SOURCES

Paraquat (1,1’-dimethyl-4, 4’-bipyridyl) was first synthesized in 1882, but its herbicidal action was not discovered until 1959.¹ Paraquat dichloride has been marketed commercially since 1965 and is formulated in many countries. It is a nonselective herbicide and has rapid contact action when applied as a post-emergent herbicide. Paraquat is used as a herbicide, defoliant, desiccant, and plant growth regulator. It is sold worldwide under the trade names Cekupat, Dextron X, Dextrone, Gramoxone, Herbaxon, Herboxone, Pillarxone, Pillarquat, Total, and Toxer and was previously sold under the trade names Esgram, Goldquat, Dexuron, Sweep, and Weedol. It is also known by the code names PP-148 and PP-910.

The usual paraquat formulation available is as the dichloride salt form. Other forms of the compound are the cationic form (bipyridylium ion) and the dimethyl sulfate form. To increase the herbicidal action, it is often formulated with surface-acting agents as an aqueous solution. Commercial products are available as granular, solid, and soluble concentrate preparations. In some commercial preparations paraquat is combined with diquat and sold under the trade names Actor, Herbaxon, Pregalone, Priglone, and Weedol. In these preparations paraquat is present as the dichloride or dimethyl sulfate salt and is very stable under alkaline conditions. It has no appreciable vapor pressure.

Paraquat is one of the most specific pulmonary toxicants known. It has been the subject of intensive international scrutiny because it has been responsible for severe and often fatal poisonings in humans. Many countries have effectively banned or severely restricted paraquat use because of the large number of reported accidental and suicidal fatalities. Diquat, the analogue of paraquat, is considerably less potent than paraquat as a pulmonary toxicant, but may also cause severe acute and chronic poisoning.

If used according to the manufacturer’s instructions on the label, paraquat is a safe agricultural chemical because with routine agricultural or commercial use little of the diluted material is absorbed across intact skin or becomes systemic by inhalation of the spray. The aerosol particles generated are too large to enter into the lower airways. The most common ailments resulting from inhalation of the aerosol are sore throat and nosebleeds, but systemic toxicity is rare. Injury can become severe if prolonged and excessive contact with the chemical occurs. Most occupational injuries reported are caused by irritation and corrosive effects to the mucous membranes, cornea, and skin.

TOXIC DOSE

In animals, paraquat shows a moderate degree of toxicity. The oral median lethal dose (LD₅₀) for various species ranges from 22 to 262 mg/kg. Specifically the oral LD₅₀ for dogs is 25 to 50 mg/kg, and for cats it is 40 to 50 mg/kg.² Most cases of poisoning in domestic animals are caused by ingestion of paraquat-contaminated vegetation, access to spills or improperly stored or disposed of material, or as a result of malicious poisoning.³ Ingestion of paraquat in toxic doses causes similar clinical signs and pathological lesions in humans, monkeys, rats, dogs, and cats.⁴ Most of the accidental or suicidal poisonings have been reported in humans, whereas most of the experimental data on paraquat toxicosis have come from animal studies.

Paraquat causes rapid leaf desiccation when applied to plants. Photochemical degradation occurs on plant surfaces rather than in plant metabolism. Methylamine hydrochloride and 4-carboxyl-1-(methyl)pyridinium chloride are identified products of paraquat photodegradation.⁵ No cases of residual toxicity have been reported from ingestion of paraquat-treated plant products in either humans or animals. Once paraquat has reached the soil, absorption by soil components makes it biologically unavailable, and it is then considered of little toxic consequence to plants or animals.

TOXICOKINETICS

Pulmonary absorption

Paraquat is selectively sequestered in the lung’s type I and II alveolar cells and in Clara cells by an active energy-dependent process (Figure 68-1), resulting in the lungs having the highest paraquat retention; at 4 hours, the concentration is 10 times higher than in other selective sites, and by 4 to 10 days after exposure paraquat concentrations in the lungs are 30 to 80 times greater than in the plasma.⁷ Experimental studies have shown a diphasic efflux of the paraquat in lungs with a rapid-phase half-life of 2.6 minutes and a slow-phase half-life of 356 minutes. The slow phase represents the storage pool of paraquat in the lungs and is probably responsible for its pulmonary toxicity.

Figure 68-1. Proposed biochemical mechanism of paraquat toxicity.

(Modified from Lewis CPL, Nemery B: Pathophysiology and biochemical mechanisms of the pulmonary toxicant of paraquat. In Bismuth C, Hall A, editors: Paraquat poisoning, New York, 1995, Marcel Dekker.)

MECHANISMs OF TOXICITY

The mechanisms of toxic action of paraquat have been extensively studied in animals. Paraquat participates in cyclic reduction-oxidation reactions in biological systems. The compound readily undergoes a single-electron reduction in tissues (plant and animal), forming a free radical. In an aerobic environment the generated free radical is soon oxidized by molecular oxygen, generating the superoxide radical (O₂-). The reoxidized paraquat again accepts another electron, and the reaction continues in a catalytic manner (Figure 68-1).

