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

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. Draft reports for the positive control Benzo(a)pyrene and the less potent PAC, Phenanthrene have been completed and final reports are expected in Q4FY17. In life studies for five additional compounds, pyrene, dibenzothiophene, acenaphthenequinone, dibenzo(a,l)pyrene and dibenz(a,h)anthracene have been completed and the data are in QA. Two more compounds, benzo(c)fluorine and benzo(k)fluoranthene are scheduled to begin in Q1FY18. Draft reports have been received and reviewed 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. A developmental immunotoxicology study following exposure to bisphenol AF was conducted in FY17. Developmental immunotoxicology studies on the flame retardant Tris(Chloropropyl) phosphate and the plasticizer N-Butylbenzenesulfonamide are ongoing. An evaluation of the ability of the insect growth regulator, 2-{[1-(4-Phenoxyphenoxy)propan-2-yl]oxy}pyridine to affect viral clearance and resistance are also ongoing. 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 FY18. 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 150 compounds have been procured for testing.