W5 PM Toxicity of Complex Mixtures
Wednesday, 16 November 2005: 1:50 PM - 5:30 PM in 321-323

(DAW-1117-658698) Comparison of exponential vs. sigmoid dose-response curves: fitting of single chemical time-dependence data and implications for mixture toxicity assessment.

Dawson, D¹, Poch, G², ¹ Ashland University, Ashland, OH, USA² University of Graz, Graz, Austria

ABSTRACT- Microtox-derived single chemical toxicity data for several industrial organic chemicals, collected as part of a study evaluating dose-response curve (DRC) analysis in chemical mixture toxicity, were fit to exponential (2-parameter) and to sigmoid (4-parameter logistic) DRCs. Single chemical data were collected for several soft-electrophiles and for three non-polar narcotics at 15-, 30- and 45-min, to compare the fit of the single chemical data in each curve type for agents that showed time-dependent toxicity and for agents that showed no time-dependent toxicity. Careful evaluation of single chemical DRCs may allow for detection of significant differences among agents that are to some extent different in their properties, despite being classified as having the same mode of toxic action. When single chemical data were expressed as percent of control and fit to exponential and sigmoid curves (linear-linear), time-independent chemicals, which exhibited a DRC slope close to 1.0, were better expressed by sigmoid curves or at least showed a strong sigmoid component. Agents with a DRC slope of 1.5 to 1.6, were time-dependent and better characterized by the exponential curve function. Chemicals with an intermediate DRC slope appeared intermediate with respect to exponential and sigmoid curves. Longer incubation time often increased slope, so there was a tendency for better fit to exponential curves with increased exposure duration. In some cases, toxicity data did not fit either exponential or sigmoid curves well, instead showing a more biphasic fit in which data for lower concentrations came rather close to sigmoid curves, while data for higher concentrations came closer to exponential curves. Overall, the results suggest that some agents possess more than one mode of action over the concentration range tested, allowing data points to come close to one model or the other, but not fit either perfectly. These results may help explain why mixture toxicity for so many combinations roughly approaches dose-addition when chemicals in the mixture are from different mode of action classes.

Key words: soft electrophiles, Microtox®, dose addition, slope