
effects, including inflammation, sunburn cell formation, alterations of cutaneous immune cells,
and impaired induction of contact hypersensitivity responses. The molecular mechanisms of
these UV-induced effects are not completely understood. We investigated the ability of
sunscreens and liposomes containing the DNA excision repair enzyme T4 endonuclease V to
prevent these effects of UV radiation. The use of T4N5 liposomes, which increase the repair of
cyclobutyl pyrimidine dimers, provides an approach for assessing the role of DNA damage in the
effects of UV radiation on the skin. Exposing C3H mice to 500 mJ/cm2 UVB radiation from FS40
sunlamps resulted in skin edema, sunburn cell formation, and morphologic alterations and
decreased numbers of Langerhans cells and Thy-1+ dendritic epidermal T cells. In addition, the
induction of contact hypersensitivity after application of 2,4-dinitrofluorobenzene on UV-irradiated skin was diminished by 80%. Applying sunscreens containing octyl-N-dimethyl-p-aminobenzoate, 2-ethylhexyl-p-methoxycinnamate, or benzophenone-3 before this dose of UV irradiation gave nearly complete protection against all of these effects of UV irradiation. In contrast, topical application of T4N5 liposomes after UV irradiation had no effect on UV-induced skin edema and only partially protected against sunburn cell formation and local suppression of contact hypersensitivity, although its ability to protect against alterations in dendritic immune cells was comparable to that of the sunscreens. These results suggest that DNA damage is involved in only some of the local effects of UV radiation on the skin. In addition, T4N5 liposomes may be a useful adjunct to sunscreens because they can reduce some of the deleterious effects of UV radiation on skin even after a sunburn has been initiated.

According to Spielmann et al. (2000): “a process in which reactions to normally ineffective radiation doses are induced in a system by the introduction of a specific, radiation absorbing substance (the photosensitiser) that causes another substance (the substrate) to be changed by the same dose of radiation.
The term photo-sensitisation, when used in the context of UV-radiation & application of an exogenous chemical can include elements of both photoallergy & phototoxicity.

Gange, R. W., Levins P. & Murray J. (1984) “Prolonged skin photosensitization induced by
methoxsalen and subphototoxic UVA irradiation. Journal of Investigative Dermatology 82, 219-
222. Abstract. Topical 8-methoxypsoralen (8-MOP) was used to briefly provide free psoralen
sufficient for marked cutaneous photosensitization, but only a small dose of UVA was delivered
initially, in an effort to produce many monoadducts but few crosslinks. After ample time for
clearance of the remaining free psoralen a second UVA exposure was delivered. The second
exposure should not have generated any additional monoadducts in the absence of free
psoralen, but the remaining monoadducts could be converted to crosslinks. The observation of a
prolonged persistent UVA-photosensitive state caused by prior, very small doses of UVA given
while free 8-MOP was present strongly suggests that psoralen-DNA crosslinks per se initiate
much of the phototoxic effect of 8-MOP on skin, and that monoadducts induce much less acute
inflammatory response. Because erythema was studied as the end point, the data say nothing
about relative contributions of monoadducts vs crosslinks in causing mutagenesis,
hyperpigmentation, therapeutic or other cutaneous responses. Other explanations for the induced persistent photosensitive state are also possible, but less tenable or entirely hypothetical.

Laskin, J. D. (1994) “Cellular and molecular mechanisms in photochemical sensitization: studies
on the mechanism of action of psoralens.” Food and Chemical Toxicology 32, 119-127. Abstract.
The interaction of chemicals and light to induce sensitization reactions in the skin is a complex
multistep process resulting in physiological changes in both the dermal and epidermal cell layers
as well as characteristic inflammatory reactions. It is becoming increasingly apparent that an
array of growth factors and cytokines acting on different components of the skin are involved in
the regulation of these processes. One of the best characterized classes of chemical
photosensitizers are the psoralens, a group of compounds that must be activated by UV light in
wavelengths ranging from 320 to 400 nm (UVA) to initiate their biological actions. Recent
evidence suggests that the ability of the psoralens to induce sensitization reactions, which include lterations in epidermal cell growth and differentiation, is highly specific and due to interactions with the epidermal growth factor (EGF) receptor. Specific receptor proteins for the psoralens have been identified in cytoplasmic and membrane fractions of responsive cells. Binding of psoralens to these proteins is of high affinity and reversible. UVA light causes psoralens to photoalkylate their receptors, a process thought to activate the receptor. One early biochemical event at the cell surface membrane linked to psoralen-receptor activation is the inhibition of EGF binding and alterations in the structure and function of the EGF receptor. These findings suggest that the cell surface membrane is an important target for chemical photosensitizers such as the psoralens. In addition, since photoactivated psoralens modulate epidermal cell growth and differentiation, the ability of these compounds to modify the function of the EGF receptor may underlie their biological activity as chemical photosensitizers.

