A number of organophosphates are systemic insecticides, a property that correlates to some extent with the water solubility (sol) of individual compounds. Examples include demeton (sol 3.3 g/L at 20°C [68°F]), dimethoate (sol 25 g/L at 21°C [69.8°F]), disulfoton (sol 25 mg/L at 23°C [73.4°F]), phosphamidon, and trichlorphon (sol 120,000 mg/L at 20°C [68°F]).
Many highly toxic organophosphates are no longer used, but some, such as methyl parathion, are still used in agriculture. However, even the low toxicity compounds such as diazinon and malathion are no longer sold for household use. Chlorpyrifos was perhaps the insecticide used most frequently by structural pest control operators against cockroaches and other structural pests, but its household use has also been curtailed under FQPA regulations.
The cholinesterase-inhibiting N-methyl carbamates have insecticidal properties. Carbaryl is used extensively because of its slow mammalian toxicity and relatively wide spectrum of activity. Aldicarb (sol 6000 mg/L), carbofuran (sol 320 mg/L), and methomyl (sol 57.9 g/L) are highly water soluble, systemic insecticides with use limited to agriculture. Illegal applications of these compounds do occur occasionally in urban settings. Propoxur is used by structural pest control operators and in ready-to-use home formulations.
Occupational & Environmental Exposure
Organophosphates and carbamates are applied by a variety of techniques from aerial spraying to hand application. Granular and bait formulations significantly reduce exposure so that even highly toxic compounds such as aldicarb (0.5 mg/kg) can be used safely given proper precautions.
Organophosphate compounds show variable dissipation times. Compounds with high vapor pressures, including dichlorvos, naled, and mevinphos, have environmental half-lives measured in hours and may dissipate completely in less than 24 hours. Residues of dimethoate (LD50 180–330 mg/kg) have an environmental half-life ranging from 24 to 48 hours. Phosalone (LD50 82–205 mg/kg) residues, by contrast, have half-lives of 30 days or longer. Many organophosphates degrade rapidly in wet coastal environments but may persistent for prolonged periods in hot, dry climates. Consequently, long reentry intervals (eg, 90 days or more for ethyl parathion on citrus crops) have proved necessary to prevent acute poisoning of field workers.
The risk posed by a given level of residue depends on the crop and work activity. Residues of 7 μg/cm2 of phosalone, for example, cause no cholinesterase inhibition in workers picking citrus and peaches. Levels less than 1 μg/cm2 are associated with poisoning of workers harvesting wine and raisin grapes. A dermal residue transfer coefficient (in units of cm2/h) is used to summarize the relative levels of exposure associated with various agricultural tasks. Among various hand-harvested crops, transfer factors ranged from 5000 to 9000 cm2/h for row crops to 10,000 cm2/h for orchard crops and up to 130,000 cm2/h for hand-labor tasks (cane turning) in production of table grapes. The concept of a transfer coefficient is a useful generalization, but in practice the rate of transfer may vary considerably between fields planted with the same crop.
The available literature contains comparatively few studies on dissipation of carbamate compounds. Environmental fate data required by EPA include basic physical and chemical properties such as the Henry law constant, vapor pressure, water solubility, ultraviolet spectra, and residue data at time of harvest but not residue dissipation studies. However, summary values exist for carbaryl, aldicarb, propoxur, and carbofuran. For propoxur, residual systemic activity has been reported for up to 1 month. Data on carbaryl do not give a half-life but indicate that residues generally dissipate in less than 2 weeks. The half-life of carbofuran leaf residue is reported as longer than 4 days. Aldicarb presents a complicated picture because of its tendency to leach into groundwater. Plants convert aldicarb to systemic sulfoxide and sulfone transformation products, previously associated with episodes of consumer poisoning from watermelons and cucumbers. Variability in dissipation observed in extensive studies on methomyl suggests the need for caution in generalizing from limited data. A study in California established a 0.1 μg/cm2 safe-level for hand labor in methomyl-treated vineyards after an illness episode. Residue monitoring later revealed much longer dissipation times. It was therefore necessary to adjust the hand labor reentry interval from 7 days to 21 days.
