Herbicides are substances that are used to kill or control the growth of unwanted plants.
- Herbicides are classified as pesticides, defined by the U.S. Environmental Protection Agency (EPA) as any substance intended for preventing, destroying, or repelling any pest.
- The term “pesticides” also applies to fungicides, rodenticides, bactericides, and insecticides.
- In the past few decades, the production and use of modern herbicides have increased faster than for any other class of pesticides:
- > 2× that of insecticides
- > 3× that of fungicides
- Human effects of herbicides are caused by the:
- Method of application (skin exposure is the most common)
- Mode of action
- 1st nonselective contact herbicide (a bipyridyl compound)
- Rapidly acting herbicide, causing limited injury in spray or dermal exposure, but highly fatal in accidental or intentional ingestion
- Leading cause of fatal poisoning in many parts of Asia, Pacific nations, and the Americas
- 1 of only 2 pesticides still used in the United States that are banned in the European Union, China, and Brazil
Rules in the United States:
- For “restricted commercial use”
- Safety features to reduce toxicity:
- Blue coloration/dye to keep it from being confused with beverages
- Sharp odor
- Agent added to cause vomiting if ingested
- Mechanism of toxicity: reactive oxygen species are formed → nicotinamide adenine dinucleotide phosphate (NADPH) depletion and lipid peroxidation → cellular damage → mitochondrial damage → apoptosis
- Within hours to days, multiorgan failure can occur, as paraquat is distributed to other tissues within 6 hours of ingestion.
- Target tissues (have high oxygen and energy requirements): lung, kidney, liver, heart
- After ingestion → immediate pain and swelling of the mouth and throat
- Followed by:
- Oropharyngeal ulcerations: “paraquat tongue”
- Abdominal pain
- Diarrhea (may be bloody)
- GI bleeding
- Dyspnea (from pulmonary edema)
- Hemoptysis (from hemorrhage)
- Can progress to pulmonary fibrosis over days to weeks
- Severity of lung involvement correlates with outcome.
- Renal failure
- People with large ingestions of paraquat (> 30 mL of 20%–24% paraquat formulation) are not likely to survive.
- Mainly clinical by known exposure and symptoms
- Laboratory testing:
- Urine dithionite test:
- Confirms exposure
- Survival is expected if test is negative.
- Plasma paraquat
- Urine dithionite test:
- Additional tests:
- Electrolytes and renal function:
- Fast rate of increase in creatinine points to a poor outcome.
- An increase > 4.3 μmol/L per hour in 6 hours = increased mortality
- Blood gas:
- Alkalosis initially due to vomiting
- Acidosis, both respiratory and metabolic, follows (due to pulmonary edema, diarrhea, acute kidney injury, and hypotension).
- Lactic acid: High levels correlate with poor prognosis.
- Chest X-ray:
- Check for lung injuries.
- Check for mediastinal involvement (mediastinitis, pneumomediastinum).
- Electrolytes and renal function:
- Resuscitation and supportive care:
- IV fluids
- Excessive oxygen administration should be avoided because it may worsen paraquat toxicity.
- Remove all contaminated clothing.
- Wash all areas of skin.
- Flush eyes if contact occurs.
- Activated charcoal (AC)
- Nasogastric suction with gastric lavage may be considered for ingestions that present at < 1 hour.
- Hemodialysis/hemoperfusion for patients with acute renal failure, large doses, or pulmonary edema
- No proven antidote exists for paraquat poisoning but patients with systemic toxicity may benefit from:
- High-dose glucocorticoids
Agent Orange Exposure
- A tactical herbicide (a defoliant) used by the U.S. military in the Vietnam War to eliminate forest cover and crops
- Chemical was transported in storage drums with orange stripe/band.
- 60% of herbicides used in the Vietnam War
- Main ingredients: 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4,5-trichlorophenoxyacetic acid (2,4,5-T)
- Has trace 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD):
- By-product of herbicide production
- Toxic even in small amounts
- Can last in natural environment for years
- Dangerous to humans—classified as a human carcinogen
- A common exposure is by ingestion, as it accumulates in the food chain (most likely in fish, which are regulated in the United States).
- Effects of TCCD are mediated via aryl hydrocarbon receptor (AhR) signaling pathway (which modulates gene expression):
- Induces cytochrome P450 1A1 (CYP1A1)
- Disrupts normal hormone signaling pathways
- Causes reproductive and developmental defects
- Leads to immunotoxicity
- Leads to liver toxicity
- Contributes to tumorigenesis
- Darkening of the skin
- Severe acne-like skin disease called chloracne
- Muscular dysfunction
- Hormone disruption
- Birth defects due to parental exposure
- Long-lasting impacts on pregnancy:
- Abnormal fetal development
- Craniofacial deformities
- Extremity deformities
- Type 2 diabetes
- Liver disease
- Heart disease
- Amyloid light-chain (AL) amyloidosis
- Parkinson’s disease
- Porphyria cutanea tarda
- Multiple myeloma
- Lung cancer
- Soft tissue sarcoma
- Non-Hodgkin lymphoma (NHL)
- Hodgkin lymphoma
- Chronic B-cell leukemias
- Prostate cancer
Diagnosis and management
- Diagnosis is clinical, based on exposure and symptoms.
- Laboratory testing for liver function is indicated.
- Adipose tissue and blood serum analyzed for the presence of TCDD are not routinely recommended due to being expensive and time-consuming.
- Workup of long-term effects depends on presentation.
- Decontamination and removal of exposure
- No antidote exists.
