Gulf War and Health Volume 2: Insecticides and Solvents (2003) / Chapter Skim
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3. Insecticide Toxicology
3. Insecticide Toxicology
Pages 39-81
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From page 39... ...
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-diethyI-3-methy~benzamide (DEET)
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From page 40... ...
. Chemistry The structures of the organophosphorous compounds used as contact insecticides in the Gulf War are shown in Figure 3.1.
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INSECTICIDE TOXICOLOGY o ° ~ 0 1-'1 / Cot\ CH3O 1 S OCH3 Malathion \~o—p—OCH2CH3 OCH2CH3 Diazinon C15~ ,C1 C1~ —N' 'O—P OCH3 OCH3 Chlorpyrifos H Cl /c~ ~~ O ~ OCH3 OCHER Dichlorvos Cl~oi IS ~ OCH3 OCH3 Azamethiphos FIGURE 3.1 Structures of organophosphorous insecticides used in Gulf War.
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From page 42... ...
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.
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From page 43... ...
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 acety~cholinesterase depend on dosage.
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From page 44... ...
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 (LDso values, doses that kill 50% of the animals tested)
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From page 45... ...
Inhibition of NTE is not related to inhibition of acety~cholinesterase, 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 reg~stered for use as insecticides, so most commercially available insecticides do not inhibit NTE.
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From page 46... ...
Experimental Data Neurotoxic Elects As noted above, organophosphorous insecticides increase levels of the neurotransmitter acety~choline in both the central and peripheral nervous systems. Excess acety~choline at neuromuscular junctions causes excessive neuromuscular stimulation (such as tremors)
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From page 47... ...
Carcinogenicity Organophosphorous insecticides, including those used in the Gulf War, are generally not considered carcinogenic. Long-term rodent studies of dichiorvos and malathion, however, have yielded mixed results (see ATSDR, 1997, 200 1a; ARC, 1983, 1991; Kamrin, 1997; Van Maele-Fabry et al., 2000 for reviews)
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From page 48... ...
Mutagenicity and genotoxicity tests y~elded no evidence that chlorpyr~fos has such activity (GolIapudi et al., 19954. Reproductive an4 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; BalIantyne and Marrs, 1992; Breslin et al., 1996; Kamrin, 1997~.
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From page 49... ...
Effects on respiratory, cardiac, and gastrointestinal systems in humans and animals are related to the ability of the insecticides to inhibit acety~cholinesterase and increase acety~choline-mediated neural transmission (Ballantyne and Marrs, {992~. 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 acety~cholinesterase was substantially inhibited (Smallridge et al., 1991)
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From page 50... ...
Pretreatment with relatively low doses of carbamates will protect humans and animals from the irreversible acety~cholinesterase-inhibiting effects that can follow later exposure to organophosphorous compounds. That was the basis of the prophylactic use of the carbamate pyndostigmine bromide against organophosphorous nerve agents in the Gulf War (IOM, 2000~.
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Following an acute oral exposure of rats to carbary1, it could be detected in the liver, brain and heart 48 h after exposure. FIGURE 3.2 Structure of carryall.
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In addition, Loewenstein-Lichenstein and colleagues (1995) reported a soldier homozygous for "atypical" butyry~cholinesterase who experienced severe symptoms after pyridostigmine prophylaxis during the Gulf War.
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Few systematic studies have addressed the behavioral effects, however, and they generally have been earned out with end points not considered especially sensitive. For example, acute exposure via various routes appears to decrease locomotor activity as measured in several devices.
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In in viva cytogenetic studies in rats exposed to carbary1, C-mitosis and additional mitotic abnormalities were noted. In 1980, the Environmental Protection Agency concluded that the totality of the available evidence did not support the assertion that carbary]
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More recently, effects on estrogenic and progesterone systems and the ability of carbamate insecticides to act as general endocrine modulators have been described. Klotz and colleagues (1997)
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From page 56... ...
increased concentrations of 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine, biomarkers of oxidative stress. They also reported decreases in plasma butyry~cholinesterase activity and brain neurotoxic target esterase in hens after combined exposures to pyTidostigmine (gavage)
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From page 57... ...
Permethrin and phenothrin, the pyrethroid insecticides in this class used in the Gulf War, are type T pyrethroids. Other type ~ pyrethroids are resmethrin, allethrin, and cismethrin.
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From page 58... ...
