Plasticizers are added to polyvinyl chloride (PVC) to confer flexibility to the polymer. Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used of them. However, due to its non covalent bond to the PVC, DEHP tends to vaporize easily. A significant exposure has been recorded in dialyzed patients since medical tubings. Most animal species metabolize DEHP rapidly into mono-ethylhexyl phthalate (MEHP) and 2-ethylhexanol (2-EH). Because of the suspected toxicity of DEHP, an alternative plasticizer, trioctyltrimellitate (TOTM) has aroused increasing interest. The aim of this study was to determine on isolated rat hepatocytes in vitro, the direct hepatotoxic potential of both DEHP and TOTM and their hydrolytic products. To evaluate the possible toxic liver risk resulting from exposure to DEHP and TOTM, isolated rat hepatocytes were incubated with either DEHP, TOTM, MEHP or their common metabolite (2-EH) for 3 hours. Cell viability was periodically estimated thanks to trypan blue tests (15 - 180 min). The activity of lactate dehydrogenase (LDH) was also monitored (1h, 2h, 3h). The results obtained with trypan blue test and with direct LDH activity measurements, were satisfactorily correlated. Hepatocytes treated with both plasticizers and metabolites on the one hand, and the controls (untreated suspension) on the other hand, showed important differences as for cell viability. The acute toxicity on hepatocytes is mainly due to MEHP. Among DEHP, TOTM, MEHP, 2-EH and after intraperitoneal injection of those compounds, only DEHP and MEHP were able to induce a significant hydrogen peroxide (H2O2) production by the rat hepatocytes. These observations enable us to confirm the hypothesis according to which DEHP and MEHP cause an imbalance between the synthesis and the degradation of H2O2. Our results suggest a short-term in vitro cytotoxicity of MEHP. Even if trypan blue and LDH tests offered good results and were easily branded, further assays as well as MTT-tests should performed in order to confirm the cytotoxicity of the compounds tested.

Information on which regulatory authorities base their decisions for licensing new drugs and the rationales behind these decisions were often not publicly available.

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In block-randomized clinical trials where the treatments can be identified by their appearance or effects, knowledge of the length and composition of the blocks enables prediction of the nature of one or more treatments at the end of a block and may introduce a selection bias.Matts and Lachin (I) have quantified "predictability with certainty" for two-arm trials with balanced randomization. In this paper, we provide a formula which can be used for measuring predictability in other situations: trials with three or more arms, and trials with unbalanced treatment allocation. In addition, we have provided tables of values for predictability according to common lengths and composition. Examples of results obtained in common situations areprovided. The importance of bias associated with predictability and the methods to limit it are discussed, and practical recommendations are provided.

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