Acute inhalation toxicity of 3-methylfuran in the mouse: Pathology, cell kinetics, and respiratory rate effects

doi:10.1016/0041-008X(84)90256-4

Toxicology and Applied Pharmacology

Volume 72, Issue 1, January 1984, Pages 124-133

https://doi.org/10.1016/0041-008X(84)90256-4 Get rights and content

Abstract

The acute inhalation toxicity of 3-methylfuran (3MF) was investigated in male $BALB c$ mice by morphologic examination of animals killed at varying timepoints following a 1-hr exposure to an initial chamber concentration of 14 to 37 μmol/liter (343 to 906 ppm). In addition, respiratory rate measurements and cell kinetics were used to assess quantitatively pulmonary damage and repair. Necrosis of nonciliated bronchiolar epithelial (Clara) cells was seen 1 day following exposure and was followed by regeneration, which was virtually complete, within 21 days. Cell kinetic studies showed peak bronchiolar cell proliferation at 3 days with a labeling index (LI) of 5.0% compared to 0.4% in controls. An increase in parenchymal cell proliferation was also noted coincident with a mild interstitial pneumonitis. This parenchymal proliferation, peaking at 10 days with an LI of 1.4% compared to 0.2% in controls, consisted primarily of type II epithelial and endothelial cell proliferation indicating possible delayed damage and repair of type I epithelial and endothelial cells. The respiratory rate showed an initial transient increase followed by a more prolonged decrease with eventual return to control levels. 3MF toxicity was also evidenced by a necrotizing suppurative rhinitis, centrilobular hepatic necrosis, lymphocyte necrosis in the thymus and spleen, sialoadenitis, and otitis media.

References (32)

M.J. Evans et al.
Effect of NO₂ in the lungs of aging rats. II. Cell proliferation
Exp. Mol. Pathol.
(1977)
W.M. Hadley et al.
Cytochrome P-450 dependent monoxygenase activity in rat nasal epithelial membranes
Toxicol. Letters
(1982)
P.J. Hakkinen et al.
Effect of lung, liver and kidney toxicants on respiratory rate in the mouse
Toxicology
(1983)
P.J. Hakkinen et al.
Pulmonary toxicity of methylcyclopentadienyl manganese tricarbonyl (MMT): Nonciliated bronchiolar epithelial (Clara) cell necrosis and alveolar damage in the mouse rat and hamster
Toxicol. Appl. Pharmacol.
(1982)
W.M. Haschek et al.
Nonciliated bronchiolar epithelial (Clara) cell necrosis induced by organometallic carbonyl compounds
Toxicol. Lett
(1982)
S.S. Tong et al.
Clara cell damage and inhibition of pulmonary mixed-function oxidase activity by naphthalene
Biochem. Biophys. Res. Commun.
(1981)
H.P. Witschi
Proliferation of type II alveolar cells. A review of common responses in toxic lung injury
Toxicology
(1976)
I.Y.R. Adamson et al.
Bleomycin-induced injury and metaplasia of alveolar type 2 cells
Amer. J. Pathol.
(1979)
I.Y.R. Adamson et al.
Lung injury induced by butylated hydroxytoluene. Cytodynamic and biochemical studies in mice
Lab. Invest.
(1977)
M.R. Boyd
Evidence for the Clara cells as a site of cytochrome P450-dependent mixed-function oxidase activity in lung
Nature (London)
(1977)

M.R. Boyd

Biochemical mechanisms in chemical-induced lung injury: Roles of metabolic activation

CRC Crit. Rev. Toxicol.

(1980)

M.R. Boyd

Biochemical mechanisms in pulmonary toxicity of furan derivatives

Rev. Biochem. Toxicol.

(1980)

M.R. Boyd et al.

Isolation and characterization of 4-ipomeanol, a lung-toxic furanoterpenoid produced by sweet potatoes

J. Agric. Food Chem.

(1972)

M.R. Boyd et al.

Pulmonary bronchiolar alkylation and necrosis by 3-methylfuran, a naturally occurring potential atmospheric contaminant

Nature (London)

(1978)

M.R. Boyd et al.

