Chemicals and Heavy Metals / Pesticide and Organophosphate Toxicity - What is It?
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Organophosphate Toxicity - What is it?

Globally, some 2.5 million tons of pesticides are applied annually—most targeted at agricultural crops. Approximately 250 basic chemicals made by more than 50 companies are registered for use as pesticides in food and feed production in the United States.

Organophosphate (OP) compounds are a diverse group of chemicals used in both domestic and industrial settings. Examples of organophosphates include: insecticides (malathion, parathion, diazinon, fenthion, dichlorvos, chlorpyrifos, ethion), nerve gases (soman, sarin, tabun, VX), ophthalmic agents (echothiophate, isoflurophate), and antihelmintics (trichlorfon). Herbicides (tribufos [DEF], merphos) are tricresyl phosphate–containing industrial chemicals.

Organophosphate compounds were first synthesized in the early 1800s when Lassaigne reacted alcohol with phosphoric acid. Shortly thereafter in 1854, Philip de Clermount described the synthesis of tetraethyl pyrophosphate at a meeting of the FrenchAcademy of Sciences. Eighty years later, Lange, in Berlin, and, Schrader, a chemist at Bayer AG, Germany, investigated the use of organophosphates as insecticides. However, the German military prevented the use of organophosphates as insecticides and instead developed an arsenal of chemical warfare agents (ie, tabun, sarin, soman). A fourth agent, VX, was synthesized in England a decade later. During World War II, in 1941, organophosphates were reintroduced worldwide for pesticide use, as originally intended.

Massive organophosphate intoxication from suicidal and accidental events, such as the Jamaican ginger palsy incident in 1930, led to the discovery of the mechanism of action of organophosphates. In 1995, a religious sect, Aum Shinrikyo, used sarin to poison people on a Tokyo subway. Mass poisonings still occur today; in 2005, 15 victims were poisoned after accidentally ingesting ethion-contaminated food in a social ceremony in Magrawa, India.

Nerve agents have also been used in battle, notably in Iraq in the 1980s. Additionally, chemical weapons still pose a very real concern in this age of terrorist activity.

Pesticides in Food

The main categories of chemical pesticides are chlorinated hydrocarbons, such as DDT and dieldrin; organophosphates, such as parathion; carbamates, such as carbaryl and aldicarb; and inorganic pesticides made from basic elements, such as copper, lead, arsenic, and mercury. Organophosphates, the most common group in use today, work by interfering with the normal transmission of nerve impulses. Although they do not persist in the environment like chlorinated hydrocarbons, organophosphates as a class are highly toxic, which is why some were produced as nerve agents during World War II. Alarmed by the potential of these chemicals to harm the developing nervous systems of infants and children, environmental groups have called for a ban on many of them. Of all these substances, only copper is allowable under organic certification standards, and its use is limited to highly controlled conditions.

As a result of growing popular concern about pesticides, the Food Quality Protection Act of 1996 (FQPA)—born in a rare burst of bipartisanship on Capitol Hill—passed both houses of Congress in a period of eight days without a dissenting vote. The law mandated a broad overhaul of federal pesticide regulations to better assess and prevent risks to public health, particularly for children. It directed the Environmental Protection Agency (EPA) to apply "an additional tenfold margin of safety" for infants and children except when "reliable data" indicate that a less stringent standard would be safe.

The law requires the EPA to reexamine the allowable levels of hundreds of pesticides on individual crops and ultimately come up with about 9700 new application-level determinations. It also requires the EPA to take into account the aggregate risk from different sources—drinking water and pest control efforts in the home, for example, as well as food residues—and to consider the cumulative effects of pesticides that act in a similar manner.

The FQPA mandates that pesticides be screened both as carcinogens and as endocrine disrupters. Endocrine disrupters are chemicals that imitate the body’s hormonal system and consequently disrupt chemical communication. Many scientists believe that the alarming rise in hormonally driven cancers, such as cancer of the breast and prostate, may be due to the ability of many synthetic chemicals to act as endocrine disrupters, and particularly to the ability of synthetic chemicals to imitate estrogen. The reported significant decline in sperm count of the average male over the last 60 years is also likely to be due to endocrine disrupters.

The FQPA has been the subject of an intense battle since the EPA moved to begin implementation. The stakes for both industry and the general public are huge. Depending on how tough the EPA is in restricting pesticide use, farmers and other users may have to switch to more expensive alternatives. The chemical companies that produce pesticides have been conducting a high-pressure campaign to scare farmers with warnings that "sooner or later, virtually all pesticides and pesticide uses will be jeopardized." All seven environmental and farm worker representatives to the EPA advisory panel on the reassessment process resigned en masse, charging that pesticide industry and agribusiness interests had "hijacked" the process.

