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The health risk of inhalation exposure to polychlorinated biphenyls (PCB) cannot be assessed with high confidence due to the lack of rigorous inhalation studies. One uncertainty rests on exposure regimen, as whole-body exposure systems allow oral PCB intake that confounds the exposure. We conducted contemporaneous PCB inhalation exposures with whole-body and nose-only exposure methods. Female Sprague-Dawley rats were concurrently exposed to vapor-phase PCBs (533 ± 93 µg/m³) generated from PCB11-supplemented Chicago Air Mixture resembling the Chicago airshed, 4 h/day, 6 days/week, for 4 weeks. Congener-specific analysis showed 1.5-fold higher ?PCBs in the lungs of nose-only exposed than the whole-body exposed animals (p = 0.0024). Higher ?PCB concentrations were also found in the sera, livers, brains, and adipose tissue of nose-only exposed animals (1.1-1.5-fold), but these increases were not statistically significant. Congener profiles of five tissue types were dominated by PCB 28/31 and higher-chlorinated congeners in both groups reflecting rapid metabolism of other lower-chlorinated PCBs. No toxicity was seen regarding metabolic enzyme expression, glutathione, or histopathology. However, diminished weight gain and reduced plasma total thyroxine levels were found in both groups compared with controls, after exposure to 76 µg/m³ ?PCBs as adjusted for continuous exposure. Hepatic lipid peroxidation was also elevated in the nose-only group. Our study shows that prolonged nose-only exposure was well-tolerated and eliminated the need for housing animals outside the vivarium, thus was preferred for long-term PCB inhalation studies. [ABSTRACT FROM AUTHOR]

Although inhalation of atmospheric polychlorinated biphenyls (PCBs) is the most universal exposure route and has become a substantial concern in urban areas, research is lacking to determine the body burden of inhaled PCBs and consequent health effects. To reflect the Chicago airshed environment and mimic the PCB profile in Chicago air, we generated vapors from a Chicago air mixture (CAM). Sprague-Dawley rats were exposed to the CAM vapor for 1.6 h/day via nose-only inhalation for 4 weeks, 520 ± 10 μg/m3. Congener-specific quantification in tissue and air samples was performed by gas chromatography-tandem mass spectrometry (GC/MS/MS). In contrast to the lower-chlorinated congener-enriched vapor, body tissues mainly contained tri- to hexachlorobiphenyls. Congener profiles varied between vapor and tissues and among different organs. The toxic equivalence (TEQ) and neurotoxic equivalence (NEQ) were also investigated for tissue distribution. We evaluated a variety of end points to catalogue the effects of long-term inhalation exposure, including immune responses, enzyme induction, cellular toxicity, and histopathologic abnormalities. Glutathione oxidized/reduced ratio (GSSG/GSH) was increased in the blood of exposed animals, accompanied by elevation of hematocrit. This study demonstrated that inhalation contributed to the body burden of mostly tri- to hexachlorobiphenyls and produced a distinct profile of congeners in tissue, yet minimal toxicity was found at this exposure dose, estimated at 134 μg/rat. [ABSTRACT FROM AUTHOR]

Despite the continued presence of PCBs in indoor and ambient air, few studies have investigated the inhalation route of exposure. While dietary exposure has declined, inhalation of the semivolatile, lower-chlorinated PCBs has risen in importance. We measured the uptake, distribution, and time course of elimination of inhaled PCB congeners to characterize the pulmonary route after short-term exposure. Vapor-phase PCBs were generated from Aroclor 1242 to a nose-only exposure system and characterized for congener levels and profiles. Rats were exposed via inhalation acutely (2.4 mg/m³ for 2 h) or subacutely (8.2 mg/m³, 2 h × 10 days), after which pulmonary immune responses and PCB tissue levels were measured. Animals acutely exposed were euthanized at 0, 1, 3, 6, and 12 h post exposure to assess the time course of PCB uptake and elimination. Following rapid absorption and distribution, PCBs accumulated in adipose tissue but decayed in other tissues with half-lives increasing in liver (5.6 h) < lung (8.2 h) < brain (8.5 h) < blood (9.7 h). PCB levels were similar in lung, liver, and adipose tissue, lower in brain, and lowest in blood. Inhalation of the airborne PCB mixture contributed significantly to the body burden of lower-chlorinated congeners. Congeners detected in tissue were mostly ortho-substituted ranging from mono- to pentachlorobiphenyls. Selective uptake and elimination led to accumulation of a distinct congener spectrum in tissue. Minimal evidence of toxicity was observed. [ABSTRACT FROM AUTHOR]

