2,4-Dichlorophenoxyacetic acid (2,4-D), 2,4,5-trichlorophe-noxyacetic acid (2,4,5-T), and their salts and esters are com-pounds of interest as herbicides used for the destruction of weeds (Figure 56–1). They have been assigned toxicity ratings of 4 or 3, respectively, which place the probable human lethal dosages at 50–500 or 500–5000 mg/kg, respectively.
Because 2,4,5-T is often contaminated with dioxins and other polychlorinated compounds, it is no longer used. It was the com-pound used in “Agent Orange” and caused severe agricultural damage and social disruption.
In humans, 2,4-D in large doses can cause coma and general-ized muscle hypotonia. Rarely, muscle weakness and marked hypotonia may persist for several weeks. In laboratory animals, signs of liver and kidney dysfunction have also been reported with chlorphenoxy herbicides. Several epidemiologic studies performed by the US National Cancer Institute confirmed the causal link between 2,4-D and non-Hodgkin’s lymphoma. Evidence for a causal link to soft tissue sarcoma, however, is considered equivocal.The toxicologic profile for these agents, particularly that of 2,4,5-T, is complicated by the presence of chemical contaminants (dioxins) produced during the manufacturing process . 2,3,7,8-Tetrachlorodibenzo-p-dioxin (dioxin, TCDD) is the mostimportant of these contaminants. Dioxin is a potent animal car-cinogen and a likely human carcinogen.
Glyphosate (N-[phosphonomethyl] glycine, Figure 56–1) is now the most widely used herbicide in the world. It functions as a contact herbicide and is absorbed through the leaves and roots of plants. Because it is nonselective, it may damage important crops even when used as directed. Therefore, genetically modified plants such as soy-bean, corn, and cotton that are glyphosate-resistant have been devel-oped and patented. They are widely grown throughout the world.Glyphosate-related poisoning incidents are commonly reported. Most injuries are minor, although some lethal outcomes have been reported.Glyphosate is a significant eye and skin irritant. It has caused lethal outcomes, although it is far less potent than the bipyridyl herbicides. Although the pure chemical seems to have little persis-tence and lower toxicity than other herbicides, the commercial formulations of glyphosate often contain surfactants and other active compounds that complicate the toxicity of the product. No specific treatment is available for glyphosate toxicity.
Paraquat is the most important agent of this class (Figure 56–1).Its mechanism of action is said to be similar in plants and animals and involves single-electron reduction of the herbicide to free radical species. It has been given a toxicity rating of 4, which places the probable human lethal dosage at 50–500 mg/kg. Lethal human intoxications (accidental or suicidal) have been reported. Paraquat accumulates slowly in the lung by an active process and causes lung edema, alveolitis, and progressive fibrosis. It probably inhibits superoxide dismutase, resulting in intracellular free radical oxygen toxicity.In humans, the first signs and symptoms after oral exposure are hematemesis and bloody stools. Within a few days, however, delayed toxicity occurs, with respiratory distress and the develop-ment of congestive hemorrhagic pulmonary edema accompanied by widespread cellular proliferation. Hepatic, renal, or myocardial involvement may also be evident. The interval between ingestion and death may be several weeks. Because of the delayed pulmo-nary toxicity, prompt removal of paraquat from the digestive tract is important. Gastric lavage, the use of cathartics, and the use of adsorbents to prevent further absorption have all been advocated; after absorption, treatment is successful in fewer than 50% of cases. Oxygen should be used cautiously to combat dyspnea or cyanosis, because it may aggravate the pulmonary lesions. Patients require prolonged observation, because the proliferative phase begins 1–2 weeks after ingestion. Management of severe paraquat poisoning is complex and largely symptomatic. Many approaches have been used, including immunosuppressive therapy to slow or stop the progressive pulmonary fibrosis. None of the currently proposed methods of treatment is universally successful.