Murphy G.N. (2001) "Diseases associated with photosensitivity." Journal of Photochemistry and
Photobiology B: Biology 64(2-3), 93-98. Abstract. Photosensitive disorders may be classified as
those entirely caused by solar exposure and the photoaggravated disorders. Those in the former category include polymorphic light eruption, juvenile spring eruption, actinic prurigo, hydroa vacciniforme, solar urticaria, also chronic actinic dermatitis. Genodermatoses whose expression mainly depends on UV or light exposure include the DNA repair deficient disorders, some disorders of cornification, the Smith–Lemli–Opitz syndrome and porphyria. Examples of
photoaggravated diseases include lupus erythematosus, erythema multiforme, atopic eczema,
psoriasis, viral exanthemata, pemphigus, dermatitis herpetiformis and rosacea. Drugs and
chemicals may interact with UV to induce photosensitivity. In many of these diseases the action
spectrum is known or may be determined by phototesting. Recognition of the reaction patterns
associated with the photodermatoses greatly assists clinical classification of the

Pathak M.A. & Joshi P.C. (1983) "The nature and molecular basis of cutaneous photosensitivity
reactions to psoralens and coal tar." J. Invest Dermatol. 80, Suppl. 66s-74s. Abstract. The basic
aspects of cutaneous photosensitization reactions and the mode of therapeutic effectiveness of
psoralens and coal tar, the two groups of photosensitizing agents used extensively in the
photochemotherapy of psoriasis, have been reviewed. Psoralen-induced skin photosensitization
and the therapeutic action of psoralens involve two distinct types of reactions, and these two
reactions occur independently of each other and concurrently when the psoralen-treated skin
(oral or topical) is exposed to 320 to 400 nm of radiation. The first, type I, is an oxygenindependent reaction and primarily involves photoreaction with DNA; the second, type II, is a sensitized reaction dependent on oxygen and involves the formation of singlet oxygen (1O2). The photoreactive form of psoralen is its triplet state, and the sites of reaction are (1) the cell membrane of the epidermal, dermal, and endothelial cells; (2) the cytoplasmic constituents, such as enzymes, RNA, lysosomes, etc.; (3) the cell nuclei (DNA and chromatin); and (4) the sensitized production of 1O2, which is responsible for cell-membrane damage and vasodilation. The major damage would be initiated by a type I reaction and would be seen in the form of nuclear damage to DNA resulting from the interaction of psoralen with DNA and to a lesser extent with RNA. The skin photosensitization response (erythema, edema, membrane damage, etc.) would result from a type II reaction involving the generation of 1O2. Crude coal tar (CCT), widely used in the Goeckerman therapy for psoriasis, also produces type I and type II reactions. The therapeutic and photosensitizing actions of CCT are due to (1) the photoconjugation of the photoreactive ingredients of CCT with DNA, causing interstrand cross-links; and (2) the production of 1O2. CCT is an efficient producer of 1O2, more so than 8-methoxypsoralen, and is responsible for cell-membrane damage and cellular edema.

Potapenko Ala (1991) "Mechanisms of photodynamic effects of furocoumarins." : J Photochem
Photobiol B. 9(1), 1-33. Abstract. The photosensitizing action of furocoumarins on biological
systems occurs by both an oxygen-independent pathway, which involves the photoaddition of the sensitizer to nucleic acids, proteins and lipids, and an oxygen-dependent pathway, which includes furocoumarins in the category of photodynamic sensitizers. The photodynamic action of
furocoumarins, as studied using isolated biomolecules, human erythrocytes and human skin,
appears to involve both activated oxygen species (singlet oxygen, superoxide anion, and hydroxyl radicals) and radical species formed by electron transfer from or to photoexcited furocoumarins. Another oxygen-dependent process involves the formation of photo-oxidized furocoumarin derivatives, which can react in the dark with several substrates (in particular, membrane components), causing an irreversible damage of cells. The latter type of process is temperature dependent. The relative importance of the different photosensitization mechanisms under various experimental conditions is discussed.

