We contributed to NTP technical reports of rodent bioassays on dibromoacetonitrile, isoeugenol, 5-(hydroxymethyl)-2-furfural, 1,2-dibromo-2,4-dicyanobutane, chromium picolinate monohydrate, androstenedione, goldenseal root powder, alpha,beta-thujone, kava kava extract, methyl trans-styryl ketone and styrene-acrylonitrile trimer that were reviewed and accepted by the NTP Board of Scientific Counselors. We also participated in study design committees for over 10 chemicals that will be tested by the NTP. We published papers in the scientific literature on chemicals that were recently tested by the NTP: Panax ginseng, goldenseal root powder, milk thistle extract, green tea extract, hexavalent chromium, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. The NTP is interested in reducing, replacing and refining the use of rodents in laboratory studies. As part of this effort, we are evaluating the utility of growth, reproduction, feeding and movement assays using the nematode, C. elegans, for testing toxicity of chemicals. Under typical conditions, C. elegans has a lifespan of about 4-5 days during which it undergoes 4 larval stages then adulthood. We developed a mathematical model of the progression through larval stages into adulthood, then applied the model to data from assays of a large number of chemicals (>1000) to determine which chemicals inhibited growth and which did not. In addition to the growth assay, we also analyze movement of the nematodes as capture by a high speed camera mounted on a microscope. By tracking the (x,y) coordinates of each nematode at each time point, we can calculate the distance, velocity and other characteristics of the path traveled. We then compare these characteristics across groups of C. elegans exposed to different doses of a chemical, exposed to different chemicals or across groups having different genetic mutations. This work is ongoing. We continued to provide advice on statistical methods for evaluating alternative methods for NTP's toxicity and carcinogenicity testing. These include: 1) evaluating electrocardiogram data from a dog model for testing whether drugs prolong the QT wave in the heart beat which may ultimately lead to lethal arrhythmias, 2) providing advice about the analysis of high throughput data from cell-based assays of chemicals selected by the NTP, that were generated by the NIH Chemical Genomics Center, and 3) providing advice about the analysis of cell cytotoxicity assays.
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