Studies on the mechanism of the lung toxicity of paraquat: Comparison of tissue distribution and some biochemical parameters in rats and rabbits

doi:10.1016/0041-008X(74)90007-6

Toxicology and Applied Pharmacology

Volume 28, Issue 2, May 1974, Pages 216-226

https://doi.org/10.1016/0041-008X(74)90007-6 Get rights and content

Abstract

After iv injection of [¹⁴C]paraquat (20 mg/kg) tissue localization was preferential in lungs of rats as well as rabbits although the latter did not show any histopathologic or biochemical signs of lung damage. No preferential subcellular localization of [¹⁴C]paraquat was found in lungs of either species, but all subcellular levels decreased more rapidly in the rabbit than in the rat. [¹⁴C]Paraquat was not covalently bound to tissue macromolecules. In vitro measurements of lipid peroxidation, H₂O₂ formation and lung lysosomal stability failed to account adequately for the lung damage in the rat.

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This chapter explores the chemical identity, toxicity, and usage of paraquat. Paraquat is usually formulated as the dichloride salt also known as methyl viologen. Code designations for the material are PP148 for the dichloride salt and PP910 for the bis salt. Paraquat dichloride forms colorless, hygroscopic crystals, which decompose at 300 °C. It is practically non-volatile with a vapor pressure of < 0.1 mPa. It is very soluble in water (700 g/l at 20 °C) and practically insoluble in most other organic solvents. It is mainly formulated as an aqueous solution with surface-active agents. It is used for broad-spectrum control of broad-leaved weeds and grasses in fruit orchards and plantations and for inter-row weed control in many crops. It is also used for general weed control on non-crop land, as a defoliant on cotton and hops, for destruction of potato haulms, as a desiccant, and for control of aquatic weeds. Paraquat is rapidly deactivated upon contact with the soil and does not leach. Following a lethal dose of paraquat to rats mortality is first seen on days 2–5 after dosing but deaths can also occur around days 10–12, indicating there is considerable inter-individual animal response to the chemical. The major cause of death after a median lethal dose (MLD) is due to lung damage. The MLD of pure paraquat dichloride expressed as the cation was about 150 mg/kg to female rats and ranged from 100–143 mg/kg in a number of different strains from a number of different laboratories. As in experimental animals, paraquat is not metabolized in humans, but is reduced to an unstable free radical, which is then re-oxidized to produce a superoxide radical. The therapy of paraquat intoxication has focused on three main areas: prevention of absorption from the gastrointestinal tract, enhancement of elimination of paraquat from the body, and therapy directed against the mechanisms of toxicity.
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2010, Hayes' Handbook of Pesticide Toxicology, Third Edition: Volume 1
This chapter explores the chemical identity, toxicity, and usage of paraquat. Paraquat is usually formulated as the dichloride salt also known as methyl viologen. Code designations for the material are PP148 for the dichloride salt and PP910 for the bis salt. Paraquat dichloride forms colorless, hygroscopic crystals, which decompose at 300 °C. It is practically non-volatile with a vapor pressure of < 0.1 mPa. It is very soluble in water (700 g/l at 20 °C) and practically insoluble in most other organic solvents. It is mainly formulated as an aqueous solution with surface-active agents. It is used for broad-spectrum control of broad-leaved weeds and grasses in fruit orchards and plantations and for inter-row weed control in many crops. It is also used for general weed control on non-crop land, as a defoliant on cotton and hops, for destruction of potato haulms, as a desiccant, and for control of aquatic weeds. Paraquat is rapidly deactivated upon contact with the soil and does not leach. Following a lethal dose of paraquat to rats mortality is first seen on days 2–5 after dosing but deaths can also occur around days 10–12, indicating there is considerable inter-individual animal response to the chemical. The major cause of death after a median lethal dose (MLD) is due to lung damage. The MLD of pure paraquat dichloride expressed as the cation was about 150 mg/kg to female rats and ranged from 100–143 mg/kg in a number of different strains from a number of different laboratories. As in experimental animals, paraquat is not metabolized in humans, but is reduced to an unstable free radical, which is then re-oxidized to produce a superoxide radical. The therapy of paraquat intoxication has focused on three main areas: prevention of absorption from the gastrointestinal tract, enhancement of elimination of paraquat from the body, and therapy directed against the mechanisms of toxicity.
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Accordingly, in vitro mechanistic experiments showed that both compounds produce significant oxidative stress after administration (Chun et al., 2001). However, paraquat has long been known to undergo redox cycling with generation of reactive oxygen species (ROS) (Fisher et al., 1973; Ilett et al., 1974). Furthermore, it has been directly demonstrated that paraquat does not act by direct inhibition of complex I (Richardson et al., 2005).
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Efficient administration of drugs represents a leading challenge in pulmonary medicine. Dry powder aerosols are of great interest compared to traditional aerosolized liquid formulations in that they may offer improved stability, ease of administration, and simple device design. Particles 1–5 μm in size typically facilitate lung deposition. Nanoparticles may be exhaled as a result of their small size; however, they are desired to enhance the dissolution rate of poorly soluble drugs. Nanoparticles of the hypertension drug nifedipine were co-precipitated with stearic acid to form a colloid exhibiting negative surface charge. Nifedipine nanoparticle colloids were destabilized by using sodium chloride to disrupt the electrostatic repulsion between particles as a means to achieve the agglomerated nanoparticles of a controlled size. The aerodynamic performance of agglomerated nanoparticles was determined by cascade impaction. The powders were found to be well suited for pulmonary delivery. In addition, nanoparticle agglomerates revealed enhanced dissolution of the drug species suggesting the value of this formulation approach for poorly water-soluble pulmonary medicines. Ultimately, nifedipine powders are envisioned as an approach to treat pulmonary hypertension.
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¹: Present Address: Department of Pharmacology, University of Western Australia, Nedlands, 6009, Western Australia.

²: Supported by NHLI Fellowship FO2 HE51972-01 and by Hoffman-La Roche, Nutley, New Jersey.

³: Present address: Reston-Georgetown Medical Center, Hunter's Woods Plaza, Reston, Virginia.

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Studies on the mechanism of the lung toxicity of paraquat: Comparison of tissue distribution and some biochemical parameters in rats and rabbits

Abstract

J. Biol. Chem.

Methods Enzymol.

J. Biol. Chem.

Exp. Mol. Pathol.

J. Biol. Chem.

J. Biol. Chem.

Exp. Mol. Pathol.

Anal. Biochem.

The role of lysosomes in the action of drugs and hormones

Treatment of paraquat ingestion

Brit. Med. J.

Accidental poisoning by paraquat: Report of two cases in man

Brit. Med. J.

Paraquat in the rabbit

Brit. J. Ind. Med.

The bipyridylium herbicides

Advan. Pest Contr. Res.

The toxicity of paraquat

Brit. J. Ind. Med.

Paraquat and related bipyridyls

Brit. Med. Bull.

Absorption and excretion of diquat and paraquat in rats

Brit. J. Ind. Med.

The significance of the lysosomes in toxicology

Crit. Rev. Toxicol.