Cancer risk of immunosuppressants in manufacturing.

During the chemical and pharmaceutical production of active pharmaceutical substances which are intended for immunosuppressive therapy, the employees may be exposed to these substances via inhalation. Immunosuppressants are linked to development of certain types of cancers e.g., lymphoma or skin cancer in transplant patients. The development of these cancers in patients is linked to the level of immunosuppression needed for transplantation in order to avoid organ rejection. Below these levels, with the immune system functioning uninhibited, cancer is unlikely to develop. An internal workshop was conducted to compare several pharmaceutical substances with the intrinsic property to cause immunosuppression, with the attempt to define the risk of healthy employees to develop cancer due to exposure to immunosuppressive substance at work and to determine the appropriate hazard classification for regulatory purposes. Data are discussed with emphasis on cyclosporine to reason the dose-response relationship and the safe level for occupational exposure. Our review indicates that if the exposure to cyclosporine at the workplace is below the threshold necessary to induce immunosuppression, the risk to develop cancer is negligible. Non-mutagenic immunosuppressants do not contribute to malignancies in occupational setting if their air concentrations do not exceed the immunosuppressive threshold limited with occupational exposure limits (OELs), which is for cyclosporine 17.5µg/m(3).

Genotoxicity of glycidamide in comparison to 3-N-nitroso-oxazolidin-2-one.

Acrylamide (AA) is generated by thermal processing of foods, depending on processing conditions and precursor availability. AA is not genotoxic by itself but becomes activated to its genotoxic metabolite glycidamide (GA) via epoxidation, mediated primarily by cytochrome P450 2E1. In the Comet assay in V79 cells and in human lymphocytes, GA induced DNA damage down to 300 microM concentration (4 h). After post-treatment with the DNA repair enzyme formamidopyrimidine-DNA-glycosylase (FPG), DNA damage became already detectable at 10 microM (4 h). By comparison, the N-nitroso compound 3- N-nitroso-oxazolidin-2-one (NOZ-2) is a much stronger genotoxic agent, significantly inducing DNA damage already at 15 min (3 microM). Post-treatment with FPG in this case did not enhance response. GA induced DNA damage in V79 cells rather slowly, with first response detectable at 4 h. The hPRT forward mutation test encompasses 5 days of expression time during which also repair can take place. GA-induced hPRT mutations only became detectable at concentrations of 800 microM and above. This is 80-fold higher than the lowest significant response to GA in the Comet assay (10 microM with FPG). In contrast, NOZ-2 was as effective in the hPRT test as in the Comet assay (3 microM). These results demonstrate substantial differences in the genotoxic potency of GA and NOZ-2. Whereas NOZ-2 is a pontent genotoxic mutagen, GA in comparison shows only low genotoxic and mutagenic potential, presumably as a result, at least in part, of preferential N7-G alkylation.

Genotoxicity of glycidamide in comparison to (+/-)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide and alpha-acetoxy-N-nitroso-diethanolamine in human blood and in mammalian V79-cells.

Genotoxic activity of glycidamide (GA) was investigated in comparison to that of the known carcinogens (+/-)-anti-benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide ((+/-)-BPDE) and alpha-acetoxy-N-nitroso-diethanolamine (alpha-A-NDELA), using the hypoxanthine-phosphoribosyl-transferase (hPRT) gene mutation assay with V79 mammalian cells and modified alkaline single cell gel electrophoresis (alkaline comet assay with and without treatment of cells with formamido-pyrimidine-DNA-glycosylase (FPG)) in lymphocytes from human whole blood. As shown earlier, GA induced significant DNA damage in lymphocytes from treated whole blood at > or = 300 microM (4 h) (Baum et al., Mutat. Res. 2005, 580, 61-69). In the present study, using the alkaline comet assay with FPG treatment, increased formation of DNA strand breaks was observed in lymphocytes treated with GA (10 microM; 4 h). alpha-A-NDELA and (+/-)-BPDE were genotoxic at 10-30 microM (1 h). Genotoxic activity of these compounds was not enhanced after FPG treatment. FPG treatment thus offers an enhanced sensitivity of DNA damage detection for genotoxic compounds with preference for N(7)- resp. N(3)-purine alkylation. In the hPRT assay with V79 cells, mutagenic activity of (+/-)-BPDE became significant at > or = 3 microM (24 h). For alpha-A-NDELA significant activity was observed at greater, not dbl 10 microM (24 h). As previously observed, GA was considerably less effective, inducing significant mutagenicity roughly at about 80-300-fold higher concentrations (800 microM; 24 h) (Baum et al., Mutat. Res. 2005, 580, 61-69).