3
INSECTICIDE TOXICOLOGY

Insecticides offer many benefits such as improved health of humans and animals, increased agricultural productivity, and reduced worldwide hunger. The use and misuse of insecticides, however, have been associated with health risks, environmental contamination, and poisoning (Ecobichon and Joy, 1994; Ecobichon, 2001; Ware, 1989). The toxicity of insecticides has been studied extensively in humans and animals (Ecobichon et al., 1990). Insecticides were used in the Gulf War to control insects that could serve as vectors for disease.

This chapter discusses the toxicity of several insecticides and classes of insecticides believed to have been used in the Gulf War including: organophosphorous compounds, carbamates, pyrethrins and pyrethroids, lindane, and N,N-diethyl-3-methylbenzamide (DEET). Although organophosphorous compounds and carbamates have similar mechanisms of toxicity and many insecticides have neurotoxic effects, it is difficult to summarize the general toxicity of insecticides. Therefore, the chemistry, toxicokinetics, genetic polymorphisms and susceptibilities, mechanism of action, human health effects of acute exposure, experimental data (including animal toxicity data and mutagenicity data), and available information on interactions with other agents are presented separately for each chemical class. Epidemiologic studies of the effects of chronic exposure to insecticides are discussed in the chapters on specific health effects (Chapters 59).

Although this chapter focuses on the active ingredients of insecticides, it is important to remember that the toxicity of an insecticide can be altered by its formulation. Agents contributing to formulation of an insecticide are often listed as “inert ingredients” (for example, petroleum products, xylenes, oils, and surfactants), but they can alter the toxicokinetics of an insecticide, potentially increase the absorption of active ingredients, and be toxic themselves (Petrelli et al., 1993; Ware, 1989).

ORGANOPHOSPHOROUS COMPOUNDS

Exposure to organophosphorous compounds can occur under a variety of conditions. Organophosphorous compounds are used as contact insecticides and are applied to crops, gardens, and domestic animals. Some organophosphorous compounds are used as systemic insecticides, in that they are taken up by the roots of plants and disseminated into stems and leaves. Others are used as ophthalmic agents, industrial chemicals (plasticizers and



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Gulf War and Health: Insecticides and Solvents, Volume 2 3 INSECTICIDE TOXICOLOGY Insecticides offer many benefits such as improved health of humans and animals, increased agricultural productivity, and reduced worldwide hunger. The use and misuse of insecticides, however, have been associated with health risks, environmental contamination, and poisoning (Ecobichon and Joy, 1994; Ecobichon, 2001; Ware, 1989). The toxicity of insecticides has been studied extensively in humans and animals (Ecobichon et al., 1990). Insecticides were used in the Gulf War to control insects that could serve as vectors for disease. This chapter discusses the toxicity of several insecticides and classes of insecticides believed to have been used in the Gulf War including: organophosphorous compounds, carbamates, pyrethrins and pyrethroids, lindane, and N,N-diethyl-3-methylbenzamide (DEET). Although organophosphorous compounds and carbamates have similar mechanisms of toxicity and many insecticides have neurotoxic effects, it is difficult to summarize the general toxicity of insecticides. Therefore, the chemistry, toxicokinetics, genetic polymorphisms and susceptibilities, mechanism of action, human health effects of acute exposure, experimental data (including animal toxicity data and mutagenicity data), and available information on interactions with other agents are presented separately for each chemical class. Epidemiologic studies of the effects of chronic exposure to insecticides are discussed in the chapters on specific health effects (Chapters 5–9). Although this chapter focuses on the active ingredients of insecticides, it is important to remember that the toxicity of an insecticide can be altered by its formulation. Agents contributing to formulation of an insecticide are often listed as “inert ingredients” (for example, petroleum products, xylenes, oils, and surfactants), but they can alter the toxicokinetics of an insecticide, potentially increase the absorption of active ingredients, and be toxic themselves (Petrelli et al., 1993; Ware, 1989). ORGANOPHOSPHOROUS COMPOUNDS Exposure to organophosphorous compounds can occur under a variety of conditions. Organophosphorous compounds are used as contact insecticides and are applied to crops, gardens, and domestic animals. Some organophosphorous compounds are used as systemic insecticides, in that they are taken up by the roots of plants and disseminated into stems and leaves. Others are used as ophthalmic agents, industrial chemicals (plasticizers and

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Gulf War and Health: Insecticides and Solvents, Volume 2 lubricants), and chemical-warfare agents. Organophosphorous compounds used as contact insecticides during the Gulf War include malathion, diazinon, chlorpyrifos, dichlorvos, and azamethiphos (Abou-Donia, 1995; Chambers and Levi, 1992; Ecobichon, 2001; Kamrin, 1997; Ware, 1989). Chemistry The structures of the organophosphorous compounds used as contact insecticides in the Gulf War are shown in Figure 3.1. Organophosphorous compounds that are used as insecticides contain a pentavalent phosphorus atom connected by esteratic, amide, or sulfur linkages to the organic portions of the molecule. As esters or amides, organophosphorous compounds are chemically unstable and easily inactivated by hydrolysis. Organophosphorous compounds are lipophilic, some are oily liquids, and others are liquids that can be volatilized (Chambers and Levi, 1992; Ware, 1989). Toxicokinetics Toxicokinetics plays an important role in the toxicity of organophosphorous compounds. The oil-water partition coefficient, formulation, and route of exposure can affect the extent of and time needed for absorption. Dermal exposure can increase the time needed for absorption and ensuing toxicity. Almost 100% of the dermally administered dose of some of the highly lipophilic organophosphorous compounds can be absorbed. The potential for percutaneous absorption can be increased if formulations include petroleum products, oils, solvents, or surfactants or if occlusive dressings are placed on the skin (Ware, 1989). Many organophosphorous compounds are supplied commercially in inactive forms (as protoxicants that need to be activated usually by liver mixed-function oxidases). For most organophosphorous compounds, that requires the change of the phosphorus-sulfur bond to a phosphorus-oxygen bond (for example, malathion needs to be oxidized to malaoxon, chlorpyrifos to chlorpyrifos-oxon, and diazinon to diazoxon). That bioactivation is catalyzed primarily by the P450 system. Dichlorvos and azamethiphos, however, are active without the need for biotransformation. Detoxification of organophosphorous compounds involves hydrolysis, which can occur spontaneously in an aqueous environment. Hydrolysis can also be catalyzed by aryl and aliphatic hydrolases. Glutathione transferases and cytochrome P450s contribute to the detoxification of some organophosphorous compounds. Metabolic activation and inactivation of organophosphorous compounds occurs primarily in the liver, although other tissues also contribute. Extensive metabolism occurs via multiple pathways, and little, if any, unmetabolized organophosphorous compound is excreted. Differences in biotransformation of organophosphorous compounds are important contributors to differences in potency and in susceptibility among species and individuals. In addition, the effects of organophosphorous compounds on biotransformation enzymes are important in interactions between the compounds and other chemicals (Ballantyne and Marrs, 1992; Chambers and Levi, 1992; Ecobichon, 2001; Ecobichon and Joy, 1994; Gallo and Lawryk, 1991).

