For definition of Groups, see Preamble Evaluation.
Supplement 7: (1987) (p. 261)
8-Methoxypsoralen
CAS No.:
Chem. Abstr. Name: 7H-Furo[3,2-g][1]benzopyran-7-one,
9-methoxy-
A. Evidence for carcinogenicity to humans (sufficient)
The development of nonmelanocytic skin cancer (basal- and squamous-cell skin cancers) has been reported in patients treated with 8-methoxypsoralen and long-wave ultraviolet light (UVA) (PUVA) for psoriasis or mycosis fungoides [ref: 1-5]. Three cases of malignant melanomas of the skin have been reported in patients with psoriasis treated with PUVA [ref: 6,7]. The strongest evidence for a causal association between PUVA treatment and nonmelanocytic skin cancer comes from the follow-up of 1380 psoriatic patients treated in the USA. The standardized incidence ratio (SIR) for squamous-cell carcinoma increased from 4.1 (95% confidence interval, 2.3-6.8) at low doses to 22.3 (13.5-34.1) at medium doses and 56.8 (42.7-74.2) at high doses; this effect was independent of possible confounding effects of therapy with ionizing radiation and topical tar. The effect on basal-cell cancer was much weaker (high doses: SIR, 4.5; 2.8-6.9) [ref: 8]. One cohort study of 525 psoriatic patients treated with PUVA did not suggest an increase in the incidence of skin cancer (mean follow-up period, 2.1 years) [ref: 9]. This 'negative' result could have been due to lack of statistical power and to the low doses used in the study. Another study with a five-year follow up showed no skin tumour in 94 patients treated with PUVA for psoriasis or mycosis fungoides [ref: 10].
8-Methoxypsoralen alone did not alter the incidence of new skin cancer over two years in two small controlled trials of its use as a putative prophylactic for skin cancer [ref: 1].
B. Evidence for carcinogenicity to animals (sufficient)
8-Methoxypsoralen was tested by oral and intraperitoneal administration and by skin application in combination with ultraviolet A radiation in mice, producing epidermal and dermal tumours [ref: 1,11-15]. When it was tested alone in mice by intraperitoneal administration [ref: 13] or by skin application [ref: 12,13], it did not induce skin tumours. The studies were inadequate to evaluate the systemic carcinogenicity of 8-methoxypsoralen.
C. Other relevant data
In patients treated with PUVA, neither chromosomal aberrations (one study) nor sister chromatid exchanges were observed [ref: 16].
8-Methoxypsoralen in combination with ultraviolet A radiation induced sister chromatid exchanges in epithelial cells of cheek pouches of hamsters treated in vivo. In a large number of studies, it induced chromosomal aberrations, sister chromatid exchanges, mutation, DNA damage and DNA cross-links in human cells in vitro. It transformed mouse C3H 10T1/2 cells. In rodent cells in culture, it induced chromosomal aberrations, micronuclei, sister chromatid exchanges, mutation, unscheduled DNA synthesis and DNA cross-links. It induced mitotic recombination and mutation in fungi and mutation and DNA damage in bacteria [ref: 16].
8-Methoxypsoralen in the absence of ultra-violet A radiation induced mutation in bacteria, but inconclusive results were obtained with respect to chromosomal aberrations and sister chromatid exchanges in human cells in vitro, gene mutation and DNA damage in rodent cells in vitro and mutation in yeast [ref: 16].
Overall evaluation
8-Methoxypsoralen (methoxsalen) plus ultraviolet radiation is carcinogenic to humans (Group 1).
For definition of the italicized terms, see Preamble Evaluation.
Also see previous evaluation: Vol. 24 (1980)
References
1. IARC Monographs, 24, 101-124, 1980
2. Roenigk, H.H., Jr & Caro, W.A. (1981) Skin cancer in the PUVA-48 cooperative study. J. Am. Acad. Dermatol., 4, 319-324
3. Stüttgen, G., Kentsch, V., Schalla, W. & Schneider, L. (1981) The risks of photochemotherapy (Ger.). Z. Hautkr., 56, 1379-1399
4. Abel, E.A., Deneau, D.G., Farber, E.M., Price, N.M. & Hoppe, R.T. (1981) PUVA treatment of erythrodermic and plaque type mycosis fungoides. J. Am. Acad. Dermatol., 4, 423-429
5. Stern, R., Zierler, S. & Parrish, J.A. (1982) Psoriasis and the risk of cancer. J. invest. Dermatol., 78, 147-149
6. Frenk, E. (1983) Malignant melanoma in a patient with severe psoriasis treated by oral methoxsalen photochemotherapy. Dermatologica, 167, 152-154
7. Marx, J.L., Auerbach, R., Possick, P., Myrow, R., Gladstein, A.H. & Kopf, A.W. (1983) Malignant melanoma in situ in two patients treated with psoralens and ultraviolet A. J. Am. Acad. Dermatol., 9, 904-911
8. Stern, R.S., Laird, N., Melski, J., Parrish, J.A., Fitzpatrick, T.B. & Bleich, H.L. (1984) Cutaneous squamous-cell carcinoma in patients treated with PUVA. New Engl. J. Med., 310, 1156-1161
9. Lassus, A., Reunala, T., Idanpää-Heikkilä, J., Juvakoski, T. & Salo, O. (1981) PUVA treatment and skin cancer: a follow-up study. Acta dermatol. venereol., 61, 141-145
10. Fitzsimons, C.P., Long, J. & MacKie, R.M. (1983) Synergistic carcinogenic potential of methotrexate and PUVA in psoriasis. Lancet, i, 235-236
11. Kripke, M.L., Morison, W.L. & Parrish, J.A. (1982) Induction and transplantation of murine skin cancers induced by methoxsalen plus ultraviolet (320-400 nm) radiation. J. natl Cancer Inst., 68, 685-690
12. Nagayo, K., Way, B.H., Tran, R.M. & Song, P.S. (1983) Photocarcinogenicity of 8-methoxypsoralen and aflatoxin B1 with longwave ultraviolet light. Cancer Lett., 18, 191-198
13. Young, A.R., Magnus, I.A., Davies, A.C. & Smith, N.P. (1983) A comparison of the phototumorigenic potential of 8-MOP and 5-MOP in hairless albino mice exposed to solar simulated radiation. Br. J. Dermatol., 108, 507-518
14. Gibbs, N.K., Young, A.R. & Magnus, I.A. (1985) A strain of hairless mouse susceptible to tumorigenesis by TPA alone: studies with 8-methoxypsoralen and solar simulated radiation. Carcinogenesis, 6, 797-799
15. Hannuksela, M., Stenbäck, F. & Lahti, A. (1986) The carcinogenic properties of topical PUVA. A lifelong study in mice. Arch. Dermatol. Res., 278, 347-351
16. IARC Monographs, Suppl. 6, 380-385, 1987
Synonyms for 8-Methoxypsoralen
See Also:
Toxicological Abbreviations