Dose-response relationship of pulmonary disorders by inhalation exposure to cross-linked water-soluble acrylic acid polymers in F344 rats

• Published in: Particle and fibre toxicology Vol. 19; no. 1; pp. 27 - 29
• Main Authors: Takeda, Tomoki, Yamano, Shotaro, Goto, Yuko, Hirai, Shigeyuki, Furukawa, Yusuke, Kikuchi, Yoshinori, Misumi, Kyohei, Suzuki, Masaaki, Takanobu, Kenji, Senoh, Hideki, Saito, Misae, Kondo, Hitomi, Daghlian, George, Hong, Young-Kwon, Yoshimatsu, Yasuhiro, Hirashima, Masanori, Kobashi, Yoichiro, Okamoto, Kenzo, Kishimoto, Takumi, Umeda, Yumi
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 08.04.2022; BioMed Central; BMC
• Subjects: Acrylates; Acrylic acid; Aerosols; Alveoli; Animals; Antibodies; Bisphosphonates; Blood; Bronchoalveolar Lavage Fluid; Bronchus; Chemical plants; Clodronic acid; Cross-linked water-soluble acrylic acid polymer (CWAAP); Crosslinking; Damage; Depletion; Disorders; Dose-response relationship (Biochemistry); Emphysema; Environmental aspects; Exposure; Female; Females; Fibrosis; Health aspects; Inhalation; Inhalation Exposure - adverse effects; Leukocytes; Leukocytes (neutrophilic); Lowest observed adverse effect concentration (LOAEC); Lung; Lung diseases; Lungs; Lymph nodes; Lymphatic system; Macrophages; Male; Males; Morphology; Neutrophils; No observed adverse effect concentration (NOAEC); Occupational exposure; Occupational health; Occupational health and safety; Pneumonia - pathology; Pneumothorax; Polymers; Polymers - pharmacology; Pulmonary disorder; Rat; Rats; Rats, Inbred F344; Recoverability; Recovery; Respiration; Risk factors; Side effects; Water; Water chemistry; Whole-body inhalation; Japan; Cross-linked water-soluble acrylic acid polymer (CWAAP); Pulmonary disorder; Rat; Lowest observed adverse effect concentration (LOAEC); Whole-body inhalation; No observed adverse effect concentration (NOAEC)
• ISSN: 1743-8977; 1743-8977
• DOI: 10.1186/s12989-022-00468-9

In Japan, six workers handling cross-linked water-soluble acrylic acid polymer (CWAAP) at a chemical plant suffered from lung diseases, including fibrosis, interstitial pneumonia, emphysema, and pneumothorax. We recently demonstrated that inhalation of CWAAP-A, one type of CWAAP, causes pulmonary disorders in rats. It is important to investigate dose-response relationships and recoverability from exposure to CWAAPs for establishing occupational health guidelines, such as setting threshold limit value for CWAAPs in the workplace. Male and female F344 rats were exposed to 0.3, 1, 3, or 10 mg/m CWAAP-A for 6 h/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. At 1 h, 4 weeks, and 13 weeks after the last exposure the rats were euthanized and blood, bronchoalveolar lavage fluid, and all tissues including lungs and mediastinal lymph nodes were collected and subjected to biological and histopathological analyses. In a second experiment, male rats were pre-treated with clodronate liposome or polymorphonuclear leukocyte-neutralizing antibody to deplete macrophages or neutrophils, respectively, and exposed to CWAAP-A for 6 h/day for 2 days. CWAAP-A exposure damaged only the alveoli. The lowest observed adverse effect concentration (LOAEC) was 1 mg/m and the no observed adverse effect concentration (NOAEC) was 0.3 mg/m . Rats of both sexes were able to recover from the tissue damage caused by 13 weeks exposure to 1 mg/m CWAAP-A. In contrast, tissue damage caused by exposure to 3 and 10 mg/m was irreversible due to the development of interstitial lung lesions. There was a gender difference in the recovery from CWAAP-A induced pulmonary disorders, with females recovering less than males. Finally, acute lung effects caused by CWAAP-A were significantly reduced by depletion of alveolar macrophages. Pulmonary damage caused by inhalation exposure to CWAAP-A was dose-dependent, specific to the lung and lymph nodes, and acute lung damage was ameliorated by depleting macrophages in the lungs. CWAAP-A had both a LOAEC and a NOAEC, and tissue damage caused by exposure to 1 mg/m CWAAP-A was reversible: recovery in female rats was less than for males. These findings indicate that concentration limits for CWAAPs in the workplace can be determined.