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

Yamano, S.; Takeda, T.; Goto, Y.; Hirai, S.; Furukawa, Y.; Kikuchi, Y.; Misumi, K.; Suzuki, M.; Takanobu, K.; Senoh, H.; Saito, M.; Kondo, H.; Kobashi, Y.; Okamoto, K.; Kishimoto, T.; Umeda, Y.

doi:10.1101/2021.11.13.468475

bioRxiv · 10.1101/2021.11.13.468475

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

Yamano, S.·Takeda, T.·Goto, Y.·Hirai, S.·Furukawa, Y.·Kikuchi, Y.·Misumi, K.·Suzuki, M.·Takanobu, K.·Senoh, H.·Saito, M.·Kondo, H.·Kobashi, Y.·Okamoto, K.·Kishimoto, T.·Umeda, Y.

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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.

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Yamano, S., Takeda, T., Goto, Y., Hirai, S., Furukawa, Y., Kikuchi, Y., Misumi, K., Suzuki, M., Takanobu, K., Senoh, H., Saito, M., Kondo, H., Kobashi, Y., Okamoto, K., Kishimoto, T., Umeda, Y.. 2021-11-14. Pathological characteristics of pulmonary toxicity in F344 rats exposed by inhalation to cross-linked water-soluble acrylic acid polymers. https://doi.org/10.1101/2021.11.13.468475

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