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

Investigators

Abstract

Studies to investigate the potential for 4-Methylcyclohexanemethanol (MCHM) to induce dermal sensitization were conducted in FY15. On January 9, 2014 crude MCHM (~88.5% MCHM) was inadvertently released into the Elk River in Charleston, WV resulting in temporary contamination of 15% of the state?s tap water and causing significant dermal exposure. A mouse ear swelling test was used to determine irritancy potential and was conducted in combination with the Local Lymph Node Assay (LLNA). Dermal exposure to pure MCHM was found to produce irritation of the skin at the application site at concentrations above 20% and overt toxicity at the 100% concentration, but did not induce sensitization. Mice treated with ?75% crude MCHM also showed evidence of dermal irritation, although weaker when compared to pure MCHM. There was also evidence of overt toxicity in mice treated with 100% crude MCHM, although the severity was less than pure MCHM. Dermal application of crude MCHM resulted in increased lymphocyte proliferation in the draining lymph node at concentrations ?5%. The Stimulation Index (SI), a measure of sensitization, was significantly increased in mice treated with ?20% crude MCHM, relative to the vehicle control group. The SI was above 3, the threshold for positive sensitization potential, following dermal application of ?40%. These results indicate that crude MCHM has the potential to cause dermal sensitization at exposure concentrations that are non-irritating.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 have examined the potential for individual PACs to modulate the antigen specific antibody response and affect bone marrow cytology. Dose response studies for the positive control Benzo(a)pyrene and the less potent PAC, Phenanthrene have been completed. In addition, studies using rodent models to evaluate the potential immunotoxicity of oral exposure to the groundwater contaminant sulfolane are currently in progress and are expected to be completed in Q1FY16. Laboratory protocols for inhalation studies of multi walled carbon nanotubes have been finalized and the in life work for these studies will be conducted in FY16.