CAS n°: 66-97-7
According to IFRA (2007) psoralen “does not show a broad presence or high concentration in essential oils.” Stern (1994) suggests that in the long-term treatment for psoriasis with psoralen, PUVA & methotrexate increases patent incidence of squamous cell carcinoma.

Stern, R. S. & Laird N. (1994) “The carcinogenic risk of treatments for severe psoriasis. Cancer
73, 2759-2764.” Abstract. BACKGROUND. Common treatments used for severe psoriasis include psoralen and ultraviolet A radiation (PUVA), methotrexate, ultraviolet B (UVB), and tar. These therapies are often used for prolonged periods and may be carcinogenic. METHODS. For more than 13 years, the authors have prospectively determined the incidence of skin cancer and use of treatments for psoriasis in a 1380 patient cohort originally enrolled in a therapeutic trial of PUVA at 16 university centers. RESULTS. Squamous cell carcinoma (SCC) developed in more than one fourth of patients exposed to high doses of PUVA. In this group, the standard morbidity ratio for these tumors was 83 (95% confidence interval [CI], 72-96) compared with the expected number of these tumors in the general population. High-level exposure to methotrexate is a significant independent risk factor for developing SCC (relative risk, 2.1 for high versus low or no exposure; 95% CI, 1.4-2.8). Metastatic disease developed in seven patients with SCC. No significant increase in the risk of SCC was associated with long term exposure to UVB or topical tar, and no substantial increase in the risk of basal cell carcinoma was noted in association with prolonged use of any of these treatments. CONCLUSIONS. Long term exposure to PUVA and methotrexate significantly increases the risk of SCC in patients with psoriasis. This risk should be considered in selection of treatment. The ultimate morbidity of these tumors is undetermined.

[See pre-amble]. In spite of the fact that many scientific data-bases will give more than 6,000 hits for the keyword ‘PUVA’, the exact mechanism of PUVA therapy is still not known. The paper by Potapenko AIa et al. (2004) indicates at least two types of photoproducts of UVA-activated psoralens in the skin, namely those with membranotoxic properties, & others with immunosuppressory action in vivo.
Tanenbaum et al. (1974) indicate that coal tar is used with UV to treat psoriasis,
any beneficial effects are not due to coal tar’s phototoxicity. However the effects
of repeated UV-radiation alone on compromised skin may well be linked with
increased levels of skin cancer in a sub-section of the population (Tanenbaum et
al. 1976).

Beattie, P. E. Wilkie, M. J. Smith, G. Ferguson, J. Ibbotson, S. H. (2007) "Can dietary
furanocoumarin ingestion enhance the erythemal response during high-dose UVA1 therapy?" J
Amer Academ of Dermatology 56(1), 84-87. Abstract. As phototoxic skin reactions caused by
psoralen are induced by wavelengths within the UVA1 spectrum, we assessed the potential of the small amount of psoralen in a normal diet to provoke phototoxicity in volunteers with skin types I and II. Threshold erythema was unaffected by ingestion of a 200-g portion of parsnip.

Grundmann-Kollman, M., I. Tegeder, F. R. Ochsendorf, T. M. Zollner, R. Ludwig, R. Kaufmann,
and M. Podda (2001) “Kinetics and dose-response of photosensitivity in cream psoralen plus
ultraviolet A photochemotherapy: comparative in vivo studies after topical application of three
standard preparations.” British Journal of Dermatology 144, 991-995. Abstract. Background
Topical photochemotherapy with bath psoralen plus ultraviolet (UV) A irradiation (PUVA) has
been developed to reduce possible side-effects of oral PUVA therapy. Although the efficacy of
bath PUVA therapy appears to be similar to oral PUVA therapy, provision of bathing facilities has
obvious economic, logistic and sanitary implications. Cream PUVA therapy has recently been
developed as a variation of topical PUVA. Objectives To understand the photobiological effects
and to increase the safety and effectiveness of this novel topical PUVA therapy, we assessed the kinetics and dose±response of phototoxicity of 8-methoxypsoralen (8-MOP) cream in order to develop a treatment schedule for this treatment option. Methods Ninety-eight patients (63 men and 35 women) undergoing cream PUVA therapy were studied. The phototoxic properties of topically applied 8-MOP in three different water-in-oil creams as vehicles were assessed. In a
dose±response study, four concentrations of 8-MOP cream (0´0006 ± 0´005%) were used for
determination of the minimal phototoxic dose (MPD). The kinetics of photosensitization were
tested by determination of MPDs after different application times of 8-MOP cream (10, 20, 30 and 60 min). The persistence of phototoxicity was assessed by UVA exposure at defined time
intervals after application of 8-MOP cream (0, 30, 60 and 120 min) Results The concentration
required to produce sufficient but not undue photosensitization of the skin was 0´001% 8-MOP.
The duration of application leading to the lowest MPD was 30 min. Greatest photosensitization
was achieved when UVA irradiation was performed between 0 and 30 min after 8-MOP removal.
These findings showed no significant difference between the three vehicles used. Conclusions
Based on our data we recommend application of 0´001% 8-MOP in a water-in-oil cream for 30
min. Irradiation with UVA should be performed within 30 min after removal of 8-MOP cream, as
there is a rapid decrease in photosensitivity thereafter.