Mechanism of Action & Clinical Findings
Organophosphates and carbamates are absorbed easily by inhalation, skin contact, and ingestion; the primary route of occupational exposure is dermal. They differ from one another in lipid solubility and therefore distribution in the body, particularly to the CNS.
Many commercial organophosphates are applied in the-thion (sulfur-containing) form but readily undergo conversion to the -oxon (oxygen-containing) form (Figure 34–1B). Most of the -oxon forms have much greater toxicity than their corresponding -thion analogues. The conversion occurs in the environment, so the residues that crop field workers are exposed to may be more toxic than the pesticide that was applied. Some of the sulfur is released in the form of mercaptans, which produce the typical odor of the -thion form of organophosphates. The mercaptans have very low- odor thresholds, and the reactions to their noxious odor, including headache, nausea, and vomiting, often are mistaken for acute organophosphate poisoning.
The conversion from-thion to -oxon also occurs in vivo as a result of hepatic microsomal metabolism, so the -oxon becomes the active form of the pesticide in both animal pests and humans. Hepatic esterases rapidly hydrolyze organophosphate esters, yielding alkyl phosphates and phenols, which have little, if any, toxicologic activity and are excreted rapidly. Carbamates also are metabolized by the liver and excreted as metabolites in urine without evidence of significant accumulation.
Organophosphates and carbamates exert effects on insects and mammals, including humans, by inhibiting acetylcholinesterase at nerve endings. The normal function of acetylcholinesterase is the hydrolysis and inactivation of acetylcholine (Figure 34–1A). Figure 34–1B shows the reactions of organophosphates and acetylcholinesterase. The enzyme then can be dephosphorylated spontaneously and reactivated (step 3a) or aged through the hydrolysis of an alkyl (–R) group, resulting in irreversible inactivation.
Carbamates initially react with acetylcholinesterase in the same fashion as organophosphates, resulting in accumulation of acetylcholine in the same distribution as organophosphates. The carbamyl enzyme product does not progress to an aging reaction but instead dissociates relatively rapidly. As a family, the carbamates have no known health effects other than those resulting from this acute, reversible inhibition of cholinesterase and resulting overactivity of acetylcholine.
The clinical manifestations of acute organophosphate or carbamate poisoning reflect the organs where acetylcholine is the transmitter of nerve impulses (Table 34–7). Rapid rates of cholinesterase inhibition are associated with clinical illness at levels of inhibition that may not be associated with symptoms following slower rates of inhibition. Asymptomatic subacute inhibition of acetylcholinesterase results in a state in which exposure to a dose of an organophosphate that previously would have had no effect now may lower acetylcholinesterase levels below a critical threshold and result in clinical illness.
Table 34–7.Signs and symptoms of acute organophosphate poisoning by site of acetylcholine neurotransmitter activity. |Favorite Table|Download (.pdf) Table 34–7. Signs and symptoms of acute organophosphate poisoning by site of acetylcholine neurotransmitter activity.
|System ||Receptor Type ||Organ ||Action ||Sign or Symptom |
| || ||Eye, iris muscle, ciliary muscle ||Contraction ||Miosis |
| || ||Respiratory ||Smooth muscle contraction, increased respiratory secretion ||Wheezing, dyspnea |
|Parasympathetic ||Muscarinic ||Cardiac ||Stimulation of vagus nerve ||Bradycardia, arrhythmias, heart block |
| || ||Intestinal tract ||Smooth muscle contraction, increased intestinal secretion ||Vomiting, diarrhea, muscle cramps |
| || ||Glands: lacrimal, salivary ||Secretion ||Tearing, salivation, bronchorrhea, pulmonary edema, nausea, vomiting |
| || ||Bladder, fundus, sphincter ||Contraction, relaxation ||Urination, incontinence |
|Sympathetic || ||Contraction || ||Blurred vision |
|Neuromuscular ||Nicotinic ||Skeletal ||Excitation ||Fasciculations, cramps, followed by weakness, loss of reflexes paralysis |
|Central nervous || ||Brain ||Excitation (early) ||Headache, dizziness, malaise, apprehension, confusion, hallucinations, manic or bizarre behavior, convulsions |
|– || || ||Depression (late) ||Depression of, then loss of, consciousness; respiratory depression |
This type of cumulative inhibition of acetylcholinesterase is unlikely to occur from carbamates owing to the rapidly reversible nature of the enzyme inhibition. For a large proportion of patients with acute intoxication, the clinician will not know the identity of the particular pesticide or pesticides at the time of initial presentation, and decisions' regarding diagnosis and management will need to be made on the basis of clinical signs, symptoms, and laboratory data.
