Pesticide Toxicity Lecture PDF

Pesticide Toxicity Definition  of Pesticide Any substance or mixture of substanc deliberately added to the environment an intended for preventing, destroyin repelling, or mitigating pests  Pesticides may be more specifically identifie as insecticides (insects),...

Pesticide Toxicity Definition  of Pesticide Any substance or mixture of substanc deliberately added to the environment an intended for preventing, destroyin repelling, or mitigating pests  Pesticides may be more specifically identifie as insecticides (insects), herbicides (weeds fungicides (fungi and molds), rodenticide (rodents), acaricides (mites), molluscide (snails and other mollusks), miticides (mites larvicides (larvae), and pediculocides (lice)  In addition, “pheromones” plant regulator repellants, and attractants often also fall in th broad classification of chemicals  Use of pesticides  Pesticides are often, if not always, used as multi-agent formulations, in which the active ingredient is present together with other ingredients to allow mixing, dilution, application, and stability…."inert" or "other“ (e.g., formaldehyde, sulfuric acid, benzene, toluene, other organic solvents )  “Others”  “Others”: Though they do not have pesticidal action, such inert ingredients may not always be devoid of toxicity, thus, an ongoing task of manufacturers and regulatory agencies is to assure that inert ingredients do not pose any unreasonable risk of adverse health effects  US Pesticide Use 4.5 billion pounds chemicals per year 890 active ingredients, 30,000 formulations Uses 75% agricultural 25% home, garden, structural  Exposure  Exposure to pesticides can occur via the oral or dermal routes or by inhalation  High oral doses, leading to severe poisoning and death, are achieved as a result of pesticide ingestion for suicidal intent, or of accidental ingestion, commonly due to storage of pesticides in improper containers  Chronic low doses, on the other hand, are consumed by the general population as pesticide residues in food or as contaminants in drinking water  Exposure  Workers involved in the production, transport, mixing and loading, and application of pesticides, as well as in harvesting of pesticide-sprayed crops, are at the highest risk for pesticide exposure  Dermal exposure during normal handling or application of pesticides, or in case of accidental spillings, occurs in body areas not covered by protective clothing, such as the face or the hands, or by inhalation  Furthermore, pesticides deposited on clothing may penetrate the skin and/or potentially expose others, if clothes are not changed and washed on termination of  Human Poisoning  Pesticides are not always selective for their intended target species…..adverse health effects can occur in nontarget species, including humans  Concerns range from acute human poisoning to a possible association between pesticide exposure and increased risk of cancer  Several million poisonings and a couple hundred thousand of deaths….World Health Organization (WHO) classified pesticides by hazard, where acute oral or dermal toxicities in rats were Table 22–1 WHO-recommended classification of pesticides by hazard (2009). WHO Class LD50 for the rat (mg/kg body weight) Oral Dermal Ia Extremely hazardous RBC cholinesterase Insecticides: Cholinesterase Inhibitors N-methyl Carbamates (carbamic acid) Carbaryl, Carbofuran, R O Aldicarb N C Generic structure for N— methyl carbamates R X Dermal skin penetration by carbamates is increased by organic solvents and emulsifiers present in most formulations Carbamates inhibit AChE reversibly…… susceptible to a variety of enzyme-catalyzed biotransformation reactions, (oxidation and hydrolysis) Insecticides: Cholinesterase Inhibitors Organophosphates (OPs) Chlorpyrifos, Diazinon, Malathion RO O Generic structure for P OX organophosphates RO Compounds that contain a sulfur bound to the phosphorus, metabolic bioactivation is necessary for their biological activity to be manifest…..only compounds with a P=O moiety are effective inhibitors of AChE (cytP450)  Structures of some organophosphoru s insecticides and of the nerve agent sarin Most commonly used compounds are organophosphoro thioates (i.e., have a P=S bond), but some, including sarin, have a P=O bond and do not require  Insecticides: organophosphate Phosphorylated AChE is hydrolyzed by water slowly, and the rate of "spontaneous reactivation" depends on the chemical nature of the R substituents When there is loss of one of the two alkyl (R) groups, the enzyme-inhibitor complex has "aged“ and reactivation of phosphorylated AChE does not occur The enzyme is considered to be irreversibly inhibited, and synthesis of new enzyme is required to restore activity, a process that may take days  Table 22–4 Signs and symptoms of acute poisoning with anticholinesterase compounds. Site and Receptor Manifestations Affected Exocrine glands (M) Increased salivation, lacrimation, perspiration Eyes (M) Miosis, cyclospasm Gastrointestinal tract (M) Abdominal cramps, vomiting, diarrhea Respiratory tract (M) Increased bronchial secretion, bronchoconstriction Bladder (M) Urinary frequency, incontinence Cardiovascular system Bradycardia, hypotension (M) Cardiovascular system Tachycardia, transient hypertension (N) Skeletal muscles (N) Muscle fasciculations, twitching, cramps, generalized weakness, flaccid paralysis Central nervous M: muscurinic receptorsystem Dizziness, lethargy, fatigue, N: nicotininc receptor (M, N) headache, mental confusion,  Commonly-used Acronyms for Cholinesterase Inhibition Syndromes Salivation Defecation Lacrimation Urination Urination Miosis Diarrhea Bronchospasm Excessive salivation Lacrimation Salivation sweating  Treatment of Pesticide Intoxication Decontamination Procedures aimed at decontamination and/or at minimizing absorption depend on the route of