The goal of this contract is to provide support of National Toxicology Program (NTP) hazard identification activities targeted toward the prevention of diseases or adverse effects caused by environmental exposure to chemical or physical agents. Toxicity testing is an important aspect of public health research in that it serves to identify chemicals that are hazardous to human health. Proper chemical analyses are required to ensure that, in toxicity studies, the test species are exposed to the prescribed chemicals at the specified dose concentrations. This contract contributes to the ability of toxicity studies to provide evidence of heightened cancer risk along with other toxicological outcomes, by providing characterization of the chemicals studied, confirmation of the dose levels administered, and internal dose determinations. This information is critical to evaluation of toxicity tests and development of sound, scientific conclusions about the potential toxicity of the study chemical in the test species and ultimately supports the risk assessment efforts of National Toxicology Program and other federal agencies. With internal dose information provided by this contract, extrapolations to humans can be made so that the public can be adequately informed about risk factors arising from exposure to studied chemicals. During FY08, more than 286 tasks were completed in support of NTP and DIR research and testing protocols. Forty six chemicals were prepared as 10 mg aliquots and sent to the Biofocus DPI as part of a Phase 1 High Throughput Screening initiative. A gas chromatography rapid purity screen was developed to assess purity of chemicals sent to Biofocus as part of the high throughput screening initiative. Training sets of chemicals used in the high-throughput screen were used to develop DMSO solubility predictors based on physical properties of the chemicals (i.e., Log P value). The predictor is now being tested against a different set of chemicals for which the DMSO solubility is known. Work was begun on an analytical method to assess the speciation of chromium in tissue samples collected from the sodium dichromate and chromium picolinate 2-year bioassays.Definitive toxicokinetic studies, designed to evaluate plasma, kidney, heart and thymus concentrations and approximate time course information were conducted in support of a carcinogenicity study of bis (2-chloroethoxy) methane (CEM) administered by IV and dermal route. Results from the definitive parent and metabolite, Thiodiglycolic acid (TDGA), study are complete. The data suggest a two compartment model with first order elimination. The data further suggest that there was no difference between metabolisms of CEM in the tissues evaluated in male or female rats dosed IV @ 20 mg/kg, dermal @ 100 & 400 mg/kg and mice dermal @ 300 mg/kg. The liver tissue tended to have a slower metabolism in the rat TDGA IV @ 20 mg/kg compared to the other tissues. This trend seems to be consistent with mice CEM IV 50 mg/kg and dermal 60 mg/kg. However at the same dose and route, the metabolite was excreted faster by female rats compare to males. This trend seems to continue for the other doses. It was found that liver was the only tissue affected by CEM or the metabolite.Sample analysis of brain and plasma for the single administration IV and gavage toxicokinetics study of methyltetrahydrofuran (MTHF) have been completed. The partition coefficient determination for MTHF analysis was performed in two phases. The first phase used a literature method to determined the in vitro partitioning coefficient of 2-MTHF. The second phase consisted of the concentrations of MTHF from the same tissue type for an aborted toxicokinetics study. The data suggest that the in vitro correlation coefficient produced from the literature method is approximations of the results that would be obtained for an in vivo sample analysis. Toxicokinetics studies of the drinking water disinfection byproducts, dibromo-, dichloro-, and bromochloroacetic acid, were designed to compare distribution and elimination of parent compounds as well as urinary metabolites. Gavage and IV studies of all 3 di-haloacetic acids are completed and, but the 14 day dosed water studies are still in progress. These studies includes Glyoxylic which is the major urinary metabolite byproduct of the haloactic acids. Another NTP initiative is the studies of nanoscale materials, fullerenes, which are of interest for many uses including drug delivery, and nanoscale titanium dioxide, which is used in sunscreen and whitening agents. These compounds were characterized with specific attention paid to particle size and surface characteristics. The chemical analysis and comparison of commercially available anatase and rutile titanium dioxide study is on going. Further, characterization of particle roughness is in progress using Brunauer-Emmett-Teller (BET) adsorption analysis and particle size is being measured by laser diffraction and transmission electron microscopy (TEM). The data suggest that two lots of refined mixed fullerenes were found to be 99.68 to 99.97% pure. In addition, the lots were found to be similar in shape and appearance. However, there was a difference in the percent of fullerenes in both lots and other nanoparticles were also found in smaller quantities. The differences in these lots seem to be related to the difference in processing of both samples. The two methods include an extraction method using and the other is an extraction method used 1.2.4-trimethylbenzene. Quantifiable amounts of 16 polynuclear aromatic hydrocarbons (PAHs) were not found in either sample. Studies on the perfluorinated compounds continue. Feed samples for the chronic study were analyzed for residual amounts of PFOA and PFOS. Of the 11 lots analyzed, none contained any detectable levels of PFOA and only one of the lots contained 10% of the lowest standard level. Of the NIH-07 diets analyzed, no PFOS was detected, but one sample did contain PFOA with a concentration below the calibration curve (~0.655 ng/g). The PTKS studies are underway. An inhalation feasibility study is being considered to support a series of popcorn butter flavoring studies. These studies are being considered because of potential occupational safety hazard for those who work in microware popcorn flavoring plant. It has been suggested that inhalation of the fumes causes a lethal lung disease. This environmental exposure may be causing an occupational safety hazard. 4 Methylimidazole (4-MI) is one of series of reproductive assessment by continuous breeding studies. 4-MI is an intermediate /starting material used in the manufacturing of pharmaceutical and photographic chemicals. Aminopyridine are a group of compounds that are intermediates used in the production of agrochemicals like avian pesticides and pharmaceuticals (antihistamines and piroxican). Characterization along with method development of this compound is in progress. Antimony trioxide is a flame retardant compound that develops from burning elemental antimony. Thus, the NTP is in the process of developing an inhalation study to better characterize this compound.