A health effect of organophosphate pesticides that is entirely unrelated to cholinesterase inhibition is organophosphate-induced delayed neuropathy. Inhibition of an enzyme known as neurotoxic esterase (NTE), found in the central and peripheral nervous systems of various species, is an indicator of neurotoxic potential and a potential tool for biologic monitoring. Animal studies indicate that irreversible inhibition of NTE to 75% of initial activity will be followed 10–14 days later by a rapidly progressive ascending peripheral neuropathy. Currently used organophosphate pesticides with evidence of neurotoxicity include such weak cholinesterase inhibitors as merphos (S,S,S-tri-n-butyl phosphorotrithioite) and DEF (S,S,S-tri-n-butyl phosphorotrithioate), which are used as cotton defoliants rather than as insecticides.
Despite the popularity of mnemonics such as MUDDDLES (miosis, urination, diarrhea, defecation, diaphoresis, lacrimation, excitation, and salivation), the signs and symptoms of acute intoxication with organophosphates and carbamates are best learned on a neurophysiologic basis by grouping them according to the affected class of cholinergic receptor (see Table 34–7). There is some variability in parasympathetic nervous system manifestations because they are opposed by the sympathetic nervous system, which has preganglionic cholinergic innervation. Thus the heart rate may be slow, normal, or fast and the pupils may be small, normal, or large depending on which system predominates. In one large series of organophosphate-poisoned patients, 90% had at least muscarinic manifestations, 40% both muscarinic and nicotinic manifestations, 30% had muscarinic and CNS manifestations, and 10% had all three. The number of systems involved increases with the severity of intoxication. Mild poisoning usually is manifested by mild muscarinic signs and symptoms only.
The cause of death in acute organophosphate poisoning usually is respiratory failure. Bronchorrhea or pulmonary edema, bronchoconstriction, and respiratory muscular paralysis all contribute to respiratory failure. Seizures are not uncommon in cases of severe poisoning.
1. Cardiac rhythm disturbances
Cardiac arrhythmias, such as bradycardia and heart block and cardiac arrest, are less common causes of death. Ventricular arrhythmias have been observed in some of these cases, including torsade de pointes arrhythmias, associated with prolongation of the QT interval. Medications affecting the QT interval (eg, use of odansetron for treatment of nausea) should probably therefore be avoided.
Atrial fibrillation has been reported in cases of both carbamate and organophosphate poisoning.
During the 1995 terrorist attack on Tokyo using the OP nerve agent sarin, a case of coronary spasm was observed in the precordial ECG leads, attributed to the direct effect of acetylcholine on coronary nicotinic receptors. Atherosclerotic compromise of the coronary circulation was excluded by a thallium exercise study after successful treatment of the acute poisoning.
Severe poisoning from occupational exposure to carbamates is uncommon. Owing to the rapid spontaneous reactivation of acetyl cholinesterase, workers who become ill on the job are often better by the time they are seen at a medical facility. Recorded instances of serious poisoning have involved accidental reentry poisoning or accidental direct exposures to handlers involving high-toxicity (category I) carbamates.
