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(52-17) Allowable chemical emissions derived from dose-response curves: Solvents as a source of confounding. Banasik, Marek*,1,2, Ueda, Kunihiro2, Stedeford, Todd1,2, 1 Institute of Environmental Engineering, Zabrze, Poland2 Laboratory of Molecular Clinical Chemistry, Uji, Japan ABSTRACT- Regulatory agencies use a variety of methods to estimate human health and ecological risks from exposure to toxic agents; however, many of these methods have limitations in their predictive value. In addition, the inherent toxicity of a compound can be masked by the choice of solvent used to deliver the chemical of interest. The purpose of this study was to determine the effect of three organic solvents [dimethyl sulfoxide (DMSO), ethanol, or methanol and water mixtures] at modulating the activity of poly(ADP-ribose) synthetase (PARS) (also termed polymerase), a key enzyme in the repair of damaged DNA. A dose-response was performed with each of the respective solvents. A 112% and 75% increase was observed with 15% ethanol and 10% methanol, respectively. In contrast, a near 20% decrease in activity was observed with 4% DMSO. Kinetic analysis revealed that DMSO is a competitive inhibitor of PARS (Km = 61 microM). Our results indicate an activating effect on PARS activity when ethanol or methanol is used at low concentrations, compared to the inhibitory effect of DMSO. PARS overactivation has been reported to result in necrosis while apoptosis is associated with PARS-inhibition and cleavage. Our data indicates that the interpretation of dose-response studies obtained when using common organic solvents may be dramatically skewed, either exaggerating the inherent toxicity of a compound or masking its potential for damage. Key words: Solvents, DNA Repair, PARP |