School indoor air contaminated with polychlorinated biphenyls (PCBs) released from older building materials and paint pigments may pose health risks to children, as well as teachers and staff, by inhalation of PCBs. The health effects of long-term inhalation exposure to PCBs are poorly understood. We conducted a comprehensive toxicity assessment of 91-day repeated inhalation exposure to a lab-generated mixture of PCBs designed to emulate indoor school air, combining transcriptomics, metabolomics, and neurobehavioral outcomes. Female Sprague-Dawley rats were exposed to school air mixture (SAM+) at a concentration of 45.5 ± 5.9 μg/m 3 ∑ 209 PCB or filtered air 4 h/day, 6 days/week for 13 weeks using nose-only exposure systems. The congener-specific PCB body burden was quantified in major tissues using GC-MS/MS. The generated SAM+ vapor recapitulated the target school air profile with a similarity coefficient, cos θ of 0.91. PCB inhalation yielded 875-9930 ng/g ∑ 209 PCB lipid weight levels in tissues in the following ascending order: brain < liver < lung < serum < adipose tissue. We observed that PCB exposure impaired memory, induced anxiety-like behavior, significantly reduced white blood cell counts, mildly disrupted metabolomics in plasma, and influenced transcription processes in the brain with 274 upregulated and 58 downregulated genes. With relatively high exposure and tissue loading, evidence of toxicity from half the end points tested was seen in the rats.

Chitosan polyplexes containing plasmid DNA (pDNA) have significant potential for pulmonary gene delivery applications. However, prior to using chitosan/pDNA polyplexes (CSpp) in clinical applications, their potential cytotoxicity needs to be investigated. In this study, we formulated 200-400 nm CSpp with amine to phosphate (N/P) ratios that ranged from 1 to 100. We compared two types of plasmids within CSpp: pDNA that was free of CpG sequences (CpG(-)) and pDNA that contained CpG sequences (CpG(+)). Both forms of CSpp showed low cytotoxicity when cultured with A549 and HEK293 cell lines in vitro. CSpp(CpG(-)) generated higher luciferase expression both in vitro, for A549 cells, and in vivo, compared with CSpp(CpG(+)). In addition, CSpp(CpG(-)) elicited milder inflammatory responses in mice one day subsequent to nasal instillation, as determined by proinflammatory cytokine levels within the bronchoalveolar lavage fluid. Our findings suggest that to achieve optimal gene expression with minimal cytotoxicity, inflammation, and oxidative stress, the N/P ratios and CpG sequences in the pDNA of CSpp need to be considered. These findings will inform the preclinical safety assessments of CSpp in pulmonary gene delivery systems.

PCBs are contaminants in the air of older buildings and cities, which raises the concern of inhalation exposure. No reliable biomarker of such exposure is available. We exposed rats to air containing 2 mg/m(3) PCB3 via nose-only inhalation for 2 h, collected urine, and analyzed it by LC/MS. Each rat inhaled an estimated dose of 35 μg PCB3, and excreted 27 ± 2% of it as sulfates within 24 h. Peak excretion occurred within 6 h. PCB sulfates were stable in urine for at least three days at room temperature without chemical preservatives. These data support the use of PCB sulfate conjugates as suitable urinary biomarkers of PCB3 and other airborne PCBs.