Hannuksela-Svahn A, Sigurgeirsson B, Pukkala E, Lindelöf B, Berne B, Hannuksela M,
Poikolainen K, Karvonen J. (1999) "Trioxsalen bath PUVA did not increase the risk of squamous
cell skin carcinoma and cutaneous malignant melanoma in a joint analysis of 944 Swedish and
Finnish patients with psoriasis." Br J Dermatol. 141(3), 497-501. Abstract. It has been suggested that trioxsalen bath and ultraviolet (UV) A (PUVA) is associated with a very low or no risk of nonmelanoma skin cancer, but the numbers of patients in individual studies have been limited. In order to attain statistically relevant information about the cancer risk associated with trioxsalen bath PUVA, two follow-up studies were combined and the joined cancer incidence was analysed among 944 Swedish and Finnish patients with psoriasis. The mean follow-up time for skin cancer was 14.7 years. Standardized incidence ratios (SIR) were calculated as a ratio of observed and expected numbers of cases. The expected numbers of cases were based on the national cancer incidence rates in the respective countries. There was no excess of squamous cell skin carcinoma [SIR 1.1, 95% confidence interval (CI) 0.2-3.2] or malignant melanoma (SIR 0.9, 95% CI 0.1-3.2) in the combined cohort. Basal cell skin carcinoma was not studied. The incidence of all non-cutaneous cancers was not increased (SIR 1.1, 95% CI 0.8-1.4). A threefold excess risk of squamous cell skin carcinoma after trioxsalen bath PUVA could therefore be excluded, which is a markedly lower risk than that associated with oral 8-methoxypsoralen PUVA. The result needs to be confirmed in a future follow-up, however, as the number of patients with high PUVA exposures was low.

Hannuksela-Svahn A, Pukkala E, Läärä E, Poikolainen K, Karvonen J. (2000) "Psoriasis, its
treatment, and cancer in a cohort of Finnish patients." J Invest Dermatol. 114(3), 587-90.
Abstract. This study was designed to estimate the relative cancer risk of patients with moderate to severe psoriasis, with reference to different treatments. A cohort of 5687 hospitalized patients with psoriasis obtained from the Finnish Hospital Discharge Register in 1973-84 was linked with the records of the Finnish Cancer Registry. Standardized incidence ratios for cancer were calculated by dividing the observed number of cases by the expected cases, which were based on the national sex-specific and age-specific cancer incidence rates. By the end of 1995, 533 cancer cases were observed in the cohort. The overall cancer incidence was increased (standardized incidence ratio 1.3, 95% confidence interval 1.2-1.4). The estimated relative risks were highest for Hodgkin's disease (standardized incidence ratio 3.3, 95% confidence interval 1.4-6.4), squamous cell skin carcinoma (standardized incidence ratio 3.2, 95% confidence interval 2.3-4.4), non-Hodgkin's lymphoma (standardized incidence ratio 2.2, 95% confidence interval 1.4-3.4), and laryngeal cancer (standardized incidence ratio 2.9, 95% confidence interval 1.5-5.0). The role of prior oral antipsoriatic medications or phototherapy on the development of these cancers was assessed in a nested case-control study, for which 67 cases and 199 sex and age matched controls were selected from the psoriasis cohort. The relative risks were estimated using conditional logistic regression analysis. Oral 8-methoxy-psoralen plus ultraviolet-A radiation therapy and the use of retinoids were associated with an increased risk of squamous cell skin carcinoma (relative risk adjusted for the other treatment variables 6.5, 95% confidence interval 1.4-31, and 7.4, 95% confidence interval 1.4-40, respectively), whereas none of the treatments could be linked with the occurrence of non-Hodgkin's lymphoma.