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Gulf War and Health: Insecticides and Solvents, Volume 2 FIGURE 3.1 Structures of organophosphorous insecticides used in Gulf War.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Genetic Polymorphisms and Susceptibility Organisms can differ in the amounts and activities of their B esterases, and the differences affect susceptibility to organophosphorous compounds. Although acetylcholinesterase shows relatively little variation in structure and activity among individuals of a species, other esterases that interact with organophosphorous insecticides differ widely among individuals in a population. For example, several variants of pseudocholinesterase have been noted in human serum, with distinguishing differences related to capability for interaction with particular molecules (for example, succinylcholine and fluoride). A single clinical case report noted that atypical pseudocholinesterase was found in a soldier who suffered adverse effects when exposed to an acetylcholinesterase inhibitor during the Gulf War (Loewenstein-Lichtenstein et al., 1995). Differences in pseudocholinesterase activities did not, however, differentiate between symptomatic and asymptomatic Gulf War veterans when more subjects were studied (Kurt, 1998). Differences in the biotransformation of organophosphorous compounds play a role in susceptibility to them in organisms of different ages and species. The young are generally more susceptible to acetylcholinesterase inhibition because they are less likely to convert organophosphorous compounds into nontoxic metabolites. Apart from age, different species have different capabilities for organophosphorous biotransformation; for example, avians can be 10 times as susceptible as mammals. Genetic polymorphisms of A esterases (arylesterases) might play a role in susceptibility of humans and animals to organophosphorous compounds. Although other A esterases exist, the most studied are the paraoxonases, which metabolize, in addition to paraoxon, chlorpyrifos-oxon and diazoxon, the active metabolites of chlorpyrifos and diazinon, respectively, two organophosphorous insecticides used in the Gulf War. At least three gene products exist for paraoxonase. One of the gene products, paraoxonase-1 (PON1), has at least two isozymes (Q, formerly referred to as A; and R, formerly referred to as B). Those isozymes differ in their ability to metabolize organophosphorous insecticides. Population studies have demonstrated a trimodal distribution of paraoxonase activity, reflecting QQ, RR, and QR individuals. Reported individual differences in Q activities suggest that such differences contribute to the varied responses to environmental organophosphorous compounds in people and animals (Brophy et al., 2001; Cowan et al., 2001; Hernandez et al., 1999; La Du et al., 1999). In a small sample of Gulf War veterans, individuals with the neurologic symptom complexes were more likely to have the R allele (heterozygous QR or homozygous R) than to be homozygous Q for the allele (Haley et al., 1999). Animal studies also demonstrate the role of PON1 in organophosphorous metabolism and the varying activity of the differential isozymes. PON1 knockout mice (mice without PON1) were found to be very sensitive to the toxicity of organophosphorous compounds, and following introduction of the enzyme to the knockout animals, the sensitivity to specific organophosphorous compounds varied with the isoform given to the animal. Animals given the Q isozyme were less sensitive to diazoxon while animals given the R isozyme were less sensitive to chlorpyrifos-oxon and paraoxon. It is important to note, however, that although mouse and human Q isoforms are similar, the catalytic efficiencies of their R isozymes differ (Furlong et al., 2000; Li et al., 2000).

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Gulf War and Health: Insecticides and Solvents, Volume 2 Mechanism of Action Organophosphorous insecticides kill insects by affecting their nervous system. Specifically, they inhibit acetylcholinesterase, the enzyme that is responsible for the breakdown of acetylcholine and therefore the termination of its activity. Acetylcholine is a neurotransmitter that acts at two major receptor subtypes, nicotinic and muscarinic. Binding of acetylcholine to receptors at neuromuscular synapses leads to the activation of muscles. Failure to break down acetylcholine results in sustained activity and consequent overstimulation of cholinergically-mediated synapses, particularly nicotinic neuromuscular synapses, muscarinic parasympathetic synapses, and cholinergic synapses of the central nervous system (CNS). That mechanism of toxicity is the same in mammals, birds, and fish, so the acute effects are similar in humans and animals (Ecobichon, 2001). Organophosphates inhibit acetylcholinesterase when the oxygen with the coordinate bond on the organophosphate molecule (see Figure 3.1) binds to the esteratic site of the acetylcholinesterase enzyme. That binding is initially reversible, but within a matter of minutes, part of the organophosphate molecule may be cleaved from the phosphorus group, and the remainder of the molecule will become essentially irreversibly attached at the esteratic site of the enzyme. The production of the essentially irreversible bond is called aging (Abou-Donia, 1995; Ballantyne and Marrs, 1992; Chambers and Levi, 1992; Ecobichon, 2001; Ecobichon and Joy, 1994; Gallo and Lawryk, 1991; Marrs, 1996). Once aging has occurred, enzyme activity can be recovered only with the synthesis of new enzyme. Acute Human Exposures Immediate Effects Clinical signs of toxicity associated with organophosphate-induced inhibition of acetylcholinesterase depend on dosage. Toxicity in humans and animals includes the signs associated with overstimulation of muscarinic receptors of the autonomic nervous system by acetylcholine (SLUD—salivation and sweating, lacrimation, urination, and defecation—as well as emesis and bradycardia). Acetylcholinesterase inhibition can also cause overstimulation (which can be followed by depression) of nicotinic receptors at neuromuscular junctions and autonomic ganglia and result in ataxia and fasciculations that, at higher dosages, can be followed by flaccid paralysis. Electromyographic changes can be observed after acute poisoning because nicotinic sites in muscles are affected; the changes include decreases in amplitude and increases in peak latencies in nerve conduction (Baker and Wilkinson, 1990; Gallo and Lawryk, 1991; Kaloianova and El Batawi, 1991). Stimulation of autonomic ganglia can also cause hypertension. As is the case at neuromuscular junctions, excess acetylcholine in the CNS causes stimulation that can be followed by depression. Overstimulation can be manifested as nervousness, delirium, hallucinations, and psychoses. Obvious signs do not generally appear until nervous system acetylcholinesterase inhibition approaches 70%. Not all exposed people show all signs, and signs can vary with the organophosphorous compound, dose, route of exposure, and species. Signs often appear within minutes or hours, but they might not appear for several days. Duration can vary from minutes to weeks and can be followed by full recovery from obvious manifestations of

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Gulf War and Health: Insecticides and Solvents, Volume 2 cholinergic poisoning. If death occurs, it is due to respiratory failure, usually as a result of a combination of the autonomic effects mediated by the muscarinic and nicotinic acetylcholine receptors and the effects of acetylcholine at CNS receptors. Those effects include excessive fluid in the respiratory tract, paralysis of the respiratory muscles, and depression of the respiratory centers of the CNS. Of the organophosphorous insecticides shipped from the United States to the Gulf War, oral lethal doses (LD50 values, doses that kill 50% of the animals tested) are highest for malathion (about 1 g/kg), intermediate for diazinon and chlorpyrifos (about 150–250 mg/kg), and lowest for dichlorvos (about 50 mg/kg) (Abou-Donia, 1995; Ballantyne and Marrs, 1992; Brown and Brix, 1998; Cecchine et al., 2000; Chambers and Levi, 1992; Ecobichon, 2001; Ecobichon and Joy, 1994; Gallo and Lawryk, 1991; Kaloianova and El Batawi, 1991; Lotti, 2001; Marrs, 1996; Ware, 1989). Diagnosis of organophosphorous-induced acute toxicity is based on exposure history, clinical manifestations of acetylcholinesterase inhibition, and laboratory findings. Erythrocyte acetylcholinesterase activity is used as an indicator of enzyme status in the nervous system. Metabolites of organophosphorous compounds to which humans and animals are exposed can also be detected in urine. Toxicity is unlikely to be overt unless blood acetylcholinesterase is substantially decreased (for example, by at least 50%; 70% inhibition is more likely to be correlated with clinical signs). Response to administration of atropine, an anticholinergic agent, has also been used as a diagnostic tool: poisoned organisms will not respond to atropine at doses that a nonpoisoned organism will respond to but require doses about 10 times higher before the expected pupil dilation, increased heart rate, and decreased secretions are noted (Ballantyne and Marrs, 1992; Ecobichon and Joy, 1994; Gallo and Lawryk, 1991; Marrs, 1996). Treatment for organophosphorous-caused acetylcholinesterase inhibition includes administration of atropine to antagonize acetylcholine stimulation of muscarinic receptors and administration of an oxime (such as pralidoxime) to regenerate acetylcholinesterase that is inhibited but not yet irreversibly bound. In the Gulf War and elsewhere, a carbamate compound (pyridostigmine bromide) has been used prophylactically when exposure to organophosphorous nerve gases was expected, because it inhibits but does not age the enzyme and so provides time for clearance of the organophosphate before sites on acetylcholinesterase are available to bind it irreversibly. Other treatments for acute acetylcholinesterase inhibition are not specific and consist of decreasing absorption, enhancing excretion, and addressing symptoms. Time is needed for recovery of acetylcholinesterase activity after aging because recovery requires synthesis of new enzyme. Weeks of supportive treatment might be needed if acetylcholinesterase remains sufficiently inhibited to cause signs of cholinergic poisoning (Ballantyne and Marrs, 1992; Ecobichon, 2001; Ecobichon and Joy, 1994; Feldman, 1999; Gallo and Lawryk, 1991; Lotti, 2001). Delayed Effects Tolerance. Tolerance can occur after repeated exposure to cholinesterase-inhibiting organophosphorous insecticides. In general, tolerance can develop due to prolonged stimulation of cholinergic receptors by acetylcholine. Those receptors no longer respond as effectively to the neurotransmitter. Tolerance is more likely to occur at muscarinic than at nicotinic receptors and can develop when erythrocyte acetylcholinesterase is low but cholinergic poisoning is not overt (Bushnell et al., 1993).