A number of nonspecific laboratory findings may be present in an individual with acute poisoning, including leukocytosis, proteinuria, glucosuria, and hemoconcentration. However, changes in cholinesterase activity, along with the typical signs and symptoms, provide sufficient information for the diagnosis and management of most cases. Red cell cholinesterase is called “true” cholinesterase because it is the same enzyme present in nerve endings and because its activity more closely parallels that in the nervous system than does plasma cholinesterase, particularly in the time course of recovery, after inhibition. However, red cell cholinesterase is more difficult to measure and therefore more susceptible to analytic error than plasma cholinesterase. Organophosphates and carbamates may differentially inhibit one enzyme relative to the other, so if one and not the other appears depressed, it is conservative to assume that neuronal cholinesterase more closely corresponds to the lower of the two. For example, the commonly used organophosphate chlorpyrifos (Dursban, Lorsban) preferentially depresses plasma cholinesterase, causing illness without significant depression of red cell cholinesterase.
A number of analytic methods are used to measure both red cell and plasma cholinesterase. Results obtained by one method usually cannot be compared with results from another, even if the units expressed by each are the same. There is considerable variability in cholinesterase activity in unexposed persons, so reports of results relative to “normal” may not reflect the true level of inhibition present.
Individuals with a genetic trait for atypical plasma cholinesterase have lowered plasma but not red cell cholinesterase. They have prolonged muscular paralysis after administration of succinyl choline and other neuromuscular blocking agents that are normally metabolized by plasma cholinesterase, but they are not more susceptible to cholinesterase-inhibiting pesticides. Unlike red cell cholinesterase, plasma cholinesterase is not a reliable indicator of exposure or poisoning in these individuals.
Plasma cholinesterase production may be lowered as a result of liver disease extensive enough to impair the production of proteins such as albumin. Albumin-losing conditions, such as nephrotic syndrome, may be accompanied by elevated levels of plasma cholinesterase as a result of increased hepatic protein synthesis. The only medical conditions known to influence red cell cholinesterase activity are those associated with reticulocytosis, such as recovery from hemorrhage, pernicious anemia, and some other anemias.
Two circumstances in which cholinesterase determinations may be useful are (1) routine biologic monitoring of exposure to organophosphates and (2) diagnosis of acute poisoning. In assessing exposure to carbamates, cholinesterase depression may prove difficult to document unless treatment facilities can run cholinesterase assays on-site shortly after phlebotomy.
Severe poisoning usually is accompanied by cholinesterase levels well below normal for the laboratory. However, patients with mild to moderate poisoning often have cholinesterase levels reported as equivocal, normal, and even above normal. The diagnosis can be confirmed retrospectively by periodic (ie, weekly or biweekly) determinations of cholinesterase until levels fluctuate by no more than 30%. If the average level at this time—the retrospective baseline—is more than 30% higher than the level at the time of illness, exposure to cholinesterase-inhibiting pesticides almost certainly was present, and the illness may have been due to that exposure. The rate of recovery of red cell cholinesterase, in the absence of treatment with pralidoxime and of further exposure, depends on the rate of formation of new red cells, which is approximately 1% per day. Red blood cell cholinesterase levels will reach a plateau in about 60–70 days and plasma cholinesterase in 30–50 days.
2. Intact pesticides and metabolites
Measurement of the parent organophosphate or carbamate, or their metabolites, in blood or urine has been investigated to a limited extent. No such measurements are currently likely to be helpful in the diagnosis of acute intoxication. Measurement of alkyl phosphate metabolites in urine has not been of use in biologic monitoring of exposure because of its lack of specificity and instability. Measurement of p-nitrophenol in urine can be useful for monitoring exposure to parathion; 0.5 mg/L in a sample collected at the end of an exposure interval corresponds to exposure to parathion at the current threshold limit value (TLV). Measurement of 1-naphthol in urine is used to monitor exposure to carbaryl.
