Skip to main content
Log in

Comparative toxicity of polyhexamethylene guanidine phosphate in three strains of rats

  • Original Article
  • Published:
Molecular & Cellular Toxicology Aims and scope Submit manuscript

Abstract

Background

Although polyhexamethylene guanidine phosphate (PHMG) is the main antibacterial ingredient in humidifier disinfectants, inhalation of PHMG causes severe respiratory diseases, including pulmonary fibrosis and asthma. Many studies using animal models have been conducted to investigate the molecular mechanisms of PHMG-induced pulmonary diseases. However, there have been no comparative studies analyzing the differences in sensitivity according to different strains, especially in rats.

Objective

In this study, we investigated pulmonary toxicity by comparing the pathological features in various strains of PHMG-instilled rats including Fischer 344 (F344), Sprague Dawley (SD), and Wistar rats.

Results

During the experimental periods, mortality rates of 1 and 2 mg/kg PHMG-instilled F344 rats and 2 mg/kg PHMG-instilled SD rats were 16.7%, 33.3%, and 33% respectively. However, there were no deaths in PHMG-instilled Wistar rats. Body weight significantly decreased in all rat strains immediately after the first PHMG instillation, and gradually recovered again after Day 5. Absolute and relative lung weights in all rat strains significantly increased after dose-dependent PHMG instillation. Histopathological analysis of all PHMG-instilled rat strains showed clear granulomatous inflammation, interstitial inflammation, squamous cell metaplasia, and macrophage infiltration in the alveoli. Specifically, eosinophilic infiltration in the alveoli was only observed in PHMG-instilled SD and Wistar rats. In addition, immunohistochemistry assessment revealed the presence of TGF-β1-positive cells in the lung tissues of all PHMG-instilled rat strains, and IL-5-positive cells in the lung tissues of PHMG-instilled SD and Wistar rats.

Conclusion

These results could potentially provide baseline data on the selection of experimental species for inhalation toxicity studies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Antonik LM, Lopyrev VA, Korchevin NA, Tomin VP (2002) Phosphorus-containing salts of polyhexamethyleneguanidinium for protection of metals from corrosion, biological overgrowing, and salt deposition. Russian J Appl Chem 75:257–260

    Article  CAS  Google Scholar 

  • Chinedu E, Arome D, Ameh FS (2013) A new method for determining acute toxicity in animal models. Toxicol Int 20(3):224–226

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cho WS et al (2011) Progressive severe lung injury by zinc oxide nanoparticles; the role of Zn2+ dissolution inside lysosomes. Part Fibre Toxicol 8(27):1–16

    CAS  Google Scholar 

  • Dishop MK (2010) Diagnostic pathology of diffuse lung disease in children. Pediatr Allergy Immunol Pulmonol 23(1):69–85

    Article  PubMed  PubMed Central  Google Scholar 

  • Dunnill MS (1990) Pulmonary fibrosis. Histopathology 16(4):321–329

    Article  CAS  PubMed  Google Scholar 

  • Ezz-Eldin YM, Aboseif AA, Khalaf MM (2020) Potential anti-inflammatory and immunomodulatory effects of carvacrol against ovalbumin-induced asthma in rats. Life Sci 1(242):117222

    Article  Google Scholar 

  • Gao FS, Qiao JO, Zhang Y, Jin XQ (2009) Chronic intranasal administration of Aspergillus fumigatus spores leads to aggravation of airway inflammation and remodelling in asthmatic rats. Respirology 14(3):360–370

    Article  PubMed  Google Scholar 

  • Gharaee-Kermani M, Phan HS (1997) Lung interleukin-5 expression in murine bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 16(4):438–447

    Article  CAS  PubMed  Google Scholar 

  • Halle W (2003) The registry of cytotoxicity: toxicity testing in cell cultures to predict acute toxicity (LD50) and to reduce testing in animals. Altern Lab Anim 31(2):89–198