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Gulf War and Health: Insecticides and Solvents, Volume 2 Tolerance can also occur when there is an increase in the proteins other than acetylcholinesterase to which organophosphorous compounds can bind. The alternative binding sites protect animals from organophosphate-induced acetylcholinesterase inhibition. Such sites include other esterases, notably pseudocholinesterase and carboxylesterases that are found in serum, liver, and other tissues. Although their precise physiologic role is unknown, those esterases can be involved in the metabolism of drugs and other compounds that contain ester and amide groups. Quantities of the alternative esterases, especially the carboxylesterases, depend on age, tissue, species, and exposure to agents that induce or inhibit enzymes. Agents that induce or inhibit enzymes include a number of drugs and other foreign compounds. When the esterases are induced, animals and humans are likely to be less susceptible to some of the organophosphorous compounds used as insecticides (Ballantyne and Marrs, 1992; Ecobichon, 2001; Gallo and Lawryk, 1991). Intermediate syndrome. Clinical manifestations of acute acetylcholinesterase inhibition in humans or animals are not generally long-lasting or delayed, but there are exceptions. An “intermediate syndrome” has been described after severe poisoning: muscle weakness that occurs about 16 to 120 hours after exposure and 7 to 75 hours after the onset of acute poisoning symptoms (He et al., 1998; Shailesh et al., 1994). Overstimulation of nicotinic receptors followed by depression at neuromuscular junctions and muscle necrosis might be contributing factors. The muscle weakness can become severe and result in respiratory insufficiency. If respiration can be sustained, recovery occurs, although it can take weeks. Intermediate syndrome has been reported in humans after exposure to malathion and diazinon (Gallo and Lawryk, 1991). Organophosphorous-induced delayed neuropathy. Another type of toxicity caused by a few organophosphorous compounds is a progressive, irreversible delayed neuropathy termed organophosphate-induced delayed neuropathy (OPIDN). OPIDN can occur in many species, including humans. Clinical manifestations of OPIDN include progressive, irreversible ataxia that develops weeks to months after exposure. Lesions are found in peripheral nerves and the spinal cord (Ehrich and Jortner, 2001). OPIDN occurs only if organophosphorous compounds sufficiently, and essentially irreversibly, inhibit neuropathic target esterase (NTE) within hours of exposure. Inhibition of NTE is not related to inhibition of acetylcholinesterase, and organophosphorous compounds used as contact insecticides generally do not inhibit NTE. Organophosphorous compounds are tested for their potential to cause OPIDN before they are registered for use as insecticides, so most commercially available insecticides do not inhibit NTE. Commercially available insecticides that do inhibit NTE, such as chlorpyrifos and dichlorvos, do so only at doses that are sufficient to cause lethal cholinergic poisoning. OPIDN can occur only after rescue from acute chlorpyrifos or dichlorvos poisoning; even then it might not occur. At least six cases of OPIDN have been documented after ingestion of near-lethal doses of chlorpyrifos or dichlorvos (Aiuto et al., 1993; Lotti et al., 1986; Martinez-Chuecos et al., 1992; Vasilescu and Florescu, 1980); all but one occurred after unsuccessful suicide attempts. The absence of documented cases of OPIDN after exposure to diazinon or malathion is consistent with their lack of NTE inhibition in animal models. In fact, the chemical structures of malathion, diazinon, and azamethiphos make them exceedingly unlikely to inhibit NTE at all, and OPIDN has not been produced in experimental animals exposed to either malathion or diazinon (Ballantyne and Marrs, 1992; Cecchine et al., 2000; Chambers and Levi, 1992; Ecobichon, 2001; Ecobichon and Joy,

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Gulf War and Health: Insecticides and Solvents, Volume 2 1994; Ehrich and Jortner, 2001; Gallo and Lawryk, 1991; Johnson and Glynn, 2001; Kamrin, 1997; Lotti, 2001; Richardson, 1995). Other delayed effects. Some studies have reported other persistent symptoms after poisoning with organophosphorous compounds or symptoms that appear 5–10 years after a poisoning episode, including neurologic and visual deficits, behavioral alterations, and impairment of cognition. Those effects, however, might be confounded by other factors or be the result of inappropriate study designs (Abou-Donia, 1995; Baker and Wilkinson, 1990; Chambers and Levi, 1992; Ecobichon and Joy, 1994; Eyer, 1995; Gallo and Lawryk, 1991; Jamal, 1997; Kaloianova and El Batawi, 1991; Lotti, 2001). Although some latent effects have been noted in laboratory rats, the symptoms reported in people have been difficult to verify in animal studies partly because of difficulties in replication of exposures and extrapolation of end points from humans to animals (Ballantyne and Marrs, 1992; Bushnell et al., 1993; Ecobichon and Joy, 1994; Gallo and Lawryk, 1991; Marrs, 1996; Mattsson et al., 1996; Maurissen et al., 2000). Experimental Data Neurotoxic Effects As noted above, organophosphorous insecticides increase levels of the neurotransmitter acetylcholine in both the central and peripheral nervous systems. Excess acetylcholine at neuromuscular junctions causes excessive neuromuscular stimulation (such as tremors), which can be followed by neuromuscular block. Excess acetylcholine at synapses of the autonomic nervous system affects quantity of secretions, heart rate, blood pressure, gastrointestinal function, urination, and pupil size. Excess acetylcholine at synapses of the CNS can alter behavior and cognition. Studies in animals generally require substantial inhibition of acetylcholinesterase (for example, greater than 40% inhibition of erythrocyte acetylcholinesterase) before those effects are seen. Even when doses of organophosphorous compounds are sufficient to cause notable evidence of cholinergic poisoning in animals or people, it is unusual for signs and symptoms to continue after recovery of acetylcholinesterase activity (Ballantyne and Marrs, 1992; Cecchine et al., 2000; Chambers and Levi, 1992; Ecobichon, 2001; Ecobichon and Joy, 1994; Eyer, 1995; Gallo and Lawryk, 1991; Marrs, 1996; Mattsson et al., 1996). There has also been discussion around the potential effects of organophosphorous compounds on learning and memory following fetal and childhood exposures. In animals, however, some experiments have not demonstrated an increased sensitivity during the developing periods. Mattsson and colleagues (2000) treated rats with chlorpyrifos (0.3, 1.0, and 5.0 mg/kg/day) from gestational day 6 to postnatal day 10 and measured chlorpyrifos concentrations and cholinesterase inhibition in the fetuses and the dams. The nursing pups had a lower concentration than the dams and cholinesterase activity in all tissues of the high-dose pups rapidly returned to near control levels. Another study in rats with the same dosing regimen examined learning and memory, but no effects were seen in the absence of maternal toxicity (Maurissen et al., 2000). Animal studies have been conducted to assess the persistence of neurotoxic effects of organophosphorous compounds. The results of a study of chlorpyrifos (at 1, 3, and 10 mg/kg per day, 5 days/week for 4 weeks followed by 4 weeks of recovery) do not indicate effects on short-term memory in adult rats, but do indicate a decrease in motor activity (Maurissen