The pulmonary Clara cell as a target for toxic chemicals requiring metabolic activation: Studies with carbon tetrachloride

J. Pharmacol. Exp. Ther.

(1980)

C.H. Collis et al.

Cyclophosphamide-induced lung damage in mice: Protection by a small preliminary dose

Brit. J. Cancer

(1980)

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2018, Comprehensive Toxicology: Third Edition
The toxicity of environmental chemicals, that is, nontherapeutic agents, to respiratory tissues is described in significant detail throughout this volume. In the vast majority of cases, these environmental toxicants are inhaled chemicals that interact with respiratory cells on a contact basis, after inhalation. There is, however, an ever-expanding repertoire of chemicals that produce selective or specific toxicity to cells within the respiratory system after systemic circulation throughout the biological system. Many of these chemicals are therapeutic agents such as bleomycin (BLM) or amiodarone (AM), and some are nontherapeutic chemicals such as 3-methylindole (3MI), aflatoxin B₁ (AFB₁), butylated hydroxytoluene (BHT), halogenated hydrocarbons, naphthalenes, paraquat (1,19-dimethyl-4,49-bipyridilium, PQ), the pyrrolizidine alkaloids (PZAs), and the substituted furans that are ingested and circulated systemically. This article deals with chemicals that are known to cause damage to respiratory tissues following exposure and the mechanisms of their toxicity, which is generally mediated by oxidative metabolism of the chemicals to reactive electrophiles by cytochrome P450 enzymes in cells of the respiratory tract. These compounds are generally toxic to nonciliated bronchiolar epithelial cells and alveolar epithelial cells of the gas exchange region although some agents are highly toxic to nasal epithelial or pulmonary endothelial cells. The purpose of this chapter is to provide chemical and biochemical insights into the generalized mechanisms of toxicity of certain circulating pneumotoxicants, through the enumeration and compilation of a few examples of well-documented, chemically induced lung damage.
A 90-day subchronic gavage toxicity study in Fischer 344 rats with 3-methylfuran
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Citation Excerpt :
Until recently, little attention had been paid to the effects and presence of methylfurans in foods until 2-methylfuran and 3-methylfuran were identified to be potent hepatotoxins (Wiley et al., 1984; Ravindranath et al., 1984; Ravindranath and Boyd, 1991). Little toxicological information was available for 3-methylfuran and in most of the available studies, the route of administration was by inhalation (Haschek et al., 1983;1984; Morse et al., 1984; Gammal et al., 1984) or intraperitoneal injection. With inhalation studies, furan, 2-methylfuran and 3-methylfuran were found to induce pulmonary, nasal and kidney toxicity (Gammal et al., 1984; Haschek et al., 1983;1984; Morse et al., 1984; Ravindranath et al., 1984; Witschi et al., 1985).
A 90-day gavage study was conducted with 0.0, 0.02, 0.075, 0.25, 1.0 and 4.0 mg/kg bw/day dose groups of 3-methylfuran to identify a no-observed adverse effect level for hepatotoxicity and to characterize non-neoplastic effects including changes in gross anatomy, histopathology, clinical biochemistry and hematology. There were significant changes in the serum clinical biochemistry markers related to liver injury where males were more affected than the females for most parameters analysed. The serum liver injury marker γ−glutamyltransferase, alanine and aspartate aminotransferases were significantly increased in males in the 4.0 mg/kg dose group. Alkaline phosphatase was increased in females and males. There were increases in both gross and histological lesions in the liver of both sexes in addition to statistical differences in female liver weights at the 4.0 mg/kg bw/day dose. Significant increases in spleen weights were found in both genders. This was accompanied by a dose–dependent atrophy of both B- and T-cell regions in which the males were more affected. There were no significant changes in male kidney weights but there was microscopically decreased protein in the proximal tubules and crowding of their nuclei in the 4.0 mg/kg bw/day dose group. There were also significant changes in the kidney serum biomarkers including various electrolytes, blood urea nitrogen, creatinine and uric acid. A small, but significant increase in female kidney weights was observed and which increase was accompanied by changes in electrolytes, kidney specific markers and a dose-dependent increase in mineralization. In both genders, amylase decreased whereas lipase increased but these were not accompanied by any histological changes in the pancreas.
Histopathological changes in the liver were observed consistently in male and female rats in the 0.25 mg/kg dose group and higher. Hence, a lowest observed adverse effect level (LOAEL) of 0.25 mg/kg bw/d and a no observed adverse effect level (NOAEL) of 0.075 mg/kg bw/day are proposed for 3-methylfuran-induced hepatic lesions in this study. Benchmark dose modelling based on a BMR of 10% change in lesion incidence, generated BMDLs₁₀ of 0.08 mg/kg bw/day in male rats and 0.05–0.17 mg/kg bw/day in female rats for increased incidence of liver lesions.
Selected Pneumotoxic Agents
2010, Comprehensive Toxicology, Second Edition