Other investigators, however, have demonstrated that fetal or young rats and mice are sensitive to the neurochemical and neurobehavioral effects of pyrethroids (Aziz et al 2001; Eriksson and Fredriksson, 1991; Husain et al., 1994; Lazarini et al., 20014. Mechanism of Action ., Type ~ and type IT pyrethroids exert their toxicity by affecting the voltage-gated sodium channels of neurons (Narahashi, 1996, 2001; Soderiund et al., 2002; Vijverberg and van den Bercken, 1990~.
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in the rate of pyrethroid detoxification between mammals and insects also contributes to the selective toxicity. Acute Human Exposures Ray and Forshaw (2000)
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Experimental Data Neurotoxic Effects Type ~ and type IT pyrethroids cause different acute symptoms in rats, the animal species in which most toxicity studies of pyrethroids have been conducted (AIdridge, ~ 990; Vijverberg and van den Bercken, ~ 990~. Type ~ pyrethroids, such as those used in the Gulf war, co not have the a-cyano moiety and cause what is called the T syndrome.
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From page 61... ...
Immunotoxic Effects Although detailed studies of the effects of pyrethrins and pyrethroids on immune measures have not been conducted, perrnethrin has been reported to suppress immune responses in animals. The toxicological significance of these effects to human exposures, however, is difficult to detennine because few studies have been conducted in humans and because of interindividual vanability (ATSDR, 200Ib)
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From page 62... ...
also investigated open field locomotor activity. In males pyr~dostigmine and DEET decreased locomotor activity, but DEET in combination with permethrin increased locomotor activity.
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Although it is a misnomer, "benzene hexachloride" is a common name used in the United States for the mixture of HCH isomers. The structure of lindane is shown in Figure 3.4.
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From page 64... ...
seriously questioned the role of lindane in blood dyscrasias. Experimental Data Neurotoxic Effects Acute exposure of animals to lindane causes CNS stimulation, motor impairment, excitation, clonic (intermittent)
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Acute lindane administration decreased motor activity, whereas repeated lindane administration increased motor activity. The authors suggested that the effect was due to an imbalance of the central monoaminergic and GABAA neurotransmitter system (Rivera et al., 19981.
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From page 66... ...
binding in the brainstem, indicating a decrease in expression of GABAA receptors, but the clinical significance is unknown (Brannen et al., 19981. Immunotoxic Effects WeanTing rats fed high doses of HCH for 90 days showed hypertrophy of the adrenals, reduction of steroidogenic enzymes, and accumulation of lipids that contain cholesterol (Shivanandappa et al., 19821.
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From page 67... ...
Acute Human Exposures DEET's overall safety record is good when it is used as directed in the labeling, but three deaths and 10 cases of encephalopathy (all cases except one were in children ~ years old and younger) have been reported to be associated with heavy, and sometimes even shortterm, use of DEET formulations (Qiu et al., 1998~.
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From page 68... ...
and motor activity measurements were studied following the acute exposure. In addition to the FOB and motor activity tests, an M-maze, passive avoidance acquisition and retention tests, acoustic-startle habituation, and histologic outcomes were also assessed in the multigenerational study.
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From page 69... ...
Such research has also been conducted to explore hypotheses related to unexplained illness among US forces in the Gulf War, many of whom used the anticholinesterase drug pyridostigmine bromide (PB) prophylactically against possible nerve-agent exposure in addition to DEET.
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on the percutaneous absorption of permethrin and carbaryl. Toxicology and Applied Pharmacology 144~2~:332-339.
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Toxicology and Applied Pharmacology 66~1~:124-133. Cullen MR, ed.
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Toxicology and Applied Pharmacology 27~3~:465-476. Desi I, Varga L, Dobrony I, Szklenarik G
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arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicology and Applied Pharmacology 157~3~:227233.
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1987. Investigation GULF WAR AND HEALTH lo.
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1998. Epidemiological association in US veterans between Gulf War illness and exposures to anticholinesterases.
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1976. Degradation, metabolism and toxicity of synthetic pyrethroids.
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1984. Lack of mutagenicity of synthetic pyrethroids in Salmonella typhimurium strains and in V-79 Chinese hamster cells.
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2000. Lack of significant estrogenic or antiestrogenic activity of pyrethroid insecticides in three in vitro assays based on classic estrogen receptor alpha-mediated mechanisms.
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-mediated testicular toxicity in Fischer 344 rats. Toxicology and Applied Pharmacology 107~1~:35-46.
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Fundamental and Applied Toxicology 18~1~:79-88. Vijverberg HPM, van den Bercken J
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1988. Classification of the actions of ten pyrethroid insecticides in the rat, using the trigeminal reflex and skeletal muscle as test systems.
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