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Gulf War and Health: Insecticides and Solvents, Volume 2 et al., 2000). Other reports noted locomotor reduction shortly after cessation of exposure and partial recovery of acetylcholinesterase inhibition in preweanling rats (Carr et al., 2001), long-term effects on cognitive end points in neonatally-exposed rats (Levin et al., 2001), and impairment of learning in preweanling rats and in rats immediately after weaning without regional brain acetylcholinesterase inhibition (Jett et al., 2001). Additional studies with relatively low, but cholinesterase-inhibiting, doses of other organophosphorous compounds have revealed behavioral and learning dysfunction in rats and in monkeys, especially after chronic administration (Eriksson and Talts, 2000; Prendergast et al., 1997, 1998). In addition to their action as esterase inhibitors, some organophosphorous compounds have been reported to directly stimulate cholinergic receptors, including receptors of the heart and the nervous system, although concentrations might be higher than those needed for acetylcholinesterase inhibition (Chambers and Levi, 1992; Pope and Liu, 2001; Richardson, 1995). Carcinogenicity Organophosphorous insecticides, including those used in the Gulf War, are generally not considered carcinogenic. Long-term rodent studies of dichlorvos and malathion, however, have yielded mixed results (see ATSDR, 1997, 2001a; IARC, 1983, 1991; Kamrin, 1997; Van Maele-Fabry et al., 2000 for reviews). Early studies in rats and mice did not show an increased incidence of tumors attributable to dichlorvos treatment (Blair et al., 1976; Horn et al., 1987, 1988). The National Toxicology Program (NTP) investigated the carcinogenicity of dichlorvos in feed in Osborne-Mendel rats (at 150 and 326 ppm) and B6C3F1 mice (at 318 and 635 ppm) (NTP, 1977); no evidence of increased tumor incidence attributable to dichlorvos was seen. More recently, NTP examined the carcinogenicity of dichlorvos given by gavage in F344/N rats (at 4 and 8 mg/kg per day, 5 days/week for 103 weeks in males and females) and B6C3F1 mice (males, at 10 and 20 mg/kg per day, 5 days/week for 103 weeks; females, at 20 and 40 mg/kg per day, 5 days/week for 103 weeks) (Chan et al., 1991; NTP, 1989). Some increased incidences of neoplastic effects were seen: in rats, adenomas of the exocrine pancreas (males and females), mononuclear cell leukemia (males), mammary gland fibroadenomas (females), combined fibroadenomas or adenomas (females), and multiple fibroadenomas (females); and in mice, squamous cell papillomas of the forestomach (males and females). In addition, two female mice developed forestomach squamous cell carcinomas. NTP concluded that there was “some evidence of carcinogenic activity of dichlorvos” in male F344/N rats and male B6C3F1 mice, “equivocal evidence of carcinogenic activity of dichlorvos” in female F344/N rats, and “clear evidence of carcinogenic activity of dichlorvos” in female B6C3F1 mice (Chan et al., 1991; NTP, 1989). Evaluation of available data by the International Agency for Research on Cancer (IARC) resulted in the conclusion that there was inadequate evidence of the carcinogenicity of dichlorvos in humans but sufficient evidence in experimental animals. Therefore, dichlorvos was classified as a possible human carcinogen (Ballantyne and Marrs, 1992; IARC, 1991; Kamrin, 1997). A recent review of studies on the carcinogenicity of dichlorvos examining the length of the studies, confounding factors, and potential for bias has led the Health Council of Belgium to conclude that there is only sparse evidence that dichlorvos is carcinogenic in experimental animals and that it is not classifiable as to carcinogenicity in humans (Van Maele-Fabry et al., 2000).

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Gulf War and Health: Insecticides and Solvents, Volume 2 Animal studies of the carcinogenicity of malathion also have produced mixed results (see summaries in ATSDR, 2001a). In feeding studies conducted by the National Cancer Institute (NCI), no evidence of carcinogenicity was seen in Osborne-Mendel rats (at about 359 and 622 mg/kg per day for 80 weeks) (NCI, 1978), B6C3F1 mice (at about 1490 and 2980 mg/kg per day for 80 weeks) (NCI, 1978), and Fischer 344 rats (at about 166 and 322 mg/kg per day for 103 weeks) (NCI, 1979a). In a 2-year unpublished study in Fischer 344 rats with a wider dose range (2–868 mg/kg per day), however, some evidence of hepatocarcinogenicity (a statistical trend) was seen in female rats (Daly, 1996). Slauter (1994) treated B6C3F1 mice with 17.4–3448 mg/kg per day for 80 weeks. They saw an increase in the incidence of hepatocellular tumors with a positive dose trend, in both male and female mice at the two highest doses. NCI also investigated the effects of malaoxon, the active metabolite of malathion, in Fischer 344 rats (at about 41 and 82 mg/kg per day for 103 weeks) and B6C3F1 mice (at about 91 and 182 mg/kg per day for 103 weeks) (NCI, 1979b). There was an increase in C-cell adenomas and carcinoma of the thyroid in female rats, but historical-control data led NCI to conclude that there was no evidence of carcinogenicity attributable to malaoxon (NCI, 1979b). NTP has since re-evaluated the histopathologic findings in the NCI studies (NCI 1978, 1979a,b) and concurred with most of the NCI conclusions, but concluded that for C-cell neoplasms of the thyroid gland after malaoxon treatment there is “equivocal evidence of carcinogenicity” in male and female Fischer 344 rats (Huff et al., 1985). A 1983 IARC evaluation of malathion concluded that available data provided no evidence that malathion was carcinogenic in animals, and that it was unlikely to present a carcinogenic risk to humans (IARC, 1983). An EPA review of more recent information provided when malathion was evaluated for reregistration, however, resulted in the conclusion that there was “suggestive evidence of carcinogenicity but not sufficient to assess human carcinogenic potential”; this was based on the appearance of liver tumors in rodents that were given doses of malathion considered excessive (US EPA, 2000). Mutagenicity and Genotoxicity Kamrin (1997) summarized results of mutagenicity tests of chlorpyrifos, diazinon, malathion, and dichlorvos. Mutagenicity tests of diazinon yielded inconclusive results, but malathion produced detectable mutagenesis in three types of cultured human cells. Dichlorvos binds to DNA and has been demonstrated to be mutagenic in vitro but not in vivo. Mutagenicity and genotoxicity tests yielded no evidence that chlorpyrifos has such activity (Gollapudi et al., 1995). Reproductive and Developmental Effects Organophosphorous insecticides have not historically been considered to be female reproductive or developmental toxicants at dosages lower than would cause acute maternal toxicity in mammals, although teratogenesis has been reported in fish and birds and endocrine changes in women (Baker and Wilkinson, 1990; Ballantyne and Marrs, 1992; Breslin et al., 1996; Kamrin, 1997). Embryotoxicity, as indicated by decreases in body weight and skeletal size and a lag in development, has been reported in mice after administration of malathion at about 15–50% of the oral LD50 values, but no indication of maternal toxicity was provided (Asmatullah et al., 1993).

