Inhalation exposure to cross-linked polyacrylic acid induces pulmonary disorders

• Published in: Toxicology (Amsterdam) 2025-01, Vol.510, p.154001, Article 154001
• Main Authors: Higashi, Yasuyuki, Nishida, Chinatsu, Izumi, Hiroto, Sato, Kazuma, Kawai, Naoki, Tomonaga, Taisuke, Morimoto, Toshiki, Yamasaki, Kei, Wang, Ke-Yong, Higashi, Hidenori, Moriyama, Akihiro, Takeshita, Jun-Ichi, Kojima, Takuma, Sakurai, Kazuo, Yatera, Kazuhiro, Morimoto, Yasuo
• Format: Article
• Language: English
• Subjects: Acetylcysteine - administration & dosage; Acetylcysteine - pharmacology; Acrylic Resins - administration & dosage; Acrylic Resins - toxicity; Animals; Bronchoalveolar Lavage Fluid - chemistry; Bronchoalveolar Lavage Fluid - cytology; Chemokine CXCL1 - metabolism; Cross-linked polyacrylic acid; Dose-Response Relationship, Drug; Heme Oxygenase-1 - metabolism; Inhalation exposure; Inhalation Exposure - adverse effects; Lung - drug effects; Lung - metabolism; Lung - pathology; Lung Diseases - chemically induced; Lung Diseases - pathology; Male; N-acetylcysteine; Oxidative stress; Oxidative Stress - drug effects; Rats; Rats, Inbred F344
• ISSN: 0300-483X; 1879-3185; 1879-3185
• DOI: 10.1016/j.tox.2024.154001

Organic polymers, widely used in food, daily necessities, and medicines, include cross-linked polyacrylic acid (CL-PAA), which has been reported to induce severe lung disease. While previous studies mainly used intratracheal instillation, our research focused on inhalation exposure to corroborate these findings. We conducted 5-day (short-term) and 13-week (subchronic) inhalation exposure studies with CL-PAA. In the short-term study, male F344 rats inhaled CL-PAA at 0.2, 2.0, or 20 mg/m³ for 6 hours/day over 5 days. Rats were dissected 3 days and 1 month post-exposure. In the subchronic study, rats inhaled CL-PAA at 0.2 or 2.0 mg/m³ for 6 hours/day, 5 days/week for 13 weeks, with dissections from 3 days to 6 months post-exposure. To investigate the mechanism of pulmonary disorders, an additional short-term study with 20 mg/m³ CL-PAA included intraperitoneal injections of the antioxidant N-acetylcysteine (NAC) (200 mg/kg) with dissection the day after exposure. Short-term exposure led to concentration-dependent increases in neutrophil influx, cytokine-induced neutrophil chemoattractant (CINC), total protein, lactate dehydrogenase (LDH) in bronchoalveolar lavage fluid (BALF), and heme oxygenase-1 (HO-1) in lung tissue. Histopathology showed concentration-dependent neutrophil infiltration. Subchronic exposure caused persistent increases in BALF total protein and lung HO-1, with ongoing neutrophil infiltration and fibrosis. NAC administration reduced neutrophils, total protein, LDH, and CINC in BALF, and HO-1 in lung tissue, improving histopathological findings. Inhalation of CL-PAA caused concentration-dependent lung inflammation and persistent fibrosis. The no observed adverse effect level (NOAEL) for chronic pulmonary disorders was 0.2 mg/m³. Oxidative stress linked to CL-PAA-induced inflammation was mitigated by NAC administration. [Display omitted] •Inhalation of cross-linked polyacrylic acid for 5 days induced concentration-dependent inflammation in the rats' lungs.•Inhalation of cross-linked polyacrylic acid for 13 weeks induced persistent inflammation and fibrosis in the rats' lungs.•The no observed adverse effect level for chronic exposure to cross-linked polyacrylic acid was considered to be 0.2 mg/m3.•Oxidative stress was associated with cross-linked polyacrylic acid-induced pulmonary inflammation.•N-acetylcysteine administration attenuated the cross-linked polyacrylic acid-induced pulmonary inflammation.