The toxicity of environmental chemicals, that is, nontherapeutic agents, to respiratory tissues is described in significant detail throughout this volume. In the vast majority of cases, these environmental toxicants are inhaled chemicals that interact with respiratory cells on a contact basis, after inhalation. There is, however, an ever-expanding repertoire of chemicals that produce selective or specific toxicity to cells within the respiratory system after systemic circulation throughout the biological system. Many of these chemicals are therapeutic agents such as bleomycin (BLM) or amiodarone (AM) and some are nontherapeutic chemicals such as 3-methylindole (3MI), aflatoxin B1 (AFB1), butylated hydroxytoluene (BHT), halogenated hydrocarbons, naphthalenes, paraquat (1,19-dimethyl-4, 49-bipyridilium, PQ), the pyrrolizidine alkaloids (PZAs), and the substituted furans that are ingested and circulated systemically. This chapter deals with chemicals that are known to cause damage to respiratory tissues following exposure and the mechanisms of their toxicity, which is generally mediated by oxidative metabolism of the chemicals to reactive electrophiles by cytochrome P450 enzymes in cells of the respiratory tract. These compounds are generally toxic to nonciliated bronchiolar epithelial cells and alveolar epithelial cells of the gas exchange region, although some agents are highly toxic to nasal epithelial or pulmonary endothelial cells. The purpose of this chapter is to provide chemical and biochemical insights into the generalized mechanisms of toxicity of certain circulating pneumotoxicants, through the enumeration and compilation of a few examples of well-documented, chemically induced lung damage.
Cell Damage and Cell Renewal in the Lung
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A basic principle of wound healing is that cell loss will also trigger cell regeneration involving proliferation. This simple concept is actually quite difficult to study in the context of the complex multicellular environment of the lung. The pattern of the proliferative response is predicated on the cell type that is damaged, the extent and degree of the damage, and whether the insult is acute or chronic. When studying cell renewal, it is critically important to define the type of damage, its extent, and the cell types involved so that the nature of the reparative response can be put into context. Toxicologists have contributed vital information that has helped define lung cell reparative potential.
Repair of Environmental Lung Injury During Development
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This chapter focuses on the repair of environmental injury in normal, full term postnatal lung after exposure to environmental toxicants and compares it to adult lung. 'Repair' is defined as all the processes that are involved in resolving an injury, and includes both cellular and acellular components. Several factors may influence both susceptibility and the capability of the lung to properly repair injury. The alterations seen in repair of the developing lung following exposure to environmental toxicants may be due to a temporary or permanent disruption of the epithelial mesenchymal trophic unit resulting in either an inability to heal the initial wound or disruption of critical morphogenic events. Many factors regulate the repair process following injury by P450-mediated toxicants, including various soluble cytokines and growth factors, interactions with integrins and matrix elements as well as cell-cell interactions. Various studies have demonstrated that when the developing lung does not repair, abnormalities may persist into adulthood. Acute ozone toxicity generates a reversible lesion without a defined long-term pathology but involving a substantial inflammatory cell response. Repair following acute injury is characterized by both proliferation and ciliary regeneration detectable in the surviving cells 24 h after exposure. In case of ozone exposure in adults, the overall response is characterized by a large influx of inflammatory cells into the lung. This influx is predominately neutrophils in the early phase while elevated macrophages persist throughout exposure.
Proliferation during early phases of bronchiolar repair in neonatal rabbits following lung injury by 4-ipomeanol
2003, Toxicology and Applied Pharmacology
Nonciliated bronchiolar (Clara cells) are progenitor cells during development. During differentiation, they are more susceptible to injury by environmental toxicants metabolized by the cytochrome P450 monooxygenase system, and injury results in altered bronchiolar repair and development. Squamous cells and abnormal cuboidal epithelium persist into early adulthood. The hypothesis tested in this study was that the failure of bronchiolar epithelium to repair normally in neonates following injury is due to an inhibition of proliferation. A model of differential repair in rabbit kits was used. Proliferation was followed for 1 week post injury in rabbit kits treated with a single dose of the P450-mediated cytotoxicant 4-ipomeanol (IPO) at 7 days old (repair abnormal) and compared to rabbits treated with a single dose of IPO at 21 days old (repair normal). Proliferation was measured by the nuclear incorporation of 5-chloro-2′-deoxyuridine (CldU) within epithelium at the target site (terminal bronchiole). The repair pattern between the two age groups was histologically defined. There was no difference in the CdlU labeling index during the week of repair between the two age groups, even though the bronchiolar epithelium did not return to normal in the animals treated at 7 days old. In summary, proliferation (through S-phase) is not inhibited during repair in neonatal rabbits treated with IPO at 7 days old compared to animals treated at 21 days old, and we conclude that other factors may be responsible for the altered repair in the young neonates injured by a P450-mediated cytotoxicant.