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Gulf War and Health: Insecticides and Solvents, Volume 2 Decreased pup weight and increased pup mortality were reported after administration of chlorpyrifos to rats. That occurred when pregnant female rats were exposed to chlorpyrifos at doses that caused maternal toxicity. Acetylcholinesterase inhibition was indicated by excessive salivation and tremors (Breslin et al., 1996). Decreased pup weight and increased pup mortality have also been reported in rats exposed to acetylcholinesterase-inhibiting doses of chlorpyrifos between birth and weaning (Carr et al., 2001). Biochemical changes other than acetylcholinesterase inhibition have been reported in neonatal rats exposed to chlorpyrifos, including changes in protein synthesis, DNA synthesis, intracellular signaling, and cholinergic receptors (Dam et al., 1998; Song et al., 1997; Tang et al., 1999; Whitney et al., 1995). Changes in righting reflex, cliff avoidance, locomotor activity, and spatial learning have been reported in neonatal, weanling, and juvenile rats exposed to chlorpyrifos at doses expected to inhibit acetylcholinesterase activity; some detriments occurred without notable enzyme inhibition or continued after substantial recovery of esterase activity (Carr et al., 2001; Chanda and Pope, 1996; Jett et al., 2001). The significance of behavioral changes in young rats with regard to possible toxicity in adult animals or in other species is unknown. Immunotoxic Effects The modulation of the immune system by malathion and its impurities depends on the dose, specific agent, cellular target, and duration of exposure; both stimulatory and suppressive effects have been reported in exposed animals. Dichlorvos has been reported to have suppressive effects on the generation of macrophages on chronic exposure and the ability to suppress cellular and humoral immune responses at cholinergic doses (Rodgers, 2001). Other Health Effects Dermatitis and hypersensitivities, including bronchospasm, have been reported after exposure to organophosphorous insecticides. The contributions of contaminants and vehicles to those responses have not been differentiated from effects of the active ingredients alone. Transient effects of malathion and dichlorvos on the immune system, including hypersensitivity and dermatitis, have been reported (Baker and Wilkinson, 1990; Chambers and Levi, 1992; Gallo and Lawryk, 1991; Kaloianova and El Batawi, 1991). Chlorpyrifos has been reported to increase lymphocyte numbers (Richardson, 1995). Effects on respiratory, cardiac, and gastrointestinal systems in humans and animals are related to the ability of the insecticides to inhibit acetylcholinesterase and increase acetylcholine-mediated neural transmission (Ballantyne and Marrs, 1992). Some organophosphorous compounds—but not the insecticides used in the Gulf War—have been reported to have endocrine effects, including dysregulation of hypothalamic releasing factors when acetylcholinesterase was substantially inhibited (Smallridge et al., 1991), decreased spermatogenesis (Somkuti et al., 1991), increased estrogen metabolism (Berger and Sultatos, 1997), and antagonism at androgen receptors (Tamura et al., 2001). Interactions with Other Agents Organophosphorous insecticides can inhibit esterases other than acetylcholinesterase, including pseudocholinesterase and carboxylesterases in both humans and animals.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Burkatzkaya EN. 1963. The effect of hexachlorocyclohexane γ-isomer on the immunobiological reactivity of the body. Gigiena i Sanitariia 28:29–33. As cited in: Hayes WJ Jr, Laws ER Jr. eds. 1991. Handbook of Pesticide Toxicology. Vol. 2, Classes of Pesticides. San Diego: Academic Press, Inc. Buselmaier W, Röerborn G, Propping P. 1973. Comparative investigations on the mutagenicity of pesticides in mammalian test systems. Mutation Research 21(1):25–26. Bushnell PJ, Pope CN, Padilla S. 1993. Behavioral and neurochemical effects of acute chlorpyrifos in rats: Tolerance to prolonged inhibition of cholinesterase. Journal of Pharmacology and Experimental Therapeutics 266(2):1007–1017. Camon L, Martinez E, Artigas F, Sola C, Rodriguez-Farré E. 1988. The effect of non-convulsant doses of lindane on temperature and body weight. Toxicology 49(2–3):389–394. Carpenter CP, Weil CS, Palm PE, Woodside MW, Nair JH, III, Smyth HF Jr. 1961. Mammalian toxicity of l-naphthyl-N-methylcarbamate (Sevin insecticide). Journal of Agricultural and Food Chemistry 9:30–39. Carr RL, Chambers HW, Guarisco JA, Richardson JR, Tang J, Chambers JE. 2001. Effects of repeated oral postnatal exposure to chlorpyrifos on open-field behavior in juvenile rats. Toxicological Sciences 59(2):260–267. Casida JE, Gammon DW, Glickman AH, Lawrence LJ. 1983. Mechanisms of selective action of pyrethroid insecticides. Annual Review of Pharmacology and Toxicology 23:413–438. Cecchine G, Golomb BA, Hilborne LH, Spektor DM, Anthony CR. 2000. A Review of the Scientific Literature as it Pertains to Gulf War Illness. Arlington, VA: RAND (National Defense Research Institute). Chambers JE, Levi PE, eds. 1992. Organophosphates, Chemistry, Fate, and Effects. San Diego: Academic Press. Chan PC, Huff J, Haseman JK, Alison R, Prejean JD. 1991. Carcinogenesis studies of dichlorvos in Fischer rats and B6C3F1 mice. Japanese Journal of Cancer Research 82(2):157–164. Chanda SM, Pope CN. 1996. Neurochemical and neurobehavioral effects of repeated gestational exposure to chlorpyrifos in maternal and developing rats. Pharmacology, Biochemistry, and Behavior 53(4):771–776. Chernoff N, Kavlock RJ. 1983. A teratology test system which utilizes postnatal growth and viability in the mouse. Environmental Science Research 27:417–427. Chowdhury AR, Venkatakrishna-Bhatt H, Guatam AK. 1987. Testicular changes of rats under lindane treatment. Bulletin of Environmental Contamination and Toxicology 38:154–156. Collins TFX, Hansen WH, Keeler HV. 1971. The effect of carbaryl (Sevin) on reproduction of the rat and gerbil. Toxicology and Applied Pharmacology 19(2):202–216. Copeland MF, Chadwick RW, Cooke N, Whitehouse DA, Hill DM. 1986. Use of γ-hexachlorocyclohexane (lindane) to determine the ontogeny of metabolism in the developing rat. Journal of Toxicology and Environmental Health 18(4):527–542. Coulston F, Rosenblum I, Dougherty WJ. 1974. Teratogenic Evaluation of Carbaryl in the Rhesus Monkey (Macaca mulatta). Albany, NY. International Center of Environmental Safety and Albany Medical College. As cited in: Baron RL. 1991. Carbamate insecticides. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of Pesticide Toxicology. Vol. 3. Classes of Pesticides. San Diego: Academic Press Inc. Pp. 1125–1189. Cowan J, Sinton CM, Varley AW, Wians FH, Haley RW, Munford RS. 2001. Gene therapy to prevent organophosphate intoxication. Toxicology and Applied Pharmacology 173(1):1–6. Cranmer MF. 1986. Carbaryl. A toxicological review and risk analysis. Neurotoxicology 7(1):247–328. Cremer JE, Seville MP. 1982. Comparative effects of two pyrethroids, deltamethrin and cismethrin, on plasma catecholamines and on blood glucose and lactate. Toxicology and Applied Pharmacology 66(1):124–133. Cullen MR, ed. 1987. The worker with multiple chemical sensitivities: An overview. In: Occupational Medicine: State of the Art Reviews 2(4)655–661. Dalsenter PR, Faqi AS, Webb J, Merker HJ, Chahoud I. 1997. Reproductive toxicity and toxicokinetics of lindane in the male offspring of rats exposed during lactation. Human & Experimental Toxicology 16(3)146–153. Daly I. 1996. A 24-month Oral Toxicity/oncogenicity Study of Malathion in the Rat via Dietary Administration. Final report: Lab project No: 90–3641: J-11 90–3641. Unpublished study prepared by Huntington Life Sciences. MRID 43942901. As cited in: ATSDR. 2001. Draft Toxicological Profile for Malathion. Atlanta, GA: ATSDR. Dam K, Seidler FJ, Slotkin TA. 1998. Developmental neurotoxicity of chlorpyrifos: Delayed targeting of DNA synthesis after repeated administration. Developmental Brain Research 108(1–2):39–45.