    Article  CAS  PubMed  Google Scholar 

  • Hernandez ML et al (2013) Vitamin E, γ-tocopherol, reduces airway neutrophil recruitment after inhaled endotoxin challenge in rats and in healthy volunteers. Free Radic Biol Med 60:56–62

    Article  CAS  PubMed  Google Scholar 

  • Hines EA et al (2014) Comparison of temporal transcriptomic profiles from immature lungs of two rat strains reveals a viral response signature associated with chronic lung dysfunction. PLoS One 9(12):e112997

    Article  PubMed  PubMed Central  Google Scholar 

  • Hong SB et al (2014) A cluster of lung injury associated with home humidifier use: clinical, radiological and pathological description of a new syndrome. Thorax 69(8):694–702

    Article  PubMed  Google Scholar 

  • Jackson M, Marks L, May GHW, Wilson JB (2018) The genetic basis of disease. Essays Biochem 62(5):643–723

    Article  PubMed  PubMed Central  Google Scholar 

  • Jeong YJ et al (2007) Eosinophilic lung diseases: a clinical, radiologic, and pathologic overview. Radiographics 27(3):617–637

    Article  PubMed  Google Scholar 

  • Jones RM, Neef N (2012) Interpretation and prediction of inhaled drug particle accumulation in the lung and its associated toxicity. Xenobiotica 42(1):86–93

    Article  CAS  PubMed  Google Scholar 

  • Justice MJ, Dhillon P (2016) Using the mouse to model human disease: increasing validity and reproducibility. Dis Model Mech 9(2):101–103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim JS et al (2010) An automatic video instillator for intratracheal instillation in the rat. Lab Anim 44(1):20–24

    Article  CAS  PubMed  Google Scholar 

  • Kodavanti UP et al (1997) Genetic variability in combustion particle-induced chronic lung injury. Am J Physiol 272(3 Pt 1):L521-532

    CAS  PubMed  Google Scholar 

  • Liu H et al (2014) Role of prostaglandin D2 /CRTH2 pathway on asthma exacerbation induced by Aspergillus fumigatus. Immunology 142(1):78–88

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lorke D (1983) A new approach to practical acute toxicity testing. Arch Toxicol 54(4):275–287

    Article  CAS  PubMed  Google Scholar 

  • Mclntosh JC et al (1992) Infection-induced airway fibrosis in two rat strains with differential susceptibility. Infect Immun 60(7):2936–2942

    Article  Google Scholar 

  • Michael B et al (2007) Evaluation of organ weights for rodent and non-rodent toxicity studies: a review of regulatory guidelines and a survey of current practices. Toxicol Pathol 35(5):742–750

    Article  PubMed  Google Scholar 

  • Mishra NC et al (2012) Inhalation of sulfur mustard causes long-term T cell-dependent inflammation: possible role of Th17 cells in chronic lung pathology. Int Immunopharmacol 13(1):101–108

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Muro AF et al (2008) An essential role for fibronectin extra type III domain a in pulmonary fibrosis. Am J Respir Crit Care Med 177(6):638–645

    Article  CAS  PubMed  Google Scholar 

  • Nemery B, Hoet PH (2015) Humidifier disinfectant-associated interstitial lung disease and the Ardystil syndrome. Am J Respir Crit Care Med 191(1):116–117

    Article  CAS  PubMed  Google Scholar 

  • Perkins MW et al (2017) Adverse respiratory effects in rats following inhalation exposure to ammonia respiratory dynamics and histopathology. Inhal Toxicol 29(1):32–41

    Article  CAS  PubMed  Google Scholar 

  • Raies AB, Bajic VB (2016) In silico toxicology: computational methods for the prediction of chemical toxicity. Wiley Interdiscip Rev Comput Mol Sci 6(2):147–172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Scabilloni JF et al (2005) Matrix metalloproteinase induction in fibrosis and fibrotic nodule formation due to silica inhalation. Am J Physiol Lung Cell Mol Physiol 288(4):L709–L717

    Article  CAS  PubMed  Google Scholar 

  • Schafer KA et al (2018) Use of severity grades to characterize histopathologic changes. Toxicol Pathol 46(3):256–265