Hudson-Peacock, M. J., Diffey B.L., & Farr P.M. (1994) “Photoprotective action of emollients in
ultraviolet therapy of psoriasis.” British Journal of Dermatology 130, 361-365.
Nijsten T.E. & Stern R.S. (2003) "The increased risk of skin cancer is persistent after
discontinuation of psoralen+ultraviolet A: a cohort study." J Invest Dermatol. 121(2), 252-8.
Abstract. Psoralen+ultraviolet A-treated psoriasis patients are at increased risk for nonmelanoma skin cancer. To assess the persistence of cancer risk among patients who have discontinued psoralen+ultraviolet A and the risk of a first tumor with the passage of time, we prospectively studied the incidence in a cohort of 1,380 psoriasis patients treated with psoralen+ultraviolet A.
We observed a total of 27,840 person-years of which 59.4% were considered years without
psoralen+ultraviolet. No significant decrease in risk was noted during the first 15 years after
psoralen+ultraviolet A was discontinued. Subsequently, the risk of squamous cell carcinoma was
reduced (incidence rate ratio=0.79; 95%CI=0.62, 1.01 on treatment vs >15 years off). After 25
years, about 7% of patients with < or =200 psoralen+ultraviolet A treatments and more than half of the patients with > or =400 treatments develop at least one squamous cell carcinoma. After 25 years, almost one third of the patients exposed to > or = 200 treatments developed at least one basal cell carcinoma. In conclusion, substantial exposure to psoralen+ultraviolet A dramatically increases the risk of nonmelanoma skin cancer and prior exposure to psoralen+ultraviolet A remains an important issue in the management of patients because the cancer risk associated with psoralen+ultraviolet A is persistent.

Katz K.A., Marcil I. & Stern R.S. (2002) "Incidence and risk factors associated with a second
squamous cell carcinoma or basal cell carcinoma in psoralen + ultraviolet a light-treated psoriasis patients." J Invest Dermatol. 118(6), 1038-43. Abstract. Psoralen + ultraviolet A-treated psoriasis patients are at increased risk for squamous cell carcinomas and basal cell carcinomas; however, the incidence and risk factors associated with second squamous cell carcinomas and basal cell carcinomas in this population are not well qualified. Incidence and risk factors for second squamous cell carcinomas and basal cell carcinomas were studied in a cohort of 1380 psoralen + ultraviolet A-treated psoriasis patients prospectively followed for over 20 y; 264 had a squamous cell carcinoma and 258 a basal cell carcinoma after beginning psoralen + ultraviolet A therapy. After a first squamous cell carcinoma, the risk of a second squamous cell carcinoma was 26% at 1 y, 62% at 5 y, and 75% at 10 y. Risk increased with high psoralen + ultraviolet A exposure prior to the first squamous cell carcinoma (hazard ratio 3.32, 95% confidence interval 1.53, 7.18). Higher rates of post-first squamous cell carcinoma psoralen + ultraviolet A treatment also were associated with greater risk (hazard ratio 1.56 for every additional 10 treatments per year for patients with low pre-first squamous cell carcinoma psoralen + ultraviolet A exposure, 95% confidence interval 1.35, 1.81). Patients exposed to high levels of tar and/or ultraviolet B before a first squamous cell carcinoma were also at higher risk (hazard ratio 1.72, 95% confidence interval 1.14-2.60). Risk of a second basal cell carcinoma was 21% at 1 y, 49% at 5 y, and 61% at 10 y. There was some evidence that high exposure to psoralen + ultraviolet A before a first basal cell carcinoma was associated with increased risk of second basal cell carcinoma (hazard ratio 1.45, 95% confidence interval 0.97-2.17). Higher post-first tumor psoralen + ultraviolet. A treatment rates also increased risk (hazard ratio 1.24 for every additional 10 treatments per year, 95% confidence interval 1.06-1.47). Psoralen + ultraviolet A-treated psoriasis patients appear to have a greatly increased incidence of second squamous cell carcinoma compared with the general population. Patients who develop a squamous cell carcinoma after starting psoralen + ultraviolet. A therapy should be closely monitored for a subsequent squamous cell carcinoma.

