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Final Progress Reports: University of Iowa: Inhalation Toxicology Core

Superfund Research Program

Inhalation Toxicology Core

Project Leader: Peter S. Thorne
Grant Number: P42ES013661
Funding Period: 2006 - 2015
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Final Progress Reports

Year:   2014  2009 

The Inhalation Toxicology Core (ITC) made great progress in 2014 toward the main objective of supporting investigations of the distribution and elimination of semi-volatile PCBs in rodents after inhalation exposure and evaluation of the biologic and toxicologic consequences. The ITC continued to maintain a vivarium for laboratory animals exposed to PCBs and to train graduate students, postdocs and faculty on animal protocols for exposure and outcomes assessment. In 2014 researchers concluded an acute inhalation exposure study in rats of PCB 11 metabolism and performed a mass balance study of [14C]-PCB 11 following lung exposure and a subchronic inhalation study of a complex airborne mixture of PCBs representing the ambient air of Chicago. Further, the ITC collaborated with PCBs: Metabolism, Genotoxicity, and Gene Expression in vivo on inhalation studies with PCB 3.

The recent discovery of PCB 11 as a by-product of pigment manufacturing propelled researchers to investigate its biological fate after inhalation exposure. The ITC performed an acute exposure study to investigate PCB 11 elimination. Researchers developed analytical methods for PCB 11 and its monohydroxylated metabolites that yielded efficient recovery of PCB 11 (73 ± 9%) and its major metabolite 4-OH-PCB 11 (82 ± 12%) from tissue matrices. Rapid first-order elimination of PCB 11 was found in lung, blood and liver. 4-OH-PCB 11 was detected in the liver but not the lung or blood of exposed animals and displayed elimination with a 2.4 h half-life. This study showed that the metabolite is not retained in the body but is susceptible to further metabolism. It further indicated that the discovery of PCB 11 in the blood of AESOP Study (Characterization of Exposures of Urban and Rural Cohorts to Airborne PCBs) subjects reflects current exposure.

To further understand the fate of inhaled PCBs and to inform risk assessment, the ITC performed a mass balance study using [14C]-PCB 11 as a signature compound for airborne PCBs. After delivering [14C]-PCB 11 to the rat lungs, radioactivity in >34 major tissues and 5 digestive matter compartments was measured at 12, 25, 50, 100, 200 and 720 min, during which time the excreta and exhaled air were also collected. [14C]-PCB 11 and metabolites in lung, liver, blood, digestive matter, urine, feces, and adipose tissues were extracted separately to establish the metabolic profile of the disposition. Researchers found that [14C]-PCB 11 distributed rapidly to all tissues after 99.8% pulmonary uptake and quickly underwent extensive metabolism. Over 50% of administered dose was discharged via urine and feces within 12 h. Elimination of the [14C]-PCB 11 and metabolites consisted of an initial fast phase (t½ = 9-33 min) and a slower clearance phase to low concentrations. Researchers showed that PCB 11 is completely absorbed after inhalation exposure and is rapidly eliminated from most tissues. Phase II metabolites dominated with a slower elimination rate than the PCB 11 or phase I metabolites and thus can best serve as urine bio-markers of exposure. These studies showed that differential congener elimination was found after inhalation of airborne PCBs, with minimal toxicity at tested exposure doses. Lower-chlorinated congeners were rapidly and extensively metabolized to phase II products and eliminated within hours.

The ITC conducted a "pre-RfC" study to determine if there were differences in absorbed dose between rats exposed by inhalation in whole body chambers versus a nose-only exposure system. Female Sprague-Dawley rats were exposed to the CAM+ vapor for 4 hr/day, 6 days/wk for 90 days at a target concentration of 533 µg/m3. The exposure phase was completed and the tissues and exposure samples have been analyzed. Toxicologic outcomes were comparable between the whole-body and nose-only exposed rats, however, exposures were slightly higher and toxicologic outcomes were more pronounced in the nose-only exposed rats. This work will be published in the first quarter of 2015.

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