Timothy C. Marrs

Clinical and experimental toxicology of organophosphates and carbamates

Basic science neurotoxicity specific organ and long-term toxicology environmental aspects exposure patterns protection and monitoring clinical toxicology by geographical regions clinical and therapeutic aspects.

Pesticide toxicology and international regulation

Preface.List of Contributors.Frequently Used Abbreviations.Toxicity Classifications and Hazard Ratings.1. Pesticides: An Overview of Fundamentals (Bryan Ballantyne & Timothy Marrs).PART I: INSECTICIDES.2. Toxicology of Organochlorine Insecticides (Andrew G. Smith).3. Anticholinesterase Insecticides (Charles M. Thompson and Rudy J. Richardson ).4. Toxicology of Pyrethrins and Synthetic Pyrethroids (David E. Ray).5. Toxicology of miscellaneous insecticides (Roland Solecki).PART II: FUNGICIDES, HERBICIDESM AND GROWTH REGULATORS.6. Toxicology of Fungicides (Bryan Ballantyne).7. Toxicology of Herbicides (Timothy C. Marrs).PART III: SPECIAL TYPES OF PESTICIDE.8. Microbial Pesticides (Ian C. Dewhurst).9. Biocides (Bryan Ballantyne and Susan L. Jordan).PART IV: RESIDUES.10. Variability of Residues in Unprocessed Food Items and its Impact on Consumer Risk Assessment (Caroline A. Harris and Alan R. C. Hill).PART V: HUMAN ASPECTS.11. Occupational Aspects of Pesticide Toxicity in Humans (Angelo Moretto).12. Treatment of Pesticide Poisoning (Gregory P. Wedin and Blaine E. Benson).PART VI: REGULATION.13. Regulation of Pesticides and Biocides in the European Union (Deborah J. Hussey and Graham M. Bell).14. Regulation in NAFTA (Cheryl E. A. Chaffey and Virginia A. Dobozy).15. The Regulatory System in Japan (Kannosuke Fujimori).Index.

Diazepam in the Treatment of Organophosphorus Ester Pesticide Poisoning

Although the main site of action of diazepam, as with other benzodiazepines, is at the γ-aminobutyric acid A (GABAA) receptor, the degree to which the beneficial actions of diazepam in organophosphorus (OP) ester pesticide poisoning are mediated through the GABAA receptor has been a matter of controversy.Although in most series of OP intoxications, convulsions have been relatively uncommon, it is probable that convulsions produce long-term sequelae in the central nervous system by causing structural damage. Animal studies have demonstrated that diazepam prevents and treats convulsions produced by OPs and may prevent the late effects caused by damage to the central nervous system induced by such convulsions. Consequently, the use of diazepam is an important part of the treatment regimen of severe OP poisoning as it prevents, or at least reduces the duration of, convulsions. In addition, case reports suggest that diazepam will also ameliorate muscle fasciculation, a subjectively unpleasant feature of OP pesticide poisoning. There are no data, either experimental or clinical, demonstrating any clear effect of diazepam alone on lethality in OP poisoning. In fact, in one study of large animals, diazepam, given alone, increased lethality. In animals experimentally poisoned with OPs, combined treatment with atropine and diazepam significantly lowered lethality compared with atropine treatment alone, indicating a clear beneficial effect.There are numerous case reports of the use of diazepam, generally as an adjunct to other more specific OP antidotes such as atropine and/or pyridinium oximes. Based on this evidence and pharmacodynamic studies in experimental animals, diazepam should be given to patients poisoned with OPs whenever convulsions or pronounced muscle fasciculation are present. In severe poisoning, diazepam administration should be considered even before these complications develop. Although diazepam has a large therapeutic index, there appears to be no place for its routine use in OP poisoning. Diazepam should be given intravenously to patients treated in hospital for OP poisoning, although the intramuscular route is used to administer diazepam outside hospital, such as on the battlefield, when an auto-injector is employed. It should be recognised, however, that absorption by the intramuscular route is poor.

CHAPTER 49 – Management of Organophosphorus Pesticide Poisoning

Publisher Summary The successful management of organophosphorus (OP) pesticide poisoning depends on: the clinician possessing an understanding of the mechanisms of OP pesticide toxicity and applying them to the treatment options; accurate diagnosis and assessment of the severity of intoxication; maintenance of vital body functions and adequate clinical monitoring; further absorption of the OP pesticide being minimized; and appropriate use of atropine, oxime, and diazepam. The chemical structure of OP pesticide and the presence of other ingredients in the formulation may have an impact on the speed of onset of features of intoxication. In addition, the fact that many OP insecticides are lipophilic means that they are distributed to and stored in body fat, and therefore, elimination takes place slowly. The severity of intoxication may increase for 12–36 hrs after exposure, intoxication may be prolonged, or relapse may occur after apparent clinical recovery. An understanding of the toxicodynamic aspects also explains why oximes may be of particular value in intoxication because of diethyl phosphates. The diagnosis of OP pesticide poisoning is based on a patients history, clinical presentation, and laboratory tests. Maintenance of vital body functions and adequate clinical monitoring, and minimizing further absorption of OP pesticide are two management proceses. A number of novel approaches to antidotal treatment of OPs have been studied, often using prophylactic protocols and mostly in relation to nerve agent poisoning, but some may be applicable, at least in principle, to OP pesticide poisoning.

The Role of Diazepam in the Treatment of Nerve Agent Poisoning in a Civilian Population

The main site of action of diazepam, as with other benzodiazepines, is at the GABAA receptor, although it has been suggested that some of the potentially beneficial actions of diazepam in nerve agent poisoning are mediated through other means. It is likely that convulsions may have long-term sequelae in the central nervous system, because of damage by anoxia and/or excitotoxicity. Numerous pharmacodynamic studies of the action of diazepam in animals experimentally poisoned with nerve agents have been undertaken. In nearly all of these, diazepam has been studied in combination with other antidotes, such as atropine and/or pyridinium oximes, sometimes in combination with pyridostigmine pretreatment. These studies show that diazepam is an efficacious anticonvulsant in nerve agent poisoning. There is considerable experimental evidence to support the hypothesis that diazepam (and other anticonvulsants) may prevent structural damage to the central nervous system as evidenced by neuropathological changes such as neuronal necrosis at autopsy. In instances of nerve agent poisoning during terrorist use in Japan, diazepam seems to have been an effective anticonvulsant. Consequently, the use of diazepam is an important part of the treatment regimen of nerve agent poisoning, the aim being to prevent convulsions or reduce their duration. Diazepam should be given to patients poisoned with nerve agents whenever convulsions or muscle fasciculation are present. In severe poisoning, diazepam administration should be considered even before these complications occur. Diazepam is also useful as an anxiolytic in those exposed to nerve agents.