The relatively simple goal of ensuring Americans that their food supply is safe turns out to be difficult to translate into practice. "The science here is enormously challenging," commented a senior EPA official. "The act requires us for the first time ever to look at all the exposure pathways for these chemicals. . . . All of it is very controversial."

An analysis made by the Environmental Working Group of more than 110,000 government-tested food samples and detailed government data on children’s food consumption found that multiple pesticides known or suspected to cause brain and nervous system damage, cancer, or hormone interference are common in foods many children consume.

• More than a quarter of a million U.S. children aged 1–5 ingest a combination of 20 different pesticides every day. More than 1 million preschoolers eat at least 15 pesticides on a given day. Overall, 20 million children aged 5 and under eat an average of 8 pesticides every day.

• Some 610,000 children aged 1–5 consume a dose of neurotoxic organophosphate insecticides that the government deems unsafe. More than half of these unsafe exposures are from one pesticide—methyl parathion.

• Preschoolers’ eating habits are even more dramatically different from those of adults than previous data indicated. When weight is taken into account, kids aged 1–5 consume 30 times more apple juice, 21 times more grape juice, and 7 times more orange juice than the average person in the population.

• Ten years after the Alar scare, apples are still loaded with pesticides. The average apple has residues of four pesticides after it is washed and cored. Some have residues of as many as ten. More than half of the children exposed to an unsafe dose of organophosphate insecticides get it from apples, apple sauce, or apple juice.

A Consumers Union report in February 1999 confirmed the findings of the Environmental Working Group study. Using U.S. Department of Agriculture statistics based on 27,000 food samples from 1994 to 1997, Consumer Reports looked at the foods children are most likely to eat. Almost all the foods tested had pesticide residues within legal limits, but parathion on peaches, green beans, pears, and apples accounted for most of the total toxicity on the foods analyzed.

A preliminary look at the data from the 1998 pesticide residue monitoring program of the Food and Drug Administration (FDA), which studied over 7000 food samples looking for detectable residues of 355 pesticides, gives no reason for hope. A third of the foods tested had detectable residues, and almost 2% had residues in excess of allowable levels. Almost of half the fruits showed residues, and 1% of domestically grown fruits (and almost 3% of imported fruits) had illegal residue levels. Blackberries, strawberries, kiwis, and melons had particularly high levels. The residues on vegetables exceeded legal levels for 1.4% of the domestically raised vegetables and for 3.6% of imported ones. Particularly frequent violators were peppers, peas, string beans, potatoes, collards, and kale.

No organic foods were listed in the FDA study. The January 1998 Consumer Reports article on pesticide residues, "Greener Greens? The Truth About Organic Food" (pp. 12–17) concluded: "Our side-by-side tests of organic, green-labeled, and conventional unlabeled produce found that organic foods had consistently minimal or nonexistent pesticide residue. . . . Buying organic food promotes farming practices that really are more sustainable and better for the environment—less likely to degrade soil, impair ecosystems, foul drinking water, or poison farmworkers" (emphasis added).

Pathophysiology

The primary mechanism of action of organophosphate pesticides is inhibition of carboxyl ester hydrolases, particularly acetylcholinesterase (AChE). AChE is an enzyme that degrades the neurotransmitter acetylcholine (ACh) into choline and acetic acid. ACh is found in the central and peripheral nervous system, neuromuscular junctions, and red blood cells (RBCs).

Organophosphates inactivate AChE by phosphorylating the serine hydroxyl group located at the active site of AChE. The phosphorylation occurs by loss of an organophosphate leaving group and establishment of a covalent bond with AChE.

Once AChE has been inactivated, ACh accumulates throughout the nervous system, resulting in overstimulation of muscarinic and nicotinic receptors. Clinical effects are manifested via activation of the autonomic and central nervous systems and at nicotinic receptors on skeletal muscle.

Once an organophosphate binds to AChE, the enzyme can undergo 1 of the following 3 processes:

• Endogenous hydrolysis of the phosphorylated enzyme by esterases or paraoxonases
• Reactivation by a strong nucleophile such as pralidoxime (2-PAM)
• Complete binding and inactivation (aging)

Organophosphates can be absorbed cutaneously, ingested, inhaled, or injected. Although most patients rapidly become symptomatic, the onset and severity of symptoms depend on the specific compound, amount, route of exposure, and rate of metabolic degradation.

