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

Background: 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. Methods: Male and female F344 rats were exposed to 0.3, 1, 3, or 10 mg/m3 CWAAP-A for 6 hours/day, 5 days/week for 13 weeks using a whole-body inhalation exposure system. At 1 hour, 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 hours/day for 2 days. Results: CWAAP-A exposure damaged only the alveoli. The lowest observed adverse effect concentration (LOAEC) was 1 mg/m3 and the no observed adverse effect concentration (NOAEC) was 0.3 mg/m3. Rats of both sexes were able to recover from the tissue damage caused by 13 weeks exposure to 1 mg/m3 CWAAP-A. In contrast, tissue damage caused by exposure to 3 and 10 mg/m3 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. Conclusions: 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/m3 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.

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

10.1101/2021.11.13.468475 ◽

2021 ◽

Author(s):

Shotaro Yamano ◽

Tomoki Takeda ◽

Yuko Goto ◽

Shigeyuki Hirai ◽

Yusuke Furukawa ◽

...

Keyword(s):

Acrylic Acid ◽

Recovery Period ◽

Inhalation Exposure ◽

Intratracheal Instillation ◽

Water Soluble ◽

Whole Body ◽

Lung Pathology ◽

Exposure System ◽

F344 Rats ◽

Male F344 Rats

Background: Recently 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. Methods: Using 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. Results: A single 4-hour exposure to CWAAP caused alveolar injury, and repeated exposures resulted in regenerative changes in the alveolar epithelium with activation of TGFβ 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. Conclusions: The 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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Chronic Inhalation Exposure of Rats for up to 104 Weeks to a Non–Carbon-Based Magnetite Photocopying Toner

International Journal of Toxicology ◽

10.1080/10915810802616560 ◽

2008 ◽

Vol 27 (6) ◽

pp. 427-439 ◽

Cited By ~ 17

Author(s):

Ronald S. Slesinski ◽

Duncan Turnbull

Keyword(s):

Lymph Nodes ◽

Inhalation Exposure ◽

Clinical Pathology ◽

Acrylic Resin ◽

Lymphocytic Infiltration ◽

Female Rats ◽

Whole Body ◽

Male And Female ◽

Male And Female Rats ◽

Carbon Based

Male and female Han Wistar rats were exposed for 6 h/day, 5 days/week for 13 or 104 weeks (whole body) to a magnetite photocopying toner. The toner contained 45% to 50% magnetite, with 45% to 50% styrene acrylic resin and less than 5% external additives, including hydrophobic amorphous silica and proprietary surface functional modifiers. Exposure levels were 1, 5, and 25 mg/m3 for the 13-week study and 1, 4, and 16 mg/m3 for the 104-week study. Lung toner burdens averaged 36, 288, and 604 μg per lung after 104 weeks’ exposure at 1, 4, and 16 mg/m3. The lung burdens were lower than have been reported in a similar study with a carbon-based toner. There were no significant effects on weight gain or food consumption in either study, or on clinical pathology parameters examined in the 13-week study. After 104 weeks’ exposure at 16 mg/m3, macroscopic examination revealed dark discoloration of the lungs and associated lymph nodes. Lung weights were significantly elevated by 21% and 14% for male and female rats, respectively. Microscopic findings indicative of a mild inflammatory response were similar in both studies, and included the presence of black-pigmented macrophages in the lungs and tracheobronchial and mediastinal lymph nodes; increased incidences of perivascular/peribronchiolar inflammatory cell infiltration; inflammation of the alveolar ducts (characterized by aggregations of black-pigmented alveolar macrophages and interstitial lymphocytic infiltration); increased cellularity of the bronchiole-associated lymphoid tissue; and a few instances of alveolar ciliated metaplasia. The 104-week study showed no increase in the incidence of pulmonary tumors.

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Effect of water-soluble metal working fluid aerosols on respiratory system after 13 weeks of repeated inhalation exposure in F344 rats

Toxicology and Industrial Health ◽

10.1191/0748233705th230oa ◽

2005 ◽

Vol 21 (7-8) ◽

pp. 207-213 ◽

Cited By ~ 1

Author(s):

Cheol-Hong Lim ◽

Il Je Yu ◽

Hyeon-Young Kim ◽

Seung-Bae Lee ◽

Daniel R Marshak ◽

...