Lindeloef B., Sigurgeirsson B., Tegner E., Larkoe O., Johannesson A., Berne B., Christensen
OB., Andersson, T., Toerngren M. et al. (1991) " PUVA and cancer: A large-scale epidemiological
study." Lancet 338(8759), 91-91. Abstract. There is concern about the long-term carcinogenic
effects of psoralen and ultraviolet A radiation (PUVA) therapy for treatment of skin disorders. A
study of 4799 Swedish patients (2343 males, 2056 females; mean age at first treatment 45
multiplied by 3 years, range 6-93; mean follow-up 6 multiplied by 9 years males, 7 multiplied by 2 years females) who received PUVA between 1974 and 1985 showed a dose-dependent increase in the risk of squamous cell cancer of the skin. Male patients who had received more than 200 treatments had over 30 times the incidence of squamous cell cancer found in the general population. Significant increases were also found in the incidences of respiratory cancer in males and females, pancreatic cancer in males, and kidney and colonic cancer in females. This study confirms previous reports of a dose-dependent increase in the incidence of squamous cell cancer in patients treated with PUVA.

Lindelöf B., Sigurgeirsson B., Tegner E., Larkö O., Johannesson A., Berne B., Ljunggren B.,
Andersson T., Molin L., Nylander-Lundqvist E. & Emtestam L. (1999) "PUVA and cancer risk: the
Swedish follow-up study." Br J Dermatol. 141(1), 108-12. Abstract. There is concern about the
long-term carcinogenic effects of psoralen and ultraviolet A radiation (PUVA) for treatment of skin disorders. Many authors have found an increased risk for cutaneous squamous cell carcinoma (SCC). Except in anecdotal reports, malignant melanoma had not been observed in patients treated with PUVA until recently. In the U.S.A., a 16-centre prospective study of 1380 patients showed for the first time that there might also be an increased risk for malignant melanoma in patients treated with high cumulative dosages of PUVA. We have therefore followed up the Swedish PUVA cohort until 1994. This cohort had previously been followed up until 1985.
Information from 4799 Swedish patients (2343 men, 2456 women) who had received PUVA
between 1974 and 1985 was linked to the compulsory Swedish Cancer Registry in order to
identify individuals with cancer. The average follow-up period was 15.9 years for men and 16.2
for women. We did not find any increased risk for malignant melanoma in our total cohort of 4799 patients treated with PUVA or in a subcohort comprising 1867 patients followed for 15-21 years. For cutaneous SCC there was an increase in the risk: the relative risk was 5.6 (95% confidence interval, CI 4. 4-7.1) for men and 3.6 (95% CI 2.1-5.8) for women. Significant (P < 0.05) increases were also found in the incidence of respiratory cancer in men and women and of kidney cancer in women. In conclusion, we did not find any increased risk for malignant melanoma in our patients treated with high doses of PUVA and followed up for a long time. We confirm previous reports of an increase in the incidence of cutaneous SCC in patients treated with PUVA, and recommend that patients should be carefully selected for PUVA and rigorously followed up.

Nijsten, T., Unaeze J., & Stern R.S. (2006) "Refinement and reduction of the Impact of Psoriasis
Questionnaire: Classical Test Theory vs. Rasch analysis." British Journal of Dermatology 154,
692-700. Abstract. BACKGROUND: Quality of life instruments are increasingly important in
assessing disease severity. However, some of these measurements have been developed on a
more or less ad hoc basis. Although not well standardized, psychometric analyses can be used to retest, refine and shorten existing quality of life instruments. OBJECTIVES: To psychometrically test and refine the Impact of Psoriasis Questionnaire (IPSO) and to compare the results of two different statistical approaches. PATIENTS AND METHODS: Among 792 psoriasis patients who were included in the PUVA Follow-up Study, we used classical test theory (CTT) and Rasch analysis to test and optimize the IPSO. Thereafter, two shortened versions of the IPSO derived from these models were compared. RESULTS: CTT analyses of the original IPSO demonstrated suboptimal item performance for six of 16 items and inappropriate subscaling. In contrast to the original four subscales, factor analysis of the CTT version yielded three subscales (mental functioning, mental wellbeing and stigmatization). The Rasch approach, which included ordering of thresholds, differential item functioning and item fit, resulted in a unidimensional 11-item questionnaire. Although the two new versions of the IPSO shared only six items, both reflected the original IPSO well. However, several arguments such as lower correlation coefficients, higher Cronbach's alpha, ordered thresholds, unidimensionality and fewer differences among subgroups of patients suggested that the Rasch version of the IPSO may be the preferred instrument to use. CONCLUSIONS: The IPSO can be improved and shortened and the Rasch-reduced version of this instrument is likely to assess the psychosocial impact of moderate to severe psoriasis on patients' lives best because it is a short, reliable and unidimensional measurement.

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