Mild acute poisoning from organophosphates or carbamates most closely resembles acute viral influenza, respiratory infections, gastroenteritis, asthma, or psychological dysfunction. The most significant differential diagnosis is between severe organophosphate poisoning and acute cerebrovascular accident; unequal pupils caused by the local effect of a direct-inhibiting (oxon) organophosphate or n-methyl carbamate in one eye of a comatose patient is a potential source of misdiagnosis. Other conditions to be distinguished from acute organophosphate poisoning include heat stroke, heat exhaustion, and infections.
The major disorder to be distinguished from organophosphate-induced delayed neuropathy is idiopathic acute symmetric polyneuropathy. Other toxic and disease-related neuropathies generally are insidious in onset and slowly progressive in course.
Treatment that is otherwise indicated should never be delayed pending determination of cholinesterase levels. The initial diagnosis can be made on clinical grounds alone, samples sent to the laboratory, and a test dose of atropine delivered. Atropine blocks the effects of acetylcholine at muscarinic receptors. A dose of atropine sulfate (0.5 mg intravenously) produces signs of mild atropinization (ie, dry mouth, dry eyes, increased heart rate, and large pupils) in a normal adult; it has no effect in an individual with organophosphate poisoning. A dose of 1–2 mg intravenously will produce marked signs of atropinization in a nonpoisoned adult and may reverse the signs of cholinergic excess in a case of poisoning.
Samples must be sent for cholinesterase measurement before administration of pralidoxime, which will regenerate cholinesterase in red cells and plasma as well as nerves. Atropine has no effect on cholinesterase levels.
Treatment of acute intoxication must be predicated on assessment of the severity of poisoning, which largely depends on clinical judgment and experience. For some occupational poisonings, removal from further exposure to cholinesterase-inhibiting insecticides may prove to be the only treatment necessary. Treatment with specific antidotes should be reserved for patients observed in the hospital setting.
Assessment of severity should focus primarily on the respiratory system because it is affected by all three types of cholinergic sites and is the critical one for survival and serious morbidity. The most commonly used severity rating defines mild toxicity as involving only muscarinic signs and symptoms, moderate toxicity as involving more than one system but not requiring assisted breathing, and severe toxicity as requiring ventilatory assistance.
Treatment modalities include the following:
Decontamination, including bathing of skin, shampooing of hair, or emptying of stomach, as dictated by the route of exposure.
Atropine sulfate in a dosage of 1–2 mg intravenously for mild to moderate poisoning, 2–4 mg intravenously for severe poisoning, as often as every 15 minutes, as needed. There is no maximum dosage. Atropine blocks muscarinic activity but not the nicotinic (muscle paralysis) or CNS effects. Patients without evidence of muscle weakness or respiratory depression may be treated with atropine alone until one or more signs of mild atropinizadon appear (ie, tachycardia, flushing, dry mucous membranes, or dilated pupils). Multiple doses may need to be administered over a prolonged time.
For organophosphate poisoning only, give pralidoxime chloride (2-PAM, Protopam) slowly, 1 g intravenously (no more than 0.5 g/min), repeated once in 1–2 hours and then at 10- to 12-hour intervals, if needed. Pralidoxime acts by breaking the bond between acetylcholinesterase and organophosphate, reactivating the enzyme and restoring acetylcholine activity to normal (Figure 34–1C). Its advantages over atropine include acting at the neuromuscular junction to reverse muscular paralysis and possibly crossing the blood-brain barrier to reverse CNS depression. Overdosage is not a problem if the drug is administered slowly to avoid inducing hypotension. The decision to use pralidoxime must be made reasonably soon after diagnosis because it is ineffective once aging has occurred. A high incidence of atropine toxicity may result from the often-recommended regimen of first using atropine until primary signs of atropine toxicity appear and then using pralidoxime if necessary. This may be avoided by making the decision to use pralidoxime early.
The use of pralidoxime for carbamate poisoning is controversial. Fortunately, it is rarely indicated. There is experimental evidence that pralidoxime may be helpful in the management of poisoning by some rarely used carbamates, but for most of the commonly used carbamates, this drug has not been studied. One animal study indicated that pralidoxime may be harmful in the treatment of carbaryl poisoning.