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Denison MS, Phelan D, Winter GM, Ziccardi MH. 1998. Carbaryl, a carbamate insecticide, is a ligand for the hepatic Ah (dioxin) receptor. Toxicology and Applied Pharmacology 152(2):406–414. Descotes J. 1986. Immunotoxicology of Drugs and Chemicals. Amsterdam: Elsevier. Dési I. 1974. Neurotoxicological effects of small quantities of lindane: Animal studies. Internationales Archiv für Arbeitsmedizin 33(2):153–162. Dési I, Gonczi L, Simon G, Farkas I, Kneffel Z. 1974. Neurotoxicological studies of two carbamate pesticides in subacute animal experiments. Toxicology and Applied Pharmacology 27(3):465–476. Dési I, Varga L, Dobrony I, Szklenarik G. 1985. Immunotoxicological investigation of the effects of a pesticide; cypermethrin. Archives of Toxicology (Suppl 8):305–309. Dési I, Nehéz M, Palotás M, Tempfli A, Hogye A, Vetró G. 1990. Experience of health status surveillance of pesticide workers in Hungary. La Medicina del Lavoro 81(6):517–523. Dewan A, Gupta SK, Jani JP, Kashyap SK. 1980. Effect of lindane on antibody response to typhoid vaccine in weanling rats. Journal of Environmental Science and Health [Part B] B15:395–402. Dewar AJ. 1981. Neurotoxicity testing with particular reference to biochemical methods. In: Gorrod J, ed. Testing for Toxicity. London: Taylor & Francis, p. 119. Dewar AJ, Moffett BJ. 1979. Biochemical methods for detecting neurotoxicity—short review. Pharmacology & Therapeutics [Part B] 5(1–3):545–562. Dick IP, Blain PG, Williams FM. 1997. The percutaneous absorption and skin distribution of lindane in man I. In vivo studies. Human & Experimental Toxicology 16(11):645–651. Diel F, Detscher M, Borck H, Schrimpf D, Diel E, Hoppe HW. 1998. Effects of permethrin on human basophils and lymphocytes in vitro. Inflammation Research 47:S11–S12. Dorman DC, Buck WB, Trammel HL, Jones RD, Beasley VR. 1990. Fenvalerate/N,N-diethyl-m-toluamide (DEET) toxicosis in two cats. Journal of the American Veterinary Medical Association 96:100–102. Drummer HL, Woolley DE. 1991. Toxicokinetics of Ro 5–4864, lindane and picrotoxin compared. Pharmacology, Biochemistry, and Behavior 38(2):235–242. Dulout FN, Pastori MC, Olivero OA, Gonjzales CM, Loria D, Matos E, Sobel N, deBujan EC, Albiano N. 1985. Sister-chromatid exchanges and chromosomal aberrations in a population exposed to pesticides. Mutation Research 143(4):237–244. DuPont de Nemours Corp. 1989. Asana XL Technical Bulletin. Wilmington, DE: Dupont. Dzierzawski A. 1977. Embryotoxicity studies of lindane in the golden hamster, rat and rabbit. Bulletin of the Veterinary Institute in Pulawy 21:85–93. Ecobichon DJ. 2001. Toxic effects of pesticides. In: Klaassen CD, ed. Casarett and Doull’s Toxicology: The Basic Science of Poisons. 6th ed. New York: McGraw-Hill. Pp. 763–810. Ecobichon DJ, Joy RM, eds. 1994. Pesticides and Neurological Diseases. 2nd ed. Boca Raton, FL: CRC Press. Ecobichon DJ, Davies JE, Doull J, Ehrich M, Joy R, McMillan D, MacPhail R, Reiter LW, Slikker W Jr, Tilson H. 1990. Neurotoxic effects of pesticides. Advances in Modern Environmental Toxicology 18:131–199. Ehrich M, Jortner BS. 2001. Organophosphorous-induced delayed neuropathy. In: Krieger RI, ed. Handbook of Pesticide Toxicology. Vol. 2, Agents. 2nd ed. San Diego: Academic Press. Pp. 997–1012. Elliott M. 1976. EPA Properties and applications of pyrethroids. Environmental Health Perspectives 14:3–13. Elliott M. 1977. Synthetic pyrethroids. In: Elliott M, ed. Synthetic Pyrethroids. American Chemical Society Symposium Series 42. Washington, DC: American Chemical Society. Pp. 1–28. Eriksson P, Fredriksson A. 1991. Neurotoxic effects of two different pyrethroids, bioallethrin and deltamethrin on immature and adult mice: changes in behavioral and muscarinic receptor variables. Toxicology and Applied Pharmacology 108:78–85. Eriksson P, Talts U. 2000. Neonatal exposure to neurotoxic pesticides increases adult susceptibility: A review of current findings. Neurotoxicology 21(2):37–47. Extoxnet. 1994. Pyrethrins and Pyrethroids. Available: http://ace.orst.edu/info/extoxnet/pips/pyrethri.htm [accessed July 2002]. Eyer P. 1995. Neuropsychopathological changes by organophosphorous compounds—A review. Human & Experimental Toxicology 14(11):857–864. Facts and Comparisons. 2001. Drug Facts and Comparisons. St. Louis, MO: Facts and Comparisons. FAO/WHO (Food and Agriculture Organization/World Health Organization). 1980. FAO Plant Production and Protection Paper 20 (Supplement). Rome: FAO. Feldman RG. 1999. Occupational and Environmental Neurotoxicology. Philadelphia: Lippincott-Raven.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Fitzhugh OG, Nelson AA, Frawley JP. 1950. The chronic toxicities of technical benzene hexachloride and its alpha, beta and gamma isomers. Journal of Pharmacology and Experimental Therapeutics 100:59–66. Fitzloff JF, Portig J, Stein K. 1982. Lindane metabolism by human and rat liver microsomes. Xenobiotica 12(3):197–202. Flannigan SA, Tucker SB. 1985. Variation in cutaneous sensation between synthetic pyrethroid insecticides. Contact Dermatitis 13(3):140–147. Forshaw PJ, Bradbury JE. 1983. Pharmacological effects of pyrethroids on the cardiovascular system of the rat. European Journal of Pharmacology 91(2–3):207–213. Fuortes L. 1999. Urticaria due to airborne permethrin exposure. Veterinary and Human Toxicology 41(2):92–93. Furlong CE, Li WF, Brophy VH, Jarvik GP, Richter RJ, Shih DM, Lusis AJ, Costa LG. 2000. The PON1 gene and detoxication. Neurotoxicology 21(4):581–587. Gaines TB. 1969. Acute toxicity of pesticides. Toxicology and Applied Pharmacology 14(3):515–534. Gallo MA, Lawryk NJ. 1991. Organic phosphorus pesticides. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of Pesticide Toxicology. San Diego: Academic Press. Pp. 917–1123. Ghiasuddin SM, Matsumura F. 1982. Inhibition of gamma-aminobutyric acid (GABA)-induced chloride uptake by gamma-BHC and heptachlor epoxide. Comparative Biochemistry Physiology C 73(1):141–144. Gilbert ME. 1995. Repeated exposure to lindane leads to behavioral sensitization and facilitates electrical kindling. Neurotoxicology and Teratology 17(2):131–141. Gleiberman SE, Volkova AP, Nikolaev GM, Zhukova V. 1975. A study on embryotoxic properties of the repellent diethyltoluamide. Farmakologiya i Toksikologiya 38:202–205 Gollapudi BB, Mendrala AL, Linscombe VA. 1995. Evaluation of the genetic toxicity of the organophosphate insecticide chlorpyrifos. Mutation Research 342(1–2):25–36. Goncharova NI. 1968. Morphological changes in the blood of animals in sevin poisoning. Veterinariia 45(2):82–83. Gray LE Jr, Kavlock RJ. 1984. An extended evaluation of an in vivo teratology screen utilizing postnatal growth and viability in the mouse. Teratogenesis, Carcinogenesis, and Mutagenesis 4(5):403–426. Haley RW, Kurt TL. 1997. Self-reported exposure to neurotoxic chemical combinations in the Gulf War: A cross-sectional epidemiologic study. Journal of the American Medical Association 227(3):231–237. Haley RW, Billecke S, LaDu BN. 1999. Association of low PON1 type Q (Type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicology and Applied Pharmacology 157(3):227–233. Hallenbeck WH, Cunningham-Burns KM. 1985. Pesticides and Human Health. New York: Springer-Verlag. Hanada M, Yutani C, Miyaji T. 1973. Induction of hepatoma in mice by benzene hexachloride. Gann 64(5):511–513. Hayes WJ Jr, Laws ER Jr. eds. 1991. Handbook of Pesticide Toxicology. Vol. 2, Classes of Pesticides. San Diego:Academic Press, Inc. He F, Sun J, Han K, Wu Y, Yao P, Wang S, Liu L. 1988. Effects of pyrethroid insecticides on subjects involved in packaging pyrethroids. British Journal of Industrial Medicine 45(8):548–551. He F, Wang S, Liu L, Chen S, Zhang Z, Sun J. 1989. Clinical manifestations and diagnosis of acute pyrethroid poisoning. Archives of Toxicology 63(1):54–58. He F, Xu H, Qin F, Xu L, Huang J, He X. 1998. Intermediate myasthenia syndrome following acute organophosphates poisoning—an analysis of 21 cases. Human and Experimental Toxicology 17(1):40–45. Heise GA, Hudson JD. 1985a. Effects of pesticides and drugs on working memory in rats: Continuous delayed response. Pharmacology, Biochemistry, and Behavior 23(4):591–598. Heise GA, Hudson JD. 1985b. Effects of pesticides and drugs on working memory in rats: Continuous non-match. Pharmacology, Biochemistry, and Behavior 23:599–606. Herbst M, Weisse I, Koellmer H. 1975. A contribution to the question of the possible hepatocarcinogenic effects of lindane. Toxicology 4(1):91–96. Hernandez AF, Gonzalvo MC, Gil F, Rodrigo L, Villanueva E, Pla A. 1999. Distribution profiles on paraoxonase and cholinesterase phenotypes in a Spanish population. Chemico-Biological Interactions 119–120:201–209. Herrera A, Laborda E. 1988. Mutagenic activity of synthetic pyrethroids in Salmonella typhimurium. Mutagenesis 3(6):509–514.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Horn KH, Teichmann B, Schramm T. 1987. Investigation of dichlorvos (DDVP). I. Testing of dichlorvos for carcinogenic activity in mice. Arch. Geschwulfstforsch 57:353–360. As cited in: IARC. 1991. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 53, Occupational Exposures in Insecticide Application, and Some Pesticides. Lyon, France: IARC. Horn KH, Teichmann B, Schramm T, Nischan P. 1988. Studies on dichlorvos (DDVP). II. Testing of dichlorvos for carcinogenic activity in rats. Arch Geschwulstforsch 58(1):1–10. As cited in: IARC. 1991. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 53, Occupational Exposures in Insecticide Application, and Some Pesticides. Lyon, France: IARC Hoy JB, Cornell JA, Karlix JL, Schmidt CJ, Tebbett IR, van Haaren F. 2000a. Interactions of pyridostigmine bromide, DEET and permethrin alter locomotor behavior of rats. Veterinary and Human Toxicology 42(2):65–71. Hoy JB, Cornell JA, Karlix JL, Tebbett IR, van Haaren F. 2000b. Repeated coadministrations of pyridostigmine bromide, DEET, and permethrin alter locomotor behavior of rats. Veterinary and Human Toxicology 42(2):72–76. Huff JE, Bates R, Eustis SL, Haseman JK, McConnell EE. 1985. Malation and malaoxon: Histopathlogy reexamination of the National Cancer Institute’s carcinogenesis studies. Environmental Research 37(1):154–173. Husain R, Malaviya M, Seth PK, Husain R. 1994. Effect of deltamethrin on regional brain polyamines and behaviour in young rats. Pharmacology & Toxicology 74(4–5):211–215. IARC (International Agency for Research on Cancer). 1983. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 30, Malathion. Lyon, France: IARC. Pp. 103–129. IARC. 1991. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. Vol. 53, Occupational Exposures in Insecticide Application, and Some Pesticides. Lyon, France: IARC. Imming RJ, Shaffer BC, Woodward G. 1969. SEVIN®. Safety Evaluation by Feeding to Female Beagles from Day One of Gestation through Weaning of the Offspring. Report from Woodward Research Corporation to Union Carbide Agricultural Products Company, Inc. Research Triangle Park, NC (as cited in Baron RL. 1991. Carbamate insecticides. In: Hayes WJ Jr, Laws ER Jr, eds. Handbook of Pesticide Toxicology. Vol. 3. Classes of Pesticides. San Diego: Academic Press Inc. Pp. 1125–1189). IOM (Institute of Medicine). 2000. Gulf War and Health, Voume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines. Washington, DC: National Academy Press. Isshiki K, Miyata K, Matsui S, Tsutsumi M, Watanabe T. 1983. Effects of post-harvest fungicides and piperonyl butoxide on the acute toxicity of pesticides in mice. Safety evaluation for intake of food additives. III. Journal of the Food and Hygiene Society of Japan 24:268–274. Ito N, Nagasaki H, Arai M, Sugihara S, Makiura S. 1973a. Histologic and ultrastructural studies on the hepatocarcinogenicity of benzene hexachloride in mice. Journal of the National Cancer Institute 51(3):817–826. Ito N, Nagasaki H, Arai M, Makiura S, Sugihara S, Hirao K. 1973b. Histopathologic studies on liver tumorigenesis induced in mice by technical polychlorinated biphenyls and its promoting effect on liver tumors induced by benzene hexachloride. Journal of the National Cancer Institute 51(5):1637–1646. Ito N, Nagasaki H, Aoe H, Sugihara S, Miyata Y, Arai M, Shirai T. 1975. Brief communication: Development of hepatocellular carcinomas in rats treated with benzene hexachloride. Journal of the National Cancer Institute 54(3):801–805. Jamal GA. 1997. Neurological syndromes of organophosphorous compounds. Adverse Drug Reactions and Toxicological Reviews 16(3):133–170. Jett DA, Navoa RV, Beckles RA, McLemore, GL. 2001. Cognitive function and cholinergic neurochemistry in weanling rats exposed to chlorpyrifos. Toxicology and Applied Pharmacology 174(2):89–98. Johnson MK, Glynn P. 2001. Neuropathy target esterase. In: Krieger RI, ed. Handbook of Pesticide Toxicology. Vol. 2: Agents. 2nd ed. San Diego: Academic Press. Pp. 953–965. Joslin EF, Forney RL, Huntington RW Jr, Hayes WJ Jr. 1960. A fatal case of lindane poisoning. In: Proceedings of the National Association of Coroners Seminars, 1958, 1959. Cleveland, Ohio: S.R.Gerber. Pp. 53–57. Kaloianova FP, El Batawi MA. 1991. Human Toxicology of Pesticides. Boca Raton, FL: CRC Press. Kamrin MA. 1997. Pesticide Profiles, Toxicity, Environmental Impact, and Fate. Boca Raton: CRC Lewis Publishers.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Kaneko H, Matsuo H, Miyamoto J. 1986. Differential metabolism of fenvalerate and granuloma formation. I. Identification of a cholesterol ester derived from a specific chiral isomer of fenvalerate. Toxicology and Applied Pharmacology 83(1):148–156. Kaneko H, Takamatsu Y, Okuno Y, Abiko J, Yoshitake A, Miyamoto J. 1988. Substrate specificity for formation of cholesterol ester conjugates from fenvalerate analogues and for granuloma formation. Xenobiotica 18:11–19. Kavlock R, Chernoff N, Baron R, Linder R, Rogers E, Carver B, Dilley J, Simmon V. 1979. Toxicity studies with decamethrin, a synthetic pyrethroid insecticide. Journal of Environmental Pathology and Toxicology 2(3):751–765. Khera KS, Whalen C, Trivett G, Angers G. 1979. Teratogenicity studies on pesticidal formulations of dimethoate, diuron and lindane in rats. Bulletin of Environmental Contamination and Toxicology 22(4–5):522–529. Kidd H, James DR, eds. 1991. The Agrochemicals Handbook. 3rd ed. Cambridge, UK: Royal Society of Chemistry Information Services. Kitagawa K, Wakakura M, Ishikawa S. 1977. Light microscopic study of endocrine organs of rats treated by carbamate pesticide. Journal of Toxicological Sciences 2:53–60. Klotz DM, Arnold SF, McLachlan JA. 1997. Inhibition of 17 beta-estradiol and progesterone activity in human breast and endometrial cancer cells by carbamate insecticides. Life Sciences 60(17):1467–1475. Knox JM 2nd, Tucker SB, Flannigan SA. 1984. Paresthesia from cutaneous exposure to a synthetic pyrethroid insecticide. Archives of Dermatology 120(6):744–746. Kolmodin-Hedman B, Swensson A, Akerblom M. 1982. Occupational exposure to some synthetic pyrethroids (permethrin and fenvalerate). Archives of Toxicology 50(1):27–33. Kurt TL. 1998. Epidemiological association in US veterans between Gulf War illness and exposures to anticholinesterases. Toxicology Letters 102–103:523–526. La Du BN, Aviram M, Billecke S, Navab M, Primo-Parmo S, Sorenson RC, Standford TJ. 1999. On the physiological role(s) of the paraoxonases. Chemico-Biological Interactions 119–120:379–388. Lawlor T, Haworth SR, Voytek P. 1979. Evaluation of the genetic activity of nine chlorinated phenols, seven chlorinated benzenes and three chlorinated hexanes. Environmental Mutagenesis 1:143. Lawrence LJ, Casida JE. 1982. Pyrethroid toxicology: Mouse intracerebral structure-toxicity relationships. Pesticide Biochemisrty and Physiology 18(1):9–14. Lazarini CA, Florio JC, Lemonica IP, Bernardi MM. 2001. Effects of prenatal exposure to deltamethrin on forced swimming behavior, motor activity, and striatal dopamine levels in male and female rats. Neurotoxicology and Teratology 23:655–673. Lechner DW, Abdel-Rahman MS. 1986. Kinetics of carbaryl and malathion in combination in the rat. Journal of Toxicology and Environmental Health 18(2):241–256. Ledirac N, Delesculse C, deSousa G, Pralavorio M, Lesca P, Amichot M, Berge JB, Rahmani R. 1997. Carbaryl induces CYP1A1 gene expression in HepG2 and HaCaT cells but is not a ligand of the human hepatic Ah receptor. Toxicology and Applied Pharmacology 144(1):177–182. Lehman AJ. 1965. Summaries of Pesticide Toxicity. Topeka, Kansas: Association of Food and Drug Officials of the U.S. LeQuesne PM, Maxwell IC, Butterworth STG. 1981. Transient facial sensory symptoms following exposure to synthetic pyrethroids: A clinical and electrophysiological assessment. Neurotoxicology 2(1):1–12. Levin ED, Addy N, Nakajima A, Christopher NC, Seidler FJ, Slotkin TA. 2001. Persistent behavioral consequences of neonatal chlorpyrifos exposure in rats. Developmental Brain Research Reviews 130(1):83–89. Li WF, Costa LG, Richter RJ, Hagen T, Shih DM, Tward A, Lusis AJ, Furlong CE. 2000. Catalytic efficiency determines the in vivo efficacy of PON1 for detoxifying organophosphorous compounds. Pharmacogenetics 10(9):767–779. Litchfield MH. 1985. Toxicity to mammals. In: Leahey JP, ed. The Pyrethroid Insecticides. London: Taylor & Francis. Pp. 99–150. Llewellyn DM, Brazier A, Brown R, Cocker J, Evans ML, Hampton J, Nutley BP, White J. 1996. Occupational exposure to permethrin during its use as a public hygiene insecticide. Annals of Occupational Hygiene 40(5):499–509. Llorens J, Sunol C, Tusell JM, Rodriguez-Farre E. 1991. Evidence for acute tolerance to the behavioral effects of lindane: Concomitant changes in regional monoamine status. Neurotoxicology 12(4):697–705.

