• Environmental Analysis Health and Toxicology
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• v.31
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• pp.13.1-13.4
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• 2016

An analysis of patients and fatalities due to exposure to polyhexamethylene guanidine (PHMG) shows that PHMG causes mainly lung diseases such as pulmonary fibrosis. However, no research on the other organs has been conducted on this matter yet. So, an in-depth discussion on toxicological techniques is needed to determine whether or not PHMG is toxic to organs other than just the lungs. For the test of target organ toxicity by PHMG exposure, a toxicokinetic study must first be conducted. However, measurement method for PHMG injected into the body has not yet been established because it is not easy to analyze polymer PHMG, so related base studies on analytical technique for PHMG including radio-labeling chemistry must come first. Moreover, research on exposure-biomarker and effect-biomarker must also be conducted, primarily related to clinical application. Several limitations seem to be expected to apply the biomarker study to the patient because much time has passed after exposure to the humidifier disinfectant. It is why a more comprehensive toxicological researches must be introduced to the causality for the victims.

• Bulletin of the Korean Chemical Society
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• v.34 no.6
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• pp.1708-1714
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• 2013

Polyhexamethylene guanidine (PHMG) polymers used as an active ingredient in an antibacterial humidifier disinfectant were reported to cause harm to the human health when inhaled, although physical contact with this material was known to present low toxicity to humans. It is therefore necessary to develop an optimal analysis method which enables detection and analysis of PHMG polymers. MALDI-TOF investigations of PHMG are performed with a variety of matrices, and it is found that CHCA and 2,5-DHB are excellent matrices which well reflects the polymer population even at high mass. For the provided PHMG sample, the number-average ($M_n$) and weight-average ($M_w$) molecular masses were determined to be 744.8 and 810.7, respectively, when the CHCA was used as a matrix. The rank of the matrices in terms of averaged molecular weight was CHCA ~2,5-DHB > 5-NSA > DHAP, THAP > ATT > IAA ~ super-DHB ~ HABA. In addition, PSD of the PHMG oligomer ions exhibited a few unique fragmenation characteristics. The formation of a- and c-type fragments was the major fragmentation pathway, and the 25-Da loss peaks generally accompanied a- and c-type fragments.

• Journal of Korean Society of Occupational and Environmental Hygiene
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• v.29 no.1
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• pp.13-20
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• 2019

Objective: This study was performed to propose a domestic occupational exposure limit(OEL) following a health hazard assessment, calculation of a non-carcinogenicity reference concentration worker($RfC_{worker}$) value, and examination of international agencies' exposure limits. It also recommends legal management within the Occupational Safety and Health Act for PHMG-Phosphate(CAS No. 89697-78-9), It is a humidifier disinfectant that generated many lung injuries. Methods: We have investigated the recommendation or guidelines of foreign OEL for PHMG-Phosphate and the actual state of legal management in Korea. To examine the procedures and methods for recommendation OEL. Toxicological hazard and health hazard classifications were examined and a non-carcinogenicity $RfC_{worker}$ value was calculated for PHMG-Phosphate. An OEL and the necessity of legal management were recommended as well. Results and Conclusions: The OEL for PHMG-Phosphate is recommended to be $0.01mg/m^3$. The recommended OEL is close to 10 times the RfCworker value of $0.000833mg/m^3$ calculated from the chemical dose-response hazard assessment, which is a 2017 study. The CMIT/MIT(3:1) mixture, which was a social issue as a humidifier disinfectant substance, was also exposed to the same ratio in March 2018, establish the OEL. It is recommended to establish OEL for PHMG-Phosphate to prevent worker health hazards and for chemical safety management.

• Biomolecules & Therapeutics
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• v.30 no.2
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• pp.126-136
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• 2022

Liver fibrosis is part of the wound healing process to help the liver recover from the injuries caused by various liver-damaging insults. However, liver fibrosis often progresses to life-threatening cirrhosis and hepatocellular carcinoma. To overcome the limitations of current in vivo liver fibrosis models for studying the pathophysiology of liver fibrosis and establishing effective treatment strategies, we developed a new mouse model of liver fibrosis using polyhexamethylene guanidine phosphate (PHMG-p), a humidifier sterilizer known to induce lung fibrosis in humans. Male C57/BL6 mice were intraperitoneally injected with PHMG-p (0.03% and 0.1%) twice a week for 5 weeks. Subsequently, liver tissues were examined histologically and RNA-sequencing was performed to evaluate the expression of key genes and pathways affected by PHMG-p. PHMG-p injection resulted in body weight loss of ~15% and worsening of physical condition. Necropsy revealed diffuse fibrotic lesions in the liver with no effect on the lungs. Histology, collagen staining, immunohistochemistry for smooth muscle actin and collagen, and polymerase chain reaction analysis of fibrotic genes revealed that PHMG-p induced liver fibrosis in the peri-central, peri-portal, and capsule regions. RNA-sequencing revealed that PHMG-p affected several pathways associated with human liver fibrosis, especially with upregulation of lumican and IRAK3, and downregulation of GSTp1 and GSTp2, which are closely involved in liver fibrosis pathogenesis. Collectively we demonstrated that the PHMG-p-induced liver fibrosis model can be employed to study human liver fibrosis.

