Intravenous repeated-dose toxicity study of ZnPcS2P2-based-photodynamic therapy in Wistar rats

The purpose of the current study was to investigate the potential repeated-dose toxicity of ZnPcP2S2-based photodynamic therapy (ZnPc-PDT) in Wistar rats. The animals were administered ZnPcS2P2 intravenously ten times successively every 4 d and irradiated with a 670 nm laser light for 6 min at subsequent 48 h and 72 h. At the end of the treatment period, 10 rats/sex/group were sacrificed, while 5 rats/sex/group were sacrificed after a two-week recovery period. During the test period, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, hematology, serum biochemistry, urinalysis, organ weights, gross findings and histopathology were examined. The association between the increased liver weight and hepatic spotty and lytic necrosis seen in high dose females corroborates the conclusion that high dose ZnPc-PDT could induce hepatic injury in Wistar rats and they are probably related to the abnormality of certain biochemical parameters of females in the high dose group. Furthermore, microscopic examination for the ZnPc-PDT groups shows the presence of some Kelly and khaki granules in Kupffer cells and endothelia of the livers, epithelia of the renal tubules, marginal sinus and medulla of the spleens, alveolar walls of the lungs, reticular cells and macrophages of the mesenteric lymph nodes, testicular Leydig cells, epididymal epithelial cells, endometrial stromal cells, and interstitial cells and corpora lutea of the ovaries from all or most of the animals. There were no adverse effects on mortality, clinical signs, food and water consumption, ophthalmoscopy, uranalysis, hematology, serum biochemistry, body weights and necropsy findings in control, low and mid dose groups. Based on these results, it was concluded that the intravenous repeated-dose of ZnPcP2S2-PDT induced the abnormalities of liver weights, hepatic biochemistry and histopathology, and pigmentation in the several important organs in Wistar rats at 4 mg kg(-1) d(-1). The target organ was determined to be liver (and spleen perhaps), but this was not so obvious in males. The no-observed-adverse-effect level (NOAEL) was considered to be 1.0 mg kg(-1) for both sexes.