STUDIES TO EVALUATE THE POTENTIAL FOR ENVIRONMENTAL&THERAPEUTIC AGENTS TO INDUCE IMMUNOTOXICITY

Investigators

Abstract

This contract was established in the fourth quarter of FY14 and as such, only limited preparatory work has been conducted to date. The protocol for studies to investigate the dose response for irritancy and the sensitizing potential of 4-methylcyclohexylmethanol (MCHM) has been approved by the NTP. MCHM is used as a frothing agent to remove impurities from fine coal. In January, 2014, a chemical storage tank leaked approximately 10,000 gallons of a mixture of Crude MCHM and propylene phenol ethers into the Elk River in West Virginia. The spilled liquid was transported downriver and was withdrawn into the West Virginia American Water treatment plant intake. This water treatment plant serves approximately 300,000 people located in nine counties in southwestern West Virginia. Due to the paucity of data on a number of the chemicals purported to have been spilled, a multi-study project was initiated by NTP to generate data on 8 compounds from the spill, a crude mixture of MCHM and 4 structural class members of the spilled chemicals. The proposed study is a combined Irritancy/Local Lymph Node assay. By combining the two tests in one assay the NTP will reduce the number of animals used to investigate the potential toxicity of the chemicals and realize a cost savings. The PAC Mixtures Assessment Program (PAC-MAP) provides the framework for assessing a breadth of individual polycyclic aromatic compounds (PACs), defined PAC mixtures, and complex PAC-containing environmental samples using an in vitro/short-term in vivo testing battery that includes a broad spectrum of endpoints. Select PACs have been associated with a wide range of toxicities (carcinogenicity, immunotoxicity, reproductive and developmental toxicity, neurotoxicity) and a complicated array of mechanisms of action. In particular, many PACs have been associated with suppression of humoral immune function and immunotoxicity has been identified as an informative parameter for estimating the carcinogenic potential of PACs. As part of the potential testing battery to predict mixture effects, we will examine the potential for individual PACs to modulate the antigen specific antibody response and affect bone marrow cytology. Initial studies will establish dose response curves for the positive control Benzo(a)pyrene and the relatively inactive PAC Phenanthrene. In addition, studies using rodent models to evaluate the potential immunotoxicity of inhalation exposure to multi-walled carbon nanotubes and oral exposure to the groundwater contaminant sulfolane have been designed. Laboratory protocols will be finalized for these studies and the work will be conducted in FY15.