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Gulf War and Health: Insecticides and Solvents, Volume 2 Loewenstein-Lichtenstein Y, Schwarz M, Glick D, Norgaard-Pedersen B, Zakut H, Soreq H. 1995. Genetic predisposition to adverse consequences of anti-cholinesterases in atypical BCHE carriers. Nature Medicine 1(10):1082–1085. Lotti M. 2001. Clinical toxicology of anticholinesterase agents in humans. In: Krieger RI, ed. Handbook of Pesticide Toxicology. Vol. 2, Agents. 2nd ed. San Diego: Academic Press. Pp. 1043–1085. Lotti M, Moretto A, Zoppellari R, Dainese R, Rizzuto N, Barusco G. 1986. Inhibition of lymphocytic neuropathy target esterase predicts the development of organophosphate-induced delayed polyneuropathy. Archives of Toxicology 59(3):176–179. Luca D, Balan M. 1987. Sperm abnormality assay in the evaluation of the genotoxic potential of carbaryl in rats. Morphologie et Embryologie 33(1):19–22. Lucier GW, McDaniel OS, Williams C, Klein R. 1972. Effects of chlordane and methylmercury on the metabolism of carbaryl and carbofuran in rats. Pesticide Biochemistry and Physiology 2:244. Marrs TC. 1996. Organophosphate anticholinesterase poisoning. Toxic Substance Mechanisms 15:357–368. Martinez-Chuecos J, del Camen Jurado M, Paz Gimenez M, Martinez D, Menendez M. 1992. Experience with hemoperfusion for organophosphate poisoning. Critical Care Medicine 20(11):1538–1543. Matsumura F. 1985. Toxicology of Insecticides. 2nd ed. New York: Plenum Press. Mattsson JL, Wilmer JW, Shankar MR, Berdasco NM, Crissman JW, Maurissen JP, Bond DM. 1996. Single-dose and 13-week repeated-dose neurotoxicity screening studies of chlorpyrifos insecticide. Food and Chemical Toxicology 34(4):393–405. Mattsson JL, Maurissen JPJ, Nolan RJ, Brzak KA. 2000. Lack of differential sensitivity to cholinesterase inhibition in fetuses and neonates compared to dams treated perinatally with chlorpyrifos. Toxicological Sciences 53(2):438–446. Maurissen JP, Shankar MR, Mattsson, JL. 2000. Chlorpyrifos: Lack of cognitive effects in adult Long-Evans rats. Neurotoxicology and Teratology 22(2):237–246. May DG, Naukam RJ, Kambam JR, Branch RA. 1992. Cimetidine-carbaryl interaction in humans: Evidence for an active metabolite of carbaryl. Journal of Pharmacology and Experimental Therapeutics 262(3):1057–1061. McCorkle F, Taylor R, Martin D, Glick B. 1980. The effect of permethrin on the immune response of chickens. Poultry Science 59(7):1568. Miyamoto J. 1976. Degradation, metabolism and toxicity of synthetic pyrethroids. Environmental Health Perspectives 14:15–28. Miyamoto J, Kaneko H, Takamatsu Y. 1986. Stereoselective formation of a cholesterol ester conjugate from fenvalerate by mouse microsomal carboxyesterase(s). Journal of Biochemical Toxicology 1(2):79–93. Morgan DP, Stockdale EM, Roberts RJ, Walter AW. 1980. Anemia associated with exposure to lindane. Archives of Environmental Health 35(5):307–310. Moser VC. 1995. Comparisons of the acute effects of cholinesterase inhibitors using a neurobehavioral screening battery in rats. Neurotoxicology and Teratology 17(6):617–625. Nagasaki H, Tomii S, Mega T, Marugami M, Ito N. 1972. Hepatocarcinogenic effect of α-, β-, γ, and δ-isomers of hexachloride in mice. Gann 63(3):393. Narahashi T. 1996. Neuronal ion channels as the target sites of insecticides. Pharmacology and Toxicology 79(1):1–14. Narahashi T. 2001. Neurophysiological effects of insecticides. In: Krieger RI, ed. Handbook of Pesticide Toxicology. Vol. 1. 2nd ed. San Diego: Academic Press. Pp. 335–351. Nayshteyn SY, Leybovich DL. 1971. Low doses of DDT, γ-HCCH and mixtures of these: Effect on sexual function and embryogenesis in rats. Gigiena i Sanitariia 36(5):19–22 [In Russian]. As cited in: Hayes WJ Jr, Laws ER Jr. eds. 1991. Handbook of Pesticide Toxicology. Vol. 2, Classes of Pesticides. San Diego: Academic Press, Inc. NCI (National Cancer Institute). 1977. Bioassay of Lindane for Possible Carcinogenicity. CAS No. 58–89–9. Springfield, VA: NTIS PB-273480. NCI. 1978. Bioassay of Malathion for Possible Carcinogenicity. Washington, DC: US Department of Commerce. NCI-CG-TR-24. Available from: National Technical Information Service; PB-278–257. NCI. 1979a. Bioassay of Malathion for Possible Carcinogenicity. Washington, DC: US Department of Commerce. NCI-CG-TR-192. Available from: National Technical Information Service; PB-300 301. NCI. 1979b. Bioassay of Malaoxon for Possible Carcinogenicity. Washington, DC: US Department of Commerce. NCI-CG-TR-135. Available from: National Technical Information Service; PB-299 858.

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