    Article  CAS  PubMed  Google Scholar 

  • Song JA et al (2014) Polyhexamethyleneguanidine phosphate induces severe lung inflammation, fibrosis, and thymic atrophy. Food Chem Toxico 69:267–275

    Article  CAS  Google Scholar 

  • Song MK, Kim DI, Lee K (2021) Causal relationship between humidifier disinfectant exposure and Th17-mediated airway inflammation and hyperresponsiveness. Toxicology 30(454):152739

    Article  Google Scholar 

  • Sperling F (1979) Introduction to toxicity evaluation session. Environ Health Perspect 32:259

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tanaka H et al (2004) Role of interleukin-5 and eosinophils in allergen-induced airway remodeling in mice. Am J Respir Cell Mol Biol 31(1):62–68

    Article  CAS  PubMed  Google Scholar 

  • Tang X et al (2017) Effects of the combined extracts of Herba Epimedii and Fructus Ligustrilucidi on airway remodeling in the asthmatic rats with the treatment of budesonide. BMC Complement Altern Med 17(1):380

    Article  PubMed  PubMed Central  Google Scholar 

  • Udwadia FE (1967) Tropical eosinophilia. A correlation of clinical, histopathologic and lung function studies. Dis Chest 52(4):531–538

    Article  CAS  PubMed  Google Scholar 

  • Verma R et al (2013) Evaluating the ameliorative potential of quercetin against the bleomycin-induced pulmonary fibrosis in wistar rats. Pulm Med 921724:1–10

    Article  Google Scholar 

  • Wahlstrom E, Ollerstam A, Sundius L, Zhang H (2013) Use of lung weight as biomarker for assessment of lung toxicity in rat inhalation studies. Toxicol Pathol 41(6):902–912

    Article  CAS  PubMed  Google Scholar 

  • Weingand K et al (1996) Harmonization of animal clinical pathology testing in toxicity and safety studies. The joint scientific committee for international harmonization of clinical pathology testing. Fundam Appl Toxicol 29(2):198–201

    Article  CAS  PubMed  Google Scholar 

  • Wigenstam E et al (2018) Anti-inflammatory and anti-fibrotic treatment in a rodent model of acute lung injury induced by sulfur dioxide. Clin Toxicol (phila) 56(12):1185–1194

    Article  CAS  Google Scholar 

  • Zhang K et al (1994) Lung monocyte chemoattractant protein-1 gene expression in bleomycin-induced pulmonary fibrosis. J Immunol 153(10):4733–4741

    Article  CAS  PubMed  Google Scholar 

  • Zhang K, Flanders KC, Phan HS (1995) Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis. Am J Pathol 147(2):352–361

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported by the Korea Institute of Toxicology (Grant No. KK-2104-04), and by grant from the National Institute of Environment Research (NIER), funded by the Ministry of Environment (MOE) of the Republic of Korea (Grant Number NIER-2021-04-03-001).

Author information

Authors and Affiliations

Authors

Contributions

JHW, KCK, HYK, IHK, SHK, and K-HL designed the research study. JHW, HYK, IHK, and SHK performed the experiments and analyzed data. JHW, KCK, and K-HL interpreted data and wrote the manuscript. K-HL obtained the resources.

Corresponding author

Correspondence to Kyuhong Lee.

Ethics declarations

Conflict of interest

Jong-Hwan Woo, Ki Cheon Kim, Hyeon-Young Kim, In-Hyeon Kim, Sung-Hwan Kim, and Kyuhong Lee declare that they have no conflict of interest.

Ethical approval

All the animal experiments were performed with Institutional Animal Care and Use Committee of the Korea Institute of Toxicology (IACUC #1707-0291).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Woo, JH., Kim, K.C., Kim, HY. et al. Comparative toxicity of polyhexamethylene guanidine phosphate in three strains of rats. Mol. Cell. Toxicol. 18, 57–69 (2022). https://doi.org/10.1007/s13273-021-00169-y

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13273-021-00169-y

Keywords

Navigation