• Korean Journal of Environmental Biology
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• v.38 no.2
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• pp.271-277
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• 2020

Toxicities to many organs caused by humidifier disinfectants have been reported. Recently, humidifier disinfectants have been reported to cause cardiovascular, embryonic, and hepatic toxicities. This study was designed to investigate the toxic mechanism of humidifier disinfectants and compare toxicity in a cellular model and a zebrafish animal model. Because brain toxicity and skin toxicity have been less studied than other organs, we evaluated toxicity in a human dermal cell line and zebrafish under various concentrations of humidifier disinfectants that included polyhexamethyleneguanidine phosphate (PHMG), oligo-[2-(2-ethoxy)-ethoxyethyl-guanidinium-chloride] (PGH) and methylchloroisothiazolinone/methylisothiazolinone (CMIT/MIT). A human dermal fibroblast cell line was treated with disinfectants (0, 2, 4, 6, 8, and 16 mg L^-1) to compare their cytotoxicity. The fewest PHMG-treated cells survived (up to 33%), while 49% and 40% of the PGH- and CMIT/MIT-treated cells, respectively, survived. The quantification of oxidized species in the media revealed that the PHMG-treated cells had the highest MDA content of around 28 nM, while the PGH- and CMIT/MIT-treated cells had 13 and 21 nM MDA, respectively. As for brain toxicity, treatment of the zebrafish tank water with CMIT/MIT (final 40 mg L^-1) for 30 min resulted in a 17-fold higher production of reactive oxygen species (ROS) than in the control. Treatment with PGH or PHMG (final 40 mg L^-1) resulted in 15- and 11-fold higher production, respectively. The humidifier disinfectants (PHMG, PGH, and CMIT/MIT) showed severe dermal cell toxicity and brain toxicity. These toxicities may be relevant factors in understanding why some children have language disorders, motor delays, and developmental delays from exposure to humidifier disinfectants.

• Macromolecular Research
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• v.17 no.6
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• pp.411-416
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• 2009

The color stabilization of antimicrobial blends was studied by using poly(hexamethylene guanidine) phosphate (PHMG) as a highly efficient biocidal and nontoxic agent. The Taguchi method was used to determine the optimum conditions for the blending of PHMG in polypropylene (PP) matrix. To improve the yellowing phenomena, two kinds of stabilizer were used together: tetrakis[methylene(3,5-di-t-butyl-4-hydroxyhydrocinnamate)](IN1010) from phenol and tris(2,4-di-t-butylphenylphosphite) (IF168) from phosphorus. According to blend composition and mixing condition, six factors were chosen, with five levels being set for each factor. The orthogonal array was selected as the most suitable for fabricating the experimental design, L25, with 6 columns and 25 variations. The-smaller-the-better was used as an optimization criterion. The optimum conditions for these parameters were 10 phr for PHMG, 2 phr for IN1010, 1 phr for IF168, 10 min for mixing time, $210^{\circ}C$ for mixing temperature, and 30 rpm for rotation speed. Under these conditions, the yellowness index of the blend was 1.52. The processibility of the blends was investigated by Advanced Rheometric Expansion System (ARES). The blend with 0.5 w% PHMG content, diluted with PP, exhibited an antimicrobial characteristic in the shake flask method.

• Macromolecular Research
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• v.14 no.5
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• pp.491-498
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• 2006

The thermal degradation of poly(hexamethylene guanidine) phosphate (PHMG) was studied by dynamic thermogravimetric analysis (TGA) and pyrolysis-GC/MS (p-GC). Thermal degradation of PHMG occurs in three different processes, such as dephosphorylation, sublimation/vaporization of amine compounds and decomposition/ recombination of hydrocarbon residues. The kinetic parameters of each stage were calculated from the Kissinger, Friedman and Flynn-Wall-Ozawa methods. The Chang method was also used for comparison study. To investigate the degradation mechanisms of the three different stages, the Coats-Redfern and the Phadnis-Deshpande methods were employed. The probable degradation mechanism for the first stage was a nucleation and growth mechanism, $A_n$ type. However, a power law and a diffusion mechanism, $D_n$ type, were operated for the second degradation stage, whereas a nucleation and growth mechanism, $A_n$ type, were operated again for the third degradation stage of PHMG. The theoretical weight loss against temperature curves, calculated by the estimated kinetic parameters, well fit the experimental data, thereby confirming the validity of the analysis method used in this work. The life-time predicted from the kinetic equation is a valuable guide for the thermal processing of PHMG.

