Liver tumour promoting effects by polychlorinated biphenyls

PCBs cause a number of toxic effects and are present in a variety of biological samples including fish, meat and diary products. Cancer is a serious toxic effect by PCBs that has been observed in animal experiments but the knowledge about PCB induced carcinogenicity is still scarce. This thesis is focused on tumour promotive effects by PCBs in rat liver. The ultimate goal was to generate data, which would improve risk assessments of these substances. The specific aims were to analyse the tumour promotive effects of some individual PCBs in livers of rats, to study interactive effects of such substances on tumour promotion, and to study foci growth with a biologically based cancer growth model, using experimental data on cell proliferation and foci occurrence for the selection of growth parameters in the model. The tumour promoting potency of two PCB congeners, 2,3,4,5,3',4'-hexachlorobiphenyl (PCB156) and 2,4,5,3',4'-pentachlorobiphenyl (PCB118), was studied individually in a two-stage initiation/promotion rat liver bioassay. The effect of PCB156 was studied after 20 weeks of administration and PCB 118 after 20 and 52 weeks of administration. Both substances enhanced the occurrence of preneoplastic lesions in rat liver and relative potencies to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) based on the tumour promotive effect were calculated to be 0.0001-0.001 for PCB156 and <0.00002 for PCB 118. Cell proliferation in focal and non-focal tissue was analysed after treatment with PCB 118 for 20 or 52 weeks. A strong correlation between proliferation and foci occurrence was found in focal and non- focal tissue. Experimentally derived foci- and proliferation data were used to simulated foci growth over time with a biologically based cancer growth model. The simulation indicated that there are at least two types of initiated cells differentially affected by PCBI18 and that increased cell proliferation occurs in conjunction with the initiating treatment and in the beginning of PCB treatment. Interactive effects between compounds were investigated for two different types of mixtures. A complex mixture of PCBs, dioxins and dibenzofurans, similar to that in fish, was studied. The tumour promotive effect was somewhat lower than expected, suggesting that the TEF concept, which is presently used for risk assessment of these substances, overestimates the risk. These results could be explained by the conservative TEF values and/or by weak antagonism between the substances in the mixture. Mixtures of three PCB congeners 3,4,5,3',4'-pentachlorobiphenyl (PCB126), 2,3,4,3',4'pentachlorobiphenyl (PCB105) and 2,4,5,2',4',5'-hexachlorobiphenyI (PCB153), representing different types of chlorine substitution in the ortho position, were studied and the results were analysed with a multivariate method of analysis. Weak antagonism was demonstrated between PCB126 and PCB105 and between PCB126 and PCB153. Collectively, these data suggest antagonistic effects on tumour promotion by mixtures of polychlorinated aromatic hydrocarbons. In summary, the present study shows that PCB 156 and PCB 118 can stimulate the growth of preneoplastic lesions in rat liver. The tumour promotive potency of PCB 156 is 1000- 10000 times less than TCDD and the potency of PCB 118 is >50000 times less than TCDD The PCB 118 promoted foci growth was successfully modeled by a biologically based cancer growth model. At the dose levels tested, additivity or weak antagonism could be demonstrated after exposure to mixtures of polychlorinated aromatic hydrocarbons. Based on these results, there is no immediate reason to change the application of the TEF concept, given the uncertainty of the estimated TEFs and the importance of protecting the general human population through conservative risk assessments