Frequency

United States

The American Association of Poison Control Centers' National Incidence Report indicates that pesticide injuries number 102,754 persons annually. Nationally, 4.2% of poisonings are due to insecticides. In 2007, Sudakin et al reported an overall decline in poison center–recorded exposures from 1995 to 2004 because of the United States Environmental Protection Agency phase out of common household and agricultural OP agents (ie, diazinon, chlorpyrifos).¹

International

Pesticide poisonings are among the most common modes of poisoning fatalities. In countries such as India, OPs are easily accessible and, therefore, a source of both intentional and unintentional poisonings.

Mortality/Morbidity

• Worldwide mortality studies report mortality rates from 3-25%. The compounds most frequently involved include malathion, dichlorvos, trichlorfon, and fenitrothion/malathion.
• Mortality rates depend on the type of compound used, amount ingested, general health of the patient, delay in discovery and transport, insufficient respiratory management, delay in intubation, and failure in weaning off ventilatory support.
• Complications include severe bronchorrhea, seizures, weakness, and neuropathy. Respiratory failure is the most common cause of death.

Clinical

History

Signs and symptoms of organophosphate poisoning can be divided into 3 broad categories, including (1) muscarinic effects, (2) nicotinic effects, and (3) CNS effects.

• Mnemonic devices used to remember the muscarinic effects of organophosphates are SLUDGE (salivation, lacrimation, urination, diarrhea, GI upset, emesis) and DUMBELS (diaphoresis and diarrhea; urination; miosis; bradycardia, bronchospasm, bronchorrhea; emesis; excess lacrimation; and salivation). Muscarinic effects by organ systems include the following:
  • Cardiovascular - Bradycardia, hypotension
  • Respiratory - Rhinorrhea, bronchorrhea, bronchospasm, cough, severe respiratory distress
  • Gastrointestinal - Hypersalivation, nausea and vomiting, abdominal pain, diarrhea, fecal incontinence
  • Genitourinary - Incontinence
  • Ocular - Blurred vision, miosis
  • Glands - Increased lacrimation, diaphoresis
• Nicotinic signs and symptoms include muscle fasciculations, cramping, weakness, and diaphragmatic failure. Autonomic nicotinic effects include hypertension, tachycardia, mydriasis, and pallor.
• CNS effects include anxiety, emotional lability, restlessness, confusion, ataxia, tremors, seizures, and coma.

Physical

Note that clinical presentation may vary, depending on the specific agent, exposure route, and amount. Symptoms are due to both muscarinic and nicotinic effects. Interestingly, a 2007 retrospective review of 31 OP poisoned children performed by Levy-Khademi et al described that, in contrast to adults, the most common presentations were seizure and coma with relatively less muscarinic or nicotinic findings.² The authors hypothesized the difference may be due to difficulty in detecting muscarinic findings in infants (eg, crying) and ingestion of contaminated produce instead of OP directly.

• Vital signs: Depressed respirations, bradycardia, and hypotension are possible symptoms. Alternatively, tachypnea, hypertension, and tachycardia are possible. Hypoxia should be monitored for with continuous pulse oximetry.
• Paralysis
  • Type I: This condition is described as acute paralysis secondary to continued depolarization at the neuromuscular junction.
  • Type II (intermediate syndrome): Intermediate syndrome was described in 1974 and is reported to develop 24-96 hours after resolution of acute organophosphate poisoning symptoms and manifests commonly as paralysis and respiratory distress. This syndrome involves weakness of proximal muscle groups, neck, and trunk, with relative sparing of distal muscle groups. Cranial nerve palsies can also be observed. Intermediate syndrome persists for 4-18 days, may require mechanical ventilation, and may be complicated by infections or cardiac arrhythmias. Although neuromuscular transmission defect and toxin-induced muscular instability were once thought to play a role, this syndrome may be due to suboptimal treatment.
  • Type III: Organophosphate-induced delayed polyneuropathy (OPIDP) occurs 2-3 weeks after exposure to large doses of certain OPs and is due to inhibition of neuropathy target esterase. Distal muscle weakness with relative sparing of the neck muscles, cranial nerves, and proximal muscle groups characterizes OPIDP. Recovery can take up to 12 months.
• Neuropsychiatric effects: Impaired memory, confusion, irritability, lethargy, psychosis, and chronic organophosphate-induced neuropsychiatric disorders have been reported. The mechanism is not proven.
• Extrapyramidal effects: These are characterized by dystonia, cogwheel rigidity, and parkinsonian features (basal ganglia impairment after recovery from acute toxicity).
• Other neurological and/or psychological effects: Guillain-Barré–like syndrome and isolated bilateral recurrent laryngeal nerve palsy are possible.
• Ophthalmic effects: Optic neuropathy, retinal degeneration, defective vertical smooth pursuit, myopia, and miosis (due to direct ocular exposure to organophosphates) are possible.
• Ears: Ototoxicity is possible.
• Respiratory effects: Muscarinic, nicotinic, and central effects contribute to respiratory distress in acute and delayed organophosphate toxicity.
• Muscarinic effects: Bronchorrhea, bronchospasm, and laryngeal spasm, for instance, can lead to airway compromise.
• Nicotinic effects: These effects lead to weakness and paralysis of respiratory oropharyngeal muscles.
• Central effects: These effects can lead to respiratory paralysis.
• Rhythm abnormalities: Sinus tachycardia, sinus bradycardia, extrasystoles, atrial fibrillation, ventricular tachycardia, and ventricular fibrillation (often a result of, or complicated by, severe hypoxia from respiratory distress) are possible.
• Other cardiovascular effects: Hypotension, hypertension, and noncardiogenic pulmonary edema are possible.
• GI manifestations: Nausea, vomiting, diarrhea, and abdominal pain may be some of the first symptoms to occur after organophosphate exposure.
• Genitourinary and/or endocrine effects: Urinary incontinence, hypoglycemia, or hyperglycemia are possible.