Lung tissue acquires much higher concentrations of paraquat in all animal species studied, including humans. Biochemical studies have shown that paraquat is actively taken up by the alveolar cells through a diamine-polyamine transport system,⁸ where it undergoes the one-electron reduction described previously. This reaction leads to two partially toxic consequences. The first is the generation of the superoxide radical, and the second is the oxidation of cellular NADPH, which is the major source of reducing equivalences for the intracellular reduction of paraquat.

Generation of the superoxide radical can lead to more toxic forms of reduced oxygen, hydrogen peroxide, and hydroxyl radicals. Hydroxyl radicals have been implicated in the initiation of the membrane damage by lipid peroxidation, depolymerization of hyaluronic acid, inactivation of proteins, and damage to DNA (Figure 68-1). The resulting cellular membrane damage effectively reduces the functional integrity of the cell, affects efficient gas transport, and damages respiratory exchange, causing respiratory impairment. In the lung tissue, this toxic damage is further exacerbated by the availability of oxygen.

CLINICAL SIGNS

Paraquat is an irritant and a vesicant and thus can cause severe local toxicity by topical exposure; it causes erythema, blistering, irritation, and ulceration of the skin. Eczematous dermatitis has been reported in paraquat-exposed experimental animals. Direct contact with concentrated paraquat solutions produces localized discoloration or a transverse band of white discoloration affecting the nail plate. If paraquat is splashed in the eyes, severe corneal inflammation can occur and proceeds to corneal ulceration and secondary bacterial infection. In uncomplicated cases full recovery is possible.

Acute poisoning in animals is almost always the result of ingestion of the compound. The signs of toxicosis vary widely depending on the dose ingested. The course of the disease can be divided into three phases.

In the initial phase lesions from the caustic action of the herbicide are seen. These lesions lead to the development of pain associated with the gastrointestinal tract. Vomiting always occurs in dogs, even in the absence of the emetic additives often found in herbicide formulations. The corrosive action of the compound can lead to abdominal pain and diarrhea. Animals with lesions in the oral cavity and gastrointestinal tract are aphagic and may require parenteral nutrition. Experimental studies using fiber optic esoph-agogastroscopy have documented instances of gastric perforation and massive gastrointestinal hemorrhage following oral paraquat exposures.

The second phase typically starts the second to third day following ingestion and includes development of renal failure and hepatocellular necrosis. Renal insufficiency is caused partly by hypovolemic conditions resulting from fluid loss (diarrhea and vomiting), and also from direct renal injury from paraquat itself. The renal injury is generally a pure tubulopathy and can progress to full recovery without sequel. In some paraquat-poisoned animals, full return to normal renal function can occur by the time of death due to other organ damage. The liver lesions seen in these animals are centrilobular hepatocellular necrosis.

Delayed development of pulmonary fibrosis is the characteristic and hallmark lesion of the third phase of paraquat poisoning; it is responsible for the poor prognosis in acute poisoning cases. Both clinically and radiographically, this effect appears several days after ingestion. In experimental animals, the weight of the lung is increased after a single paraquat exposure.

The acute pulmonary toxicity of paraquat seen in animals occurs in two stages. Initially, alveolar epithelial cells are severely damaged, and their disintegration results in a completely denuded alveolar basement membrane. Pulmonary edema sets in, leading to severe respiratory impairment that usually results in death. Animals that survive this initial destructive stage progress to a proliferative stage in which extensive fibrosis of the lung tissue occurs.⁷

In subacute or chronic paraquat poisoning, low doses can induce hyperplasia of the type II cells through which the lung attempts to repair the damaged epithelium. With ingestion of a single high dose of paraquat, the earlier structural changes occur in type I alveolar cells and are characterized by cellular and mitochondrial swelling, increased numbers of mitochondria, and the appearance of dark granules in the cytoplasm. In these animals interstitial lesions extend inexorably. The diagnosis of pulmonary fibrosis in humans can in fact be made by pulmonary function testing well before PO₂ decreases become evident.

Radiological changes do not always parallel the severity of clinical effects.⁷ Thus thoracic radiographs of poisoned animals may be normal, particularly in animals that die acutely from multiorgan failure following ingestion of paraquat. Development of pulmonary fibrosis leads to refractory hypoxemia, resulting in death over a period of a few days to several weeks. Various therapeutic modalities, including spontaneous and artificial ventilation, have little success in delaying the fatal outcome in animals.

In the final stages of fatal paraquat poisoning, when sepsis has not set in, decerebration occurs during mechanical ventilation, characterized by an inspired oxygen fraction (FiO₂) of 100% and an arterial oxygen tension (PaO₂) of less than 30 mm Hg.

In cases of massive ingestion of the compound (>55 mg/kg), animals survive less than 4 days and die of cardiogenic shock. Acidosis develops in such cases. Alveolitis is also observed, with clinical signs of acute noncardiogenic pulmonary edema. At necropsy, lesions are often seen in the gastrointestinal tract, adrenal glands, renal tubules, and hepatocytes.⁷