Inhalation Exposure to Cross-linked Polyacrylic Acid Induces Pulmonary Disorders

Abstract

Background: Organic polymers are used widely in daily necessities, foods, and medicines, but recent reports show that cross-linked polyacrylic acid (CL-PAA), an organic polymer, induces severe lung disease. Whereas most previous toxicity studies of CL-PAA were intratracheal instillation studies, we conducted inhalation exposure studies to corroborate those findings. Methods: We conducted 5-day (subacute) and 13-week (subchronic) inhalation exposure studies using CL-PAA. In the subacute inhalation study, male F344 rats inhaled 0.2 mg/m³, 2.0 mg/m³, or 20 mg/m³ of CL-PAA for 6 hours/day for 5 days. Rats were sacrificed 3 days and 1 month after the exposure. In the subchronic inhalation study, male F344 rats inhaled 0.2 mg/m³ or 2.0 mg/ m³ of CL-PAA for 6 hours/day for 5 days/week for 13 weeks. Rats were sacrificed from 3 days to 6 months after exposure. We also investigated the mechanism of pulmonary disorders by conducting an additional subacute inhalation exposure (CL-PAA 20 mg/m³) study, in which the antioxidant N-acetylcysteine (NAC) (200 mg/kg) was injected intraperitoneally. The rats in that study were sacrificed on the day after the exposure. Results: Subacute inhalation exposure resulted in concentration-dependent increases in neutrophil influx, total protein, lactate dehydrogenase (LDH), cytokine-induced neutrophil chemoattractant (CINC) in the bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in lung tissue. Histopathological findings in the lung tissue also showed neutrophil infiltration in a concentration-dependent manner. Subchronic inhalation exposure resulted in persistent increases in total protein in BALF and HO-1 in lung tissue. Histopathological findings in the lung tissue showed persistent neutrophil infiltration and fibrosis. NAC administration decreased the number of neutrophils, total protein, LDH, and CINC in the BALF, and HO-1 in the lung tissue. Histopathological findings of the lung tissue also showed that NAC administration improved neutrophil infiltration. Conclusion: Inhalation of CL-PAA for 5 days induced concentration-dependent inflammation in the rats' lungs. Inhalation of CL-PAA for 13 weeks induced persistent inflammation and fibrosis in the rats' lungs. We considered that the no observed adverse effect level (NOAEL) for chronic pulmonary disorders was 0.2 mg/m³. Furthermore, oxidative stress was associated with CL-PAA-induced pulmonary inflammation, and NAC administration attenuated the pulmonary inflammation.