Long-Term Toxicity of Oral 8-Methoxypsoralen Plus Ultraviolet Radiation in Mice

Abstract

The combined effects of 8-methoxypsoralen (8-MOP) and ultraviolet radiation (UVR) in a photosensitizing protocol (psoralen-UVA, PUVA) were studied in hairless albino mice. The psoralen was administered orally by a pulse-feeding technique in which fasted mice were provided access to psoralen-containing feed. The mice were then exposed to radiation sources consisting of flurorescent “blacklight” lamps (F74T12 PUVA, Sylvania) either with or without an intervening filter designed to eliminate shortwave (UVB, λ < 320 nm) radiation. Exposure intervals were selected so that the total amount of ultraviolet A (UVA, λ 320–400 nm) delivered by the two configurations was equal (2 J/cm²). A series of dietary levels of 8-MOP provided mice with 0, 100, 250, and 625 mg/kg of diet. Neither radiation source, nor any tested 8-MOP level, produced grossly evident cutaneous damage, produced carcinogenesis, or reduced survival. In combination with either source, there was a consistent dosage-dependent enhancement of carcinogenesis by 8-MOP. This response was statistically significant at the middle and high dosage levels in female mice. In male mice the same trend was observed, but enhancement was significant only at the highest 8-MOP level in combination with filtered radiation, and at the two 8-MOP levels in combination with unfiltered radiation. In both sexes, survival time was significantly decreased by combinations of the highest 8-MOP level and either radiation source. Early deaths accompanied relatively severe chronic phototoxicity. Accelerated mortality and chronic phototoxicity were first observed after several months, were progressive, and were more severe in female mice and in mice exposed to the unfiltered (UVB-containing) source. Although explicit causes of death were not established, mortality appeared to result from the cutaneous damage rather than from processes analogous to UVB-induced life shortening. The combination of orally administered 8-methoxypsoralen (not carcinogenic to skin) and UVA radiation (noncarcinogenic at the levels tested) is carcinogenic in male and female hairless mice. Exclusion of UVB from the radiation source slightly reduces but does not eliminate the carcinogenic efficacy of the combination.