• Journal of Environmental Health Sciences
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• v.46 no.3
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• pp.335-343
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• 2020

Objectives: The Korean Ministry of Environment has identified cases of people suspected of suffering lung disease potentially caused by polyhexamethylene guanidine (PHMG) used in humidifier disinfectants (HDs). Exposure assessment for the HDs was conducted using a questionnaire during face-to-face interview. The main purposes of this study were to develop a methodology to effectively classify levels of exposure to HDs based on a questionnaire. Methods: We first identified the overall participants' exposure characteristics by HD exposure levels; Second, we selected misclassified subjects and investigated characteristics of overestimated and underestimated subjects, focusing on exposure cases to PHMG-containing HDs. An inhalation reference concentration (RfC) for PHMG was produced on the basis of inhalation toxicity values. We made a cross-tabulation of the exposure classes (Exposure classes 1-to-4) by clinical classes based on the RfC. When the value of the exposure class minus the clinical class was 0 or 1, we assumed these were true values. When the value was ≥2 and ≤ -2, we assigned these cases to the overestimation group and underestimation group, respectively. Results: The overestimated group may have already recovered and responded excessively due to psychological anxiety or in order to receive compensation. On the other hand, relatively high mortality rates and surrogate responses for those under 10 years of age may have resulted in inaccurate exposure assessment for underestimated groups. For the characteristics of exposure, it was shown that for the underestimated group, the exposure was relatively weaker than the overestimated group, even though a high overall clinical rating was determined. Conclusions: This study may suggest ways to reduce bias and overcome the limitations of current HD exposure assessment.

• Environmental Engineering Research
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• v.18 no.4
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• pp.253-257
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• 2013

Exposure assessment for three major active ingredients used for humidifier disinfectants, polyhexamethylene guanidine (PHMG), oligo(2-(2-ethoxy)ethoxyethyl guanidinium chloride (PGH), and 5-chloro-2-methylisothiazol-3(2H)-one/2-methylisothiazol-3(2H)-one (CMIT/MIT) mixture, was conducted in a bedroom using an air sampler for a refined risk assessment. The experimental site was selected to reflect consumer exposure conditions. Aerosols formed by a humidifier were sampled during 8 hr at 7.5 L/min. Absorbed PHMG and PGH by the sampler were quantified using a spectrophotometric method, and high performance liquid chromatography-ultraviolet detection was used for CMIT/MIT. Three exposure scenarios were assumed for adding humidifier disinfectants to the humidifier water at 1, 2, and 10 times the volume recommended by the product suppliers, and the humidifier was on at its maximum rate of producing aerosols in order to consider reasonable worst-cases. The sampled mass of PHMG and PGH ranged 200 to $2,800{\mu}g$ and 140 to $1,900{\mu}g$, respectively, under different exposure conditions, whereas the absorbed mass of CMIT/MIT was barely detected at the detection limit of 0.11/0.29 mg/L, only at 10 times the recommended level. The resulting risk quotients for PHMG and PGH ranged 1,400 to 20,000 and 1,000 to 13,000, indicating that health risks could be significant. For CMIT/MIT mixture, risk quotients were much smaller than estimated by assuming that they are conservative in the indoor environment, probably due to oxidative reactions. The refined exposure assessment presented here may provide a useful tool for assessing risks posed by active ingredients in spray-type biocidal products.

• Journal of Environmental Health Sciences
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• v.46 no.2
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• pp.128-135
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• 2020

Objective: The objectives of this study are to report the number of humidifier disinfectant (HD) associated health problems, including HD associated lung injury (HDLI), by year. This data was analyzed by the type of HD and HD brand. Methods: A total of 530 patients registered with the national program on HD through its third round were distributed based on the year when they developed their first health problem including HDLI (N=221). The distribution of health problems at diagnosis was clinically evaluated in order to examine the association between their lung injury and the use of HD. Results: The number of HD associated victims and HDLI patients was found to rise sharply from 2008 to 2011, with a peak in 2011. This trend was found not only for HD brands containing polyhexamethylene guanidine phosphate (PHMG), but also chloromethylisothiazolinone/methylisothiazolinone (CMIT/MIT). The number of patients who responded as developing health problems in the specific year was 35 for 2008, 51 for 2009, 108 for 2010 and 182 for 2011. Other types of HD brands and HD chemicals did not follow the trend of abrupt increase in HD associated patients since 2008. Conclusion: This study found the number of HD associated victims and HDLI patients who used HD brands containing PHMG sharply increased starting in 2008. A significant change in the process of manufacturing PHMG can be suspected with the abrupt rise in HD associated patients in specific years.