Dermal Toxicity of 8-Methoxypsoralen Administered (by Gavage) To Hairless Mice Irradiated With Long-Wave Ultraviolet Light

Abstract

Hairless mice were administered various amounts of 8-methoxypsoralen (8-MOP) by gavage, followed by irradiation with ultraviolet light (UVA) two or more times per week for periods ranging from 1 to 12 months. The minimum phototoxic dose was 20 mg/kg body weight by this route of administration and potential for serious organ toxicity in long-term exposures was investigated. No histologic features of cutaneous malignancy were encountered under test conditions which produced prolonged phototoxicity, deep ulceration, cicatrization, and other deformities. Repeated daily gavaged doses of 20 mg psoralen/kg body weight in conjunction with twice weekly irradiation for 10 min with UVA elicited an erythematous phototoxic reaction, but did not give rise to subsequent skin lesions. 8-MOP in repeated daily gavage doses of 30 mg and 40 mg/kg body weight combined with twice weekly UVA irradiation for 10 min caused severe burning with subsequent scarring, but did not induce malignant tumors in experiments lasting lasting 8 months. No organ toxicity was seen except for toxic liver changes when severe cutaneous burn and pronounced ulcerations were produced. Limited immunologic studies disclosed no abnormalities in this system.

Induction of unscheduled DNA synthesis in hairless mouse epidermis by 8-methoxypsoralen plus ultraviolet A(PUVA).

“…We did not try other administration routes, such as p.o. and i.p., because the carcinogenicity of 8-MOP orally administered in PUVA seems to be far lower than that after topical application (Griffin, 1959;Langner et al, 1977), and i.p. administration has not been used for humans.…”

Minimising the Risks of PUVA Treatment

“…Although the precise action spectrum of actinic damage has not been determined, epidermal changes are attributed to UVB and dermal changes to UV A because the latter penetrates more deeply into the skin. Long term exposure to PUV A may thus produce changes in the skin that resemble premature aging induced by sunlight (Langner et al 1977). Early in the course of therapy the skin becomes dry and wrinkled; these changes are fully reversible after cessation of therapy.…”

Carcinogens and mutagens present as natural components of food or induced by cooking

“…Intraperitoneal administration of 8-MOP followed by irradiation with ultraviolet light also results in tumors on the skin of mice [95,98]. Oral administration of 8-MOP was less effective than intraperitoneal injection, with several reports noting little or no carcinogenic effect [95,[98][99][100][101], but the phototoxicity of orally adminitstered 8-MOP and 5-MOP, and direct chemical analyses [102], demonstrate that the compounds do reach the skin following ingestion. A recent epidemiological study [103] on humans exposed to therapeutic oral doses of 8-MOP and to ultraviolet radiation for the treatment of psoriasis has demonstrated a carcinogenic effect.…”