Keyword(s):

Respiratory System ◽

Inhalation Exposure ◽

Water Soluble ◽

Working Fluid ◽

Metal Working ◽

Effect Of Water ◽

F344 Rats

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Eugenol improves tissue damage and oxidative stress in adult female rats after ovarian torsion/detorsion

Journal of Obstetrics and Gynaecology ◽

10.1080/01443615.2020.1816938 ◽

2021 ◽

pp. 1-6

Author(s):

Bita Barghi ◽

Majid Shokoohi ◽

Amir Afshin Khaki ◽

Arash Khaki ◽

Maryam Moghimian ◽

...

Keyword(s):

Oxidative Stress ◽

Adult Female ◽

Tissue Damage ◽

Ovarian Torsion ◽

Female Rats ◽

And Oxidative Stress

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QSAR modelling of inhalation toxicity of diverse volatile organic molecules using no observed adverse effect concentration (NOAEC) as the endpoint

Chemosphere ◽

10.1016/j.chemosphere.2021.131954 ◽

2022 ◽

Vol 287 ◽

pp. 131954

Author(s):

Aniket Nath ◽

Priyanka De ◽

Kunal Roy

Keyword(s):

Adverse Effect ◽

Organic Molecules ◽

Inhalation Toxicity ◽

Qsar Modelling ◽

Volatile Organic ◽

Effect Concentration

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Highly Water-soluble [60]Fullerene-ethylenediamino-β-cyclodextrin Inclusion Complex: The Synthesis and Self-assembly with Poly (Acrylic Acid)

Supramolecular Chemistry ◽

10.1080/10610270701242372 ◽

2008 ◽

Vol 20 (3) ◽

pp. 295-299 ◽

Cited By ~ 6

Author(s):

Ying Yu ◽

Zhiqiang Shi ◽

Yingjie Zhao ◽

Yongshan Ma ◽

Mei Xue ◽

...

Keyword(s):

Acrylic Acid ◽

Inclusion Complex ◽

Self Assembly ◽

Water Soluble ◽

Cyclodextrin Inclusion ◽

Cyclodextrin Inclusion Complex ◽

Poly Acrylic Acid

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A HYBRID COMPUTATIONAL FLUID DYNAMICS AND PHYSIOLOGICALLY BASED PHARMACOKINETIC MODEL FOR COMPARISON OF PREDICTED TISSUE CONCENTRATIONS OF ACRYLIC ACID AND OTHER VAPORS IN THE RAT AND HUMAN NASAL CAVITIES FOLLOWING INHALATION EXPOSURE

Inhalation Toxicology ◽

10.1080/08958370117942 ◽

2001 ◽

Vol 13 (5) ◽

pp. 359-376 ◽

Cited By ~ 2

Author(s):

Clay B. Frederick, P. Robinan Gentr

Keyword(s):

Fluid Dynamics ◽

Computational Fluid Dynamics ◽

Acrylic Acid ◽

Pharmacokinetic Model ◽

Inhalation Exposure ◽

Physiologically Based Pharmacokinetic Model ◽

Tissue Concentrations ◽

Nasal Cavities ◽

Physiologically Based Pharmacokinetic ◽

Physiologically Based

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Inhalation of Ortho-Phthalaldehyde Vapor Causes Respiratory Sensitization in Mice

Journal of Allergy ◽

10.1155/2011/751052 ◽

2011 ◽

Vol 2011 ◽

pp. 1-12 ◽

Cited By ~ 3

Author(s):

Victor J. Johnson ◽

Jeffrey S. Reynolds ◽

Wei Wang ◽

Kara Fluharty ◽

Berran Yucesoy

Keyword(s):

