Pathological characteristics of pulmonary toxicity in F344 rats exposed by inhalation to cross-linked water-soluble acrylic acid polymers

Abstract

BackgroundRecently in Japan, six workers at a chemical plant that manufactures resins developed interstitial lung diseases after being involved in loading and packing cross-linked water-soluble acrylic acid polymers (CWAAPs). Since CWAAPs are not on the list of occupational diseases, the present study examined the lung damage potential of two CWAAPs (CWAAP-A and CWAAP-B) in rats, investigated pathological mechanisms, and established a method to rapidly evaluate the harmfulness of CWAAPs. MethodsUsing a whole-body inhalation exposure system, male F344 rats were exposed once to 40 or 100 mg/m3 of CWAAP-A for 4 hours or to 15 or 40 mg/m3 of CWAAP-A for 4 hours per day once per week for 2 months (a total of 9 exposures). In a separate set of experiments, male F344 rats were administered 1 mg/kg CWAAP-A or CWAAP-B by intratracheal instillation once every two weeks for 2 months (a total of five doses). Lung tissues, mediastinal lymph nodes, and bronchoalveolar lavage fluid were collected and subjected to biological and histopathological analyses. ResultsA single 4-hour exposure to CWAAP caused alveolar injury, and repeated exposures resulted in regenerative changes in the alveolar epithelium with activation of TGF{beta} signaling. During the recovery period after the last exposure, some alveolar lesions were partially healed, but other lesions developed into alveolitis with fibrous thickening of the alveolar septum. Rats administered CWAAP-A by intratracheal instillation developed qualitatively similar pulmonary pathology as rats exposed to CWAAP-A by inhalation. At 2 weeks after intratracheal instillation, rats administered CWAAP-B appeared to have a slightly higher degree of lung lesions compared to rats administered CWAAP-A, however, there was no difference in these lesions of CWAAP-A and CWAAP-B in rats examined 18 weeks after administration of these materials. ConclusionsThe present study provides evidence of rat lung pathogenesis after inhalation exposure to CWAAP-A. This study also demonstrates that the lung pathology of rats exposed to CWAAP-A by systemic inhalation was qualitatively similar to that of rats administered CWAAP-A by intratracheal instillation. The use of intratracheal instillation as an adjunct to systemic inhalation is expected to significantly accelerate the risk assessment for a variety of CWAAPs.