Morphine, aminophylline, and phenothiazines are contraindicated because of the increased risk of cardiac arrhythmias. Diuretics for pulmonary edema and fluids for hypotension are also contraindicated. It is recommended that atropine be withheld until adequate ventilation has reversed hypoxia because atropine may generate arrhythmias in the presence of hypoxia.
Emergency supportive measures: Artificial ventilation, ventilatory assistance, oxygen, and clearance of secretions.
Evaluation of delayed symptoms: By the time the diagnosis of organophosphate-induced delayed peripheral neuropathy is made, the initial manifestations of cholinesterase inhibition, if once present, are likely to have resolved. Administration of atropine or pralidoxime, initially or later, does not influence the course of neuropathy. Treatment of delayed neuropathy is supportive; in a few cases, mechanical ventilation has been required because of respiratory failure caused by muscular paralysis.
If treatment for organophosphate or carbamate poisoning is initiated before hypoxia results in tissue damage, antidotal therapy and respiratory support should ensure complete recovery, even in the most severe cases. Persistence of manifestations beyond 24 hours indicates the possibility of continued absorption of pesticide and the need to carefully consider and examine the skin, fingernails, eyes, and gastrointestinal tract as possible reservoirs.
Sudden death can occur in a small percentage of organophosphate-poisoned patients (2% in one series) 24–48 hours after apparent complete recovery from the acute phase of poisoning and is caused by, in at least some cases, ventricular arrhythmia. Sudden relapse of acute signs and symptoms within a few days of apparent recovery has been reported occasionally, perhaps as a result of release of pesticide from fat following mobilization of the patient from bed.
Deaths have been reported as a result of accidental or deliberate ingestion of carbamates, as a result of large doses and prolonged gastrointestinal absorption, and perhaps as a complication of delayed or inadequate treatment. Intoxication from occupational exposure may be serious but is rarely fatal and usually is of brief duration. Poisoning from contaminated fruits and vegetables with high water content also may be serious but not persistent.
A number of reports describe persistent CNS symptoms in a small percentage of patients following well-documented incidents of acute poisoning from organophosphates but not carbamates. Typical symptoms include irritability, depression, mood lability, anxiety, fatigue, lethargy, difficulty in concentrating, and short-term memory loss. Limited studies suggest that neurobehavioral test results and electroencephalograms may be different for such patients when compared with controls. Symptoms may persist for weeks or months after the initial intoxication and are difficult to distinguish from psychological reactions likely to occur after such an event. Sympathetic counseling and judicious use of antianxiety agents, when appropriate, generally will be more effective than intensive psychotherapy and antipsychotic medicine.
Organophosphates generally have high octanol/water partition coefficients and high dermal absorption rates, but most cause minimal skin irritation. Skin effects derive from the reactivity of the nonphosphate portion (termed the leaving group) of individual compounds. For example, the irritant compounds dichlorvos and naled both have reactive halogen atoms in their leaving groups. Dichlorvos also has an unconjugated carbon-carbon bond. Some organophosphate formulations produce transient irritation in the Draize assay, including acephate, diazinon, dimethoate, malathion, methamidophos, methidathion, oxydemeton-methyl, phosmet, and sulfotep; many cause mild primary irritation in the challenge (epicutareous) phase of the guinea pig maximization test. Clinically, acute irritation with these compounds occurs most frequently with accidental direct exposure to pesticide handlers (mixer/loader/applicators). These types of exposures also may provoke systemic effects; in cases of organophosphate-associated dermatitis reported from Japan, approximately 25% had at least mild coincident symptoms of systemic poisoning. Systemic poisoning also was reported in a US case of irritant dermatitis caused by dichlorvos.