Laboratory Studies

• Organophosphate (OP) toxicity is a clinical diagnosis. Confirmation of organophosphate poisoning is based on the measurement of cholinesterase activity; typically, these results are not readily available. Although RBC and plasma (pseudo) cholinesterase levels can both be used, RBC cholinesterase correlates better with CNS acetylcholinesterase (AChE) and is, therefore, a more useful marker of organophosphate poisoning.
  • If possible, draw blood for measurement of RBC and plasma cholinesterase levels prior to treatment with pralidoxime (2-PAM). Monitoring serial levels can be used to determine a response to therapy.
  • RBC AChE represents the AChE found on RBC membranes, similar to that found in neuronal tissue. Therefore, measurement more accurately reflects nervous system OP AChE inhibition.
  • Plasma cholinesterase is a liver acute-phase protein that circulates in the blood plasma. It is found in CNS white matter, the pancreas, and the heart. It can be affected by many factors, including pregnancy, infection, and medical illness. Additionally, a patient's levels can vary up to 50% with repeated testing.
  • RBC cholinesterase is the more accurate of the 2 measurements, but plasma cholinesterase is easier to assay and is more readily available.
• Cholinesterase levels do not always correlate with severity of clinical illness.
• The level of cholinesterase activity is relative and is based on population estimates. Neonates and infants have baseline levels that are lower than adults. Because most patients do not know their baseline level, the diagnosis can be confirmed by observing a progressive increase in the cholinesterase value until the values plateau over time.
• Falsely depressed levels of erythrocyte cholinesterase can be found in pernicious anemia, hemoglobinopathies, use of antimalarial drugs, and oxalate blood tubes.
• Falsely depressed levels of plasma cholinesterase are observed in liver dysfunction, low-protein conditions, neoplasia, hypersensitivity reactions, use of certain drugs (succinylcholine, codeine, morphine), pregnancy, and genetic deficiencies.
• Other laboratory findings include: leukocytosis, hemoconcentration, metabolic and/or respiratory acidosis, hyperglycemia, hypokalemia, hypomagnesemia and elevated amylase and liver function studies  A retrospective analysis of OP poisoned patients by Liu et al found a direct correlation between the severity of poisoning and mortality and the presence of pretreatment metabolic and respiratory acidosis.³

Imaging Studies

A chest radiograph may reveal pulmonary edema but typically adds little to the clinical management of a poisoned patient.

Other Tests

ECG findings include prolonged QTc interval, elevated ST segments, and inverted T waves. Although sinus tachycardia is the most common finding in the poisoned patient, sinus bradycardia, and PR prolongation can develop with increasing toxicity due to excessive parasympathetic activation.

Procedures

• Endotracheal intubation and mechanical ventilation may be necessary in patients with organophosphate poisoning for airway protection and management of bronchorrhea and seizures.
• Central venous access and arterial lines may be needed to treat the patient with organophosphate toxicity who requires multiple medications and blood-gas measurements.

Additional Information

Chemical Terrorism Agents and Syndromes. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, Click here.

Pub-Med - Organophosphorus ester-induced chronic neurotoxicity - Organophosphorus compounds are potent neurotoxic chemicals.......

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Risk Of Parkinson's Disease Increases With Pesticide Exposure And Head Trauma - Science Daily

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