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^☆: The U.S. Government's right to retain a nonexclusive, royalty-free license in and to any copyright covering this paper, for governmental purposes, is acknowledged.

^☆☆: This research was sponsored by the Office of Health and Environmental Research, U.S. Department of Energy under Contract W-7405-eng-26 with the Union Carbide Corporation. Dr. Hakkinen was supported as a postdoctoral investigator by Subcontract 3322 from the Biology Division, Oak Ridge National Laboratory, to the University of Tennessee.

³: Present address: University of Illinois, Department of Veterinary Pathobiology, Urbana, Ill.

⁴: Present address: National Cancer Institute, Bethesda, Md.

⁵: Present address: The Procter and Gamble Company, Cincinnati, Ohio.

View full text

Acute inhalation toxicity of 3-methylfuran in the mouse: Pathology, cell kinetics, and respiratory rate effects☆,☆☆

Abstract

Exp. Mol. Pathol.

Toxicol. Letters

Toxicology

Toxicol. Appl. Pharmacol.

Toxicol. Lett

Biochem. Biophys. Res. Commun.

Toxicology

Bleomycin-induced injury and metaplasia of alveolar type 2 cells

Amer. J. Pathol.

Lung injury induced by butylated hydroxytoluene. Cytodynamic and biochemical studies in mice

Lab. Invest.

Evidence for the Clara cells as a site of cytochrome P450-dependent mixed-function oxidase activity in lung

Nature (London)

Biochemical mechanisms in chemical-induced lung injury: Roles of metabolic activation

CRC Crit. Rev. Toxicol.

Biochemical mechanisms in pulmonary toxicity of furan derivatives

Rev. Biochem. Toxicol.

Isolation and characterization of 4-ipomeanol, a lung-toxic furanoterpenoid produced by sweet potatoes

J. Agric. Food Chem.

Pulmonary bronchiolar alkylation and necrosis by 3-methylfuran, a naturally occurring potential atmospheric contaminant

Nature (London)

The pulmonary Clara cell as a target for toxic chemicals requiring metabolic activation: Studies with carbon tetrachloride

J. Pharmacol. Exp. Ther.

Cyclophosphamide-induced lung damage in mice: Protection by a small preliminary dose

Brit. J. Cancer