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

Brt-Burleson Research Technologies, Inc., Raleigh NC

Investigators

Abstract

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. Final reports for 3 PAC-MAP studies, were received in FY18. Draft reports for five additional compounds, pyrene, dibenzothiophene, acenaphthenequinone, dibenzo(a,l)pyrene and dibenz(a,h)anthracene are being reviewed by the NTP or are in preparation. In life studies have been completed on 5 additional compounds and the data is in QA. Final reports have been received for the assessment of the potential immunotoxicity oral exposure to the groundwater contaminant sulfolane in adult mice and rats exposed throughout development and early adulthood and the pathology data review and NTP reporting phases are in progress. A developmental immunotoxicology study following exposure to bisphenol AF was conducted in FY17 and the report is in preparation. Developmental immunotoxicology studies on the flame retardant Tris(Chloropropyl) phosphate and the plasticizer N-Butylbenzenesulfonamide were completed in 2018. The in life studies to evaluate the ability of the insect growth regulator, 2-{[1-(4-Phenoxyphenoxy)propan-2-yl]oxy}pyridine to affect viral clearance and resistance have been completed and the data are in QA. The contractor has been optimizing a model of inflammatory bowel disease and the first autoimmunity studies to be conducted under this contract are anticipated to begin in FY19. As part of the R&D efforts on this contract, we have partnered with the Interagency Coordination Committee on the Validation of Alternative methods and are using recently published combinations of non-proprietary in vitro assays to evaluate the potential for a variety of chemicals to induce skin sensitization. Nominations were received from multiple ICCVAM partners and approximately 165 compounds have been procured for testing. This represents a major shift in the NTP approach to hypersensitivity testing and from FY19 going forward, the NTP will use in vitro methods as the primary screen to assess hypersensitivity. In FY18 the contractor optimized methods to conduct in vitro studies to screen for compounds that can suppress or enhance immune function. In FY19 we will begin to use these tools to evaluate several classes of compounds for their potential to induce immune toxicity.