Buehler (epicutaneous) sensitization assays show negative findings for acephate, chlorpyrifos, dimethoate, malathion, methamidophos, methidathion, and phosmet. Nevertheless, several are sensitizers in the guinea pig maximization test (induction of allergy by subcutaneous injection), including diazinon, fenitrothion, and methidathion. Cases of possible contact sensitivity to organophosphates have been reported for omethoate and dimethoate. A case-control study of dermatitis in farmers identified allergic reactions to malathion and oxydemeton-methyl, as well as the carbamate compounds carbofuran and carbaryl. Further studies identified allergic contact dermatitis caused by malathion and naled, but the patch testing conducted did not meet current standards, especially with regard to identifying nonirritant concentrations to conduct of the patch procedure.
A case report from Australia identified an isomer and contaminant of diazinon called isodiazinon (2-isopropyl-6-methyl-4-S-pyrimidinyl diethylthiophosphate) as a possible cause of porphyria cutanea tarda in a sheep rancher. Investigation in a rat study showed that isodiazinon affected porphyrin synthesis by inhibiting the liver enzyme ferrochelatase. Other noncontact reactions include a case of erythema multiforme associated with indoor use of methyl parathion, an unusual contact reaction to ethyl parathion resembling erysipeloid, and a case of systemic organophosphate poisoning.
A. Neurobehavioral Effects
Conjectured persistent sequelae of organophosphate poisoning remains a subject of controversy.
Numerous studies document subclinical neurobehavioral deficits relative to control subjects in previously poisoned workers and to a lesser extent in workers with applicators with long-term exposures who never experienced acute poisoning. The recorded deficits include vibrotactile sensitivity, decreased sustained attention, and decreased speed of information processing, memory and abstraction, and cognitive tests.
Poisoning by the organophosphate nerve agent sarin produced persistent neurobehavioral deficits, including significant amnesia in some victims of the 1995 terrorist attack on the Tokyo subway. The most severe deficits were seen in patients who experienced prolonged hypoxia. Cases of posttraumatic stress also occurred. Findings in less severely poisoned cases more closely resembled those seen in studies of applicators poisoned by organophosphate insecticides.
Studies of workers who handled organosphosphates without a history of overt poisoning show less consistent findings of subclinical neurobehavioral impairment. A study of sheep dippers handling organophosphates showed findings similar to the studies of overtly poisoned workers. Other studies of nonpoisoned organophosphate handlers demonstrated equivocal or negative findings.
Although none of the studies of poisoned workers shows significant clinical impairment, all involve cross-sectional measurement of neurobehavioral function, most less than 10 years after poisoning. From currently available information, it cannot be ascertained if the subclinical deficits observed eventually might progress to clinically significant impairments. A study of aging did show an association between pesticide exposure recorded at the outset of the study and mild cognitive defects recorded 3 years subsequently but did not identify exposures to particular pesticides or classes of pesticides.
Possible reactive airways cases, an asthma-like respiratory condition that occurs in some individuals exposed to environmental irritants, are commonly diagnosed, by means of a specialized pulmonary function test called a methacholine challenge. Occasionally, cases of reactive airways disease or new-onset asthma are associated with organophosphate exposure or organophosphate contaminants. Experimental studies in guinea pigs demonstrate that reactive airways following organophosphate exposure is more severe in animals previously sensitized to ovalbumin. Sensitized animals also demonstrated an increased pharmacologic sensitivity to airway constriction induced by inhibition of cholinesterase. The case described below provides a possible example:
A severe case of asthma in a nursery worker was reported to the California illness registry in 2006. The worker entered a greenhouse shortly after a Bt application and an application of diazinon in a neighboring area of the nursery. She had a prior history of sometimes poorly controlled asthma. After work she suffered a near respiratory arrest and was hospitalized. An extensive investigation followed, documenting prior workplace history. She had positive RAST/immunocap in vitro reactions to multiple pollens, plants and molds. Initial testing at an academic allergy center appeared to show an in vitro reaction to Bacillus thuringiensis (Bt) antigens, similar to those reported from farm workers in Ohio and from Denmark, but direct provocation testing (prick testing) was negative. Her near-respiratory arrest may have been solely related to her poorly controlled allergically mediated asthma. However, as noted above, studies in guinea pigs demonstrate that reactive airways following organophosphate exposure is more severe in previously sensitized animals (ovalbumin antigen). Sensitized animals also demonstrated an increased pharmacologic sensitivity to airway constriction induced by inhibition of cholinesterase.