Lymph Nodes ◽

B Lymphocytes ◽

Case Reports ◽

Inhalation Exposure ◽

Cytokine Gene Expression ◽

Respiratory Problems ◽

Specific Igg ◽

High Level ◽

Lymphocyte Populations ◽

Draining Lymph Nodes

Ortho-Phthalaldehyde (OPA) has been approved for high-level sterilization of heat-sensitive medical instruments and is increasingly being used as a replacement in the healthcare industry for glutaraldehyde, a known sensitizer. Numerous case reports have been published indicating workers and patients experiencing respiratory problems, anaphylaxis, skin reactivity, and systemic antibody production. Our laboratory previously demonstrated that OPA is a dermal sensitizer in mice. The goal of the present study was to determine if OPA is a respiratory sensitizer following inhalation exposure. Mice were exposed to OPA vapor and airway and lymph nodes were examined for cytokine gene expression and alterations in lymphocyte populations. Inhalation of OPA for 3 days resulted in a concentration-dependent increase in lymphocyte proliferation, mainly B lymphocytes, in the draining lymph nodes. A secondary challenge of mice with OPA resulted in a dramatic increase in the population of B lymphocytes expressing IgE. Expression of Th2 (IL-4, IL-5, and IL-13) and anti/proinflammatory (IL-10, TNFα, and IL-1β) cytokine genes was upregulated in the lymph nodes and the nasal mucosa. Mice exposed to the higher concentrations of OPA-produced OPA-specific IgG1 antibodies indicating systemic sensitization. These findings provide evidence that OPA has the potential to cause respiratory sensitization in mice.

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Electron microscopic changes of lymph nodes during correction of sodium glutamate action by melatonin

Reports of Morphology ◽

10.31393/morphology-journal-2020-26(1)-09 ◽

2020 ◽

Vol 26 (1) ◽

pp. 59-64 ◽

Cited By ~ 1

Author(s):

T.V. Harapko

Keyword(s):

Lymph Nodes ◽

Monosodium Glutamate ◽

Reproductive Age ◽

Female Rats ◽

Mesenteric Lymph Nodes ◽

Electron Microscopic ◽

Male And Female ◽

White Rats ◽

Mesenteric Lymph ◽

Male And Female Rats

The effect of monosodium glutamate on lymphoid organs remains insufficiently studied. Also, no less relevant is the issue of correction of changes caused by the action of monosodium glutamate. The aim of the study was to study the electron microscopic changes in the parenchyma of the lymph nodes of rats under the action of monosodium glutamate for six weeks and during correction with melatonin. The experimental study was performed on 66 white male and female rats of reproductive age. The structure of mesenteric lymph nodes of white rats under the conditions of physiological norm at the electron microscopic level was studied in 10 intact animals. Experimental animals were divided into 4 groups, each with 10 animals. The control was 16 white rats, which instead of a high-calorie diet (HCD) received a standard diet of vivarium. HCD was achieved by adding to the diet of monosodium glutamate at a dose of 0.07 g/kg body weight of rats. The dose of melatonin was 10 mg/kg body weight of rats, administered orally daily at the same time in the afternoon. The electron microscopic structure of the mesenteric lymph nodes of male and female rats of reproductive age of the intact and control groups corresponds to the species norm. The study showed that monosodium glutamate causes changes in the parenchyma of the lymph nodes as in alimentary obesity. After six weeks of HCD, the number of apoptically altered lymphocytes increases. That part of lymphocytes, which has no signs of karyorrhexis or karyolysis, has a karyolemma with deep intussusception, the cytoplasm is enlightened, the tubules of the granular endoplasmic reticulum in cells with signs of edema, dilated, mitochondrial ridges swollen, damaged. There are profound destructive changes in the cellular composition of the organ and violations at the level of all parts of the vascular bed. After six weeks of melatonin correction, the number of macrophages and plasma cells decreased, in some lymphocytes the nucleolus is not clearly expressed, the karyolemma is uneven, the cytoplasm is enlightened, the number of osmophilic (fatty) inclusions decreases both in the intercellular space and in the cytoplasm of the cell. Therefore, the introduction of melatonin led to a significant restoration of the structural organization, and hence the function of this organ.

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