- Supportive care for symptoms
- N-(Phosphonomethyl) glycine: most common brand name is “Round-Up”
- First used as an herbicide in 1971
- Classified as nonselective herbicide
- Applied directly to plant foliage
- Widely used in agriculture, forestry, industrial weed control, lawn, garden, and aquatic environments
- Inhibits enolpyruvylshikimate-3-phosphate synthase (EPSP), blocking the synthesis of aromatic amino acids (e.g., tyrosine and phenylalanine) → ↓ plant growth
- In humans, toxicity of glyphosate is due to uncoupling of mitochondrial oxidative phosphorylation.
- Relatively low toxicity in mammals, with majority of toxicity (in large doses) due to suicide attempts
Mild to moderate toxicity:
- Dermal exposure: eye and skin irritation
- Inhalation exposure: oral/nasal discomfort, tingling, and throat irritation
- Erosion of the GI tract
- GI hemorrhage
- Altered level of consciousness
- Hepatic dysfunction
- Oliguria, renal failure, acidosis, and hyperkalemia
Diagnosis and management
- Diagnosis is clinical, from exposure and presenting symptoms.
- Glyphosate measurement in blood or urine can be done but is not necessary.
- Aggressive supportive therapy
- Decontamination: Gastric lavage can be administered or AC can be given if patients without buccal irritation or burns present < 1 hour after ingestion.
- Hemodialysis and IV lipid emulsion have been used for severe toxicity.
- No known specific antidote
- Irreversible cholinesterase inhibitors
- Examples of organophosphate (OP) chemicals:
- Herbicides: tribufos (DEF), merphos
- Insecticides: malathion, parathion, diazinon, fenthion, dichlorvos, chlorpyrifos, ethion
- Nerve gases: soman, sarin, tabun, VX
- Ophthalmic agents: echothiophate, isoflurophate
- Anthelminthics: trichlorfon
- Industrial chemical (plasticizer): tricresyl phosphate
- Inhibits the cholinesterase enzyme in the synaptic cleft
- Irreversible phosphorylation of acetylcholinesterase (AChE) leading to inhibition of the AChE, which is present in:
- Parasympathetic and sympathetic ganglia
- Parasympathetic muscarinic terminal junctions
- Sympathetic fibers located in sweat glands
- Nicotinic receptors at the skeletal neuromuscular junction
- Persistently ↑ acetylcholine levels due to AChE inhibition leads to ↑ neurotransmitter signaling.
- Presents as a cholinergic toxidrome
- Pinpoint pupils
- Sweating, salivation
- CNS stimulation then depression
- Muscle fasciculations, weakness, paralysis
- Death from respiratory failure
- Primarily a clinical diagnosis based on history and examination
- Some organophosphorus agents have a distinct petroleum or garlic-like odor.
- Can be confirmed by measurement of cholinesterase activity:
- RBC AChE and plasma cholinesterase (PChE) or butyrylcholinesterase (BuChE) levels can both be used.
- Acetylcholinesterase is a more useful marker of organophosphate poisoning.
- Airway, breathing, and circulation (ABC) assessment
- Removal of clothes, irrigation or washing of exposed areas
- AC (within an hour of ingestion)
- PPE: Use neoprene gloves and gowns, as hydrocarbons can penetrate nonpolar substances such as latex and vinyl.
- Charcoal cartridge masks for respiratory protection
- Irrigate the eyes of patients who have had ocular exposure.
- Supportive care:
- IV fluids
- Avoid succinylcholine because it is metabolized by AChE.
- May be necessary in cases of respiratory distress due to laryngospasm, bronchospasm, bronchorrhea, or seizures
- Seizures: Give benzodiazepines.
- Antidotal therapy:
- Binds to muscarinic receptors, temporarily blocking them and reducing cholinergic effect(s)
- Dosing titrated to clearance of respiratory secretions and cessation of bronchoconstriction
- Pralidoxime (2-PAM):
- Effective in both muscarinic and nicotinic effects
- Reactivates AChE but has a transient inhibitory effect on the enzyme, so should be given in conjunction with atropine
SLUDGE BBB (muscarinic effects):
- Lacrimation (crying is key feature)
- Defecation (diarrhea)
- GI cramping (distress)
DUMBELS (muscarinic effects):
- Toxidrome: group of clinical signs and symptoms associated with toxic ingestion or exposure. There are 5 traditional toxidromes: anticholinergic, cholinergic, opioid, sympathomimetic, and sedative-hypnotic. Toxidromes often arise from ingestion of overdose amounts, accumulation of medications with resultant elevated serum levels, adverse drug reactions, or interactions between ≥ 2 medications. Diagnosis is by clinical findings based on medication and exposure history and physical examination.
- Insecticide poisoning: Insecticides are chemical substances used to kill or control insects. Important insecticides include dichlorodiphenyltrichloroethane (DDT), organophosphates, and carbamates. Exposure to DDT results in neurotoxicity and endocrine disruption. Organophosphates and carbamates produce cholinergic effects by inhibiting AChE. Organophosphates bind the enzyme irreversibly, while carbamates inhibit the enzyme for < 24 hours. Diagnosis is by history and clinical findings. Management involves decontamination, supportive care, and symptom control. For cholinergic toxidrome, atropine and pralidoxime are given to reverse the effects of cholinergic excess.
- Caustic ingestion: Acidic or alkaline substances damage tissues severely if ingested. Alkali ingestion typically damages the esophagus. Acids cause more severe gastric injury. In large amounts and high concentrations, caustic ingestion also leads to severe injuries such as shock, abdominal rigidity, respiratory distress, and/or altered mental status. Diagnosis is by laboratory tests, abdominal and chest imaging, and endoscopy. Management involves stabilizing the patient, decontamination, and supportive therapy. Severe injury may require surgery.
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