2,4-Dichlorophenoxyacetic acid (2,4-D) and its chemical derivatives are widely used herbicides. A large number of formulations are available containing different 2,4-D salts (sodium, amine, alkylamine, and alkanolamine) and esters (propanoic acid, butanoic acid, and other alkoxy compounds). The most frequently used agricultural product, based upon 2008 California pesticide use data, is the dimethylamine salt of 2,4-D. Current California registration data show 257 formulations for the dimethylamine salt, with concentrations ranging from 0.29% (home use products) to 46.8% (agricultural formulations). Concentrated formulations of 2,4-D esters are likely to contain petroleum solvents (identified on the “first aid” statement on the pesticide label); even though these solvents are considered “inert” ingredients because they are not pesticides, they may have their own innate toxicity (see “Toluene and Xylene”, and “Hydrocarbons”).
Agent Orange was a mixture of the chlorophenoxy herbicides 2,4-D (dichlorophenoxyacetic acid) and 2,4,5-T (trichlorophenoxyacetic acid) that also contained small amounts of the highly toxic contaminant TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin [See Dioxins]), derived from the process of manufacturing 2,4,5-T. Manufacture of 2,4-D by chlorination of phenol does not produce TCDD. Populations involved in the manufacture or handling of 2,4,5-T may show elevated levels of TCDD on serum testing and overall increased rates of cancer compared with the general population.
Mechanism of toxicity. In plants, the compounds act as growth hormone stimulators. The mechanism of toxicity is unclear but may involve mitochondrial injury. In animals, cell membrane damage, uncoupling of oxidative phosphorylation, and disruption of acetyl coenzyme A metabolism are found, widespread muscle damage occurs, and the cause of death is usually ventricular fibrillation. Toxicity is markedly increased at doses that exceed the capacity of the renal anion transport mechanism (approximately 50 mg/kg). Massive rhabdomyolysis has been described in human patients, most often in cases involving ingestion of formulations containing more than 10% active ingredient.
Toxic dose. Doses of 2,4-D of 5 mg/kg are reported to have no effect in human volunteer studies. The minimum toxic dose of 2,4-D in humans is 3–4 g or 40–50 mg/kg, and death has occurred after adult ingestion of 6.5 g. Less than 6% of 2,4-D applied to the skin is absorbed systemically, although dermal exposure may produce skin irritation. The degree of dermal absorption may be less with salt formulations than with 2,4-D esters.
Acute ingestion. Vomiting, abdominal pain, and diarrhea are common. Tachycardia, muscle weakness, and muscle spasms occur shortly after ingestion and may progress to profound muscle weakness and coma. Massive rhabdomyolysis, metabolic acidosis, and severe and intractable hypotension have been reported, resulting in death within 24 hours. Neurotoxic effects include ataxia, hypertonia, seizures, and coma. Hepatitis and renal failure may occur.
Dermal exposure to 2,4-D may produce skin irritation. Exposures to formulations containing 2,4,5-T may also produce chloracne. Substantial dermal exposure has been reported to cause a mixed sensory-peripheral neuropathy after a latent period.
Diagnosis depends on a history of exposure and the presence of muscle weakness and elevated ...