C. Carcinogenicity, Teratogenicity, Effects on Childhood Development, Male Reproductive Toxicity
Most of the carbamates and organophosphates show no evidence of carcinogenicity in animal tests. Exceptions include probable (cancer classification B2) animal carcinogens propoxur (bladder cancer and liver cancer) and dichlorvos (gastric tumors in female mice, leukemia in male rats). Possible (cancer classification C) carcinogens include acetamide, a metabolite of methomyl and thidiocarb (liver cancer in male and female rats), acephate, dimethoate, parathion, methidathion, phosphamidon, tetrachlorvinphos, and tribufos.
Some cancer case-control studies conducted in the 1990s showed associations between handling organophosphates and occurrence of non-Hodgkin lymphoma and leukemia. Effects of the reported expoures on the immune system were hypothesized as a possible mechanism. An effect of a specific compound, for example, dichlorvos, which is recognized as an animal carcinogen, also could explain the findings. A case-control study investigating causes of aplastic anemia in Thailand also revealed a strong association with dichlorvos and with the carbamate insecticide propoxur. In common with the studies of lymphoma, the study employed questionnaire information to assess exposure, and the findings could have been attributed to recall bias.
2. Teratogenicity and effects on childhood neural development
The organophosphate compounds generally are not teratogenic below maternally toxic doses. As discussed earlier, the carbamate compound carbaryl is a spermatotoxin in rodents; a study in manufacturing and formulating workers demonstrated, as discussed earlier, an effect on sperm morphology. Sperm effects related to environmental exposures to carbaryl also have been reported (see above). Carbaryl is also teratogenic to beagle dogs but not to rodent species.
The FQPA has inspired considerable work on animal models for developmental neurotoxicity, including prenatal and postnatal exposures. Cohort studies in New York and California evaluating possible long-term effects of prenatal organophosphate exposures have studied multiple outcomes including cognitive development, attention disorders and other neurobehavioral outcomes. Parallel studies on animals have shown similar effects at somewhat different dose levels.
Studies in both cohorts measured exposures prospectively. Although total exposures during pregnancy were not quantifiable, they were assumed to be related to short-term measurements done by air sampling, blood measurements, and measuring of urinary metabolites. Exposures to both groups were probably higher than the reference population in the NPB cohort but well below the no effect levels in animal studies of impaired neurodevelopment related to chlorpyrifos and other organophosphates.
Some differences in outcomes were noted between the two cohorts, but both observed an increased number of abnormal neonatal reflexes, attention deficit problems in early childhood, and effects on cognition apparent as the children reached school age. Both outcomes and the excretion of OP metabolites were associated with PON1 activity. PON1, or serum paraoxonase, is an enzyme encoded by the PON1 gene. PON1 is responsible for hydrolysing organophosphate. It may be a confounding factor in these studies that has not been completely explored. Most studies of both cohorts involved batteries of tests and psychological instruments, raising the possibility that some identified significant outcomes were related to multiple comparisons.
3. Male reproductive effects
Animal feeding studies show effects on some measures of sperm quality and effects on reproductive hormones and after prolonged exposures to organophosphates or carbamates. Possible mechanisms of action include alkylating or phosphorylating DNA or nuclear proteins, enzyme inhibition in reproductive cells and endocrine effects. Most studies were conducted in rodents, but rabbits and fish were also employed.
Some cross-sectional studies demonstrated associations between pesticide OP exposure and levels of reproductive hormones. However, the results were not entirely consistent between studies. There were more consistent associations between high dose OP exposures and measures of damage to sperm, including aneuploidy and DNA fragmentation.