exposure: Collect serum, urine, & clothing samples…..save for residue analysis Dermal exposure: contaminated clothing should be removed, and the skin washed with soap. Scrub under fingernails Ingestion: administer activated charcoal or gastric lavage in case of large ingestions, caution: possibility of seizures or rapidly changing mental status Specific Management for AChI Poisoning Respiratory distress: maintain ABC; Oxygen, bronchodilators if indicated Atropine (i.v), (muscarinic receptor antagonist), prevents the action of accumulating acetylcholine on these receptors Administration of pralidoxime (2-PAM) early after exposure can help prevent AChE aging Diazepam may be used to relieve anxiety in mild cases, and control convulsions in the more severe cases  Treatment: Atropine Reverses SLUD, DUMBELS syndrome Give atropine in escalating doses until clinical improvement is evident. Begin with 2–5 mg IV initially Double the dose administered every 5 minutes until respiratory secretions have cleared. Note: Atropine will reverse muscarinic but not nicotinic effects 2-PAM Treatment Regimen Loading dose (30–50 mg/kg, total of 1–2 g in adults) over 30 minutes followed by a continuous infusion of 8– 20 mg/kg/h Most effective if started early, before aging but may still be effective if given later, particularly after exposure to highly lipid- soluble compounds released into the blood from fat stores over days to weeks Continue pralidoxime for 24 hours after the patient becomes asymptomatic, or at least as long as atropine infusion is required  Insecticides All of the chemical insecticides in use today are neurotoxicants, and act by poisoning the nervous systems of the target organisms Cholinesterase Inhibitors Carbamates Organophosphates Pyrethrins & Pyrethroids Organochlorines  Insecticides Pyrethrins & Pyrethroids Pyrethrins Natural insecticides developed from extracts of the flower head of Chrysanthemum cinerariaefolium Unstable Pyrethroids Synthetic derivatives Used with piperonyl butoxide to Prolong their activity  Pyrethroid Insecticides Pyrethroids now account for >25% of the global insecticide market  High insecticidal potency  Relatively low mammalian toxicity (not well absorbed from skin and GIT),  Lack of environmental persistence, and  low tendency to induce insect resistance, used widely as insecticides in :  in the house and in agriculture,  in medicine topically for Tx of scabies and head lice  in tropical countries as soaks to prevent mosquito bites  Pyrethrins & Pyrethroids Mechanism of Toxicity  Pyrethroid structure Pyrethroid structure  Type I (non-cyano) · Shorter inactivation Compound R R’ · Type II (-cyano) · Longer inactivation  Pyrethrins & Pyrethroids Mechanism of Toxicity They are axonic poisons and cause paralysis of an organism The chemical causes paralysis by keeping the sodium channels open in the neuronal membranes of an organism Pyrethroids are rapidly metabolized through both type I and type II reaction (hydrolysis and oxidation as well as conjugation)  Pyrethroids Toxicity Dermal contact with pyrethroids is paresthesia (from a direct effect on cutaneous nerve endings) Symptoms include continuous tingling & tickling or, when more severe, burning Ingestion of large dose the CNS may be affected, resulting in seizures, coma, or respiratory arrest. Chronic studies indicate that at high dose levels they cause slight liver enlargement accompanied by some histopathologic changes Little evidence of teratogenicity and  Pyrethroid Toxicity Treatment Symptomatic relief Decontamination Topical application of vitamin E?? (in part due to sequestration of lypophilic pyrethroid into the vitamin E) In prophylaxis, or after 15-20 min of exposure. (oil/vaseline) administer activated charcoal orally Enhanced elimination. …no role…rapidly metabolized  Insecticides All of the chemical insecticides in use today are neurotoxicants, and act by poisoning the nervous systems of the target organisms Cholinesterase Inhibitors Carbamates Organophosphates Pyrethrins & Pyrethroids Organochlorines Insecticides: Organochlorines Chlorinated ethane derivatives (DDT) (prototype) Cyclodienes (Chlordane, aldrin, Click to add text dieldrin, heptachlor, Click to add text endrin, toxaphene) Hexachlorocyclohexane (Lindane)  DDT and Its Analogs DDT effective against agricultural pests, and insects that transmit serious diseases (malaria & yellow fever) DDT has a moderate oral acute toxicity and its dermal absorption is very limited The earliest symptom DDT poisoning is pyresthesia of the mouth and lower part of the face High doses also causes motor unrest, increased frequency of spontaneous movements, abnormal susceptibility to fear, to external stimuli, followed by  DDT and Its Analogs Both in insects and in mammals, DDT interferes with the sodium channels in the axonal membrane by a mechanism similar to that of pyrethroids An important target for chronic DDT exposure is the liver……increase liver weight and cause hepatic cell hypertrophy and necrosis Potent inducers of cytochrome P450s Both DDE and DDD (breakdown product), are carcinogenic in rodents, causing primarily an increase in hepatic tumors  Hexachlorocyclohexanes and Cyclodienes These two families of organochlorine insecticides comprise a large number of compounds that share a similar mechanism of neurotoxic action Lindane and cyclodienes have moderate to high acute oral toxicity….readily absorbed through the skin The primary target for their toxicity is the central nervous system…..bind to the chloride channel, blocking its opening and antagonizing GABA action Other Insecticides Nicotine Oral LD50 is 50-60 mg/kg Is readily absorbed through skin Mimics the action of acetylcholine Rotenoids At least six rotenoid esters (rotenone) Isolated from Derris root Toxicity due to its ability to inhibit, at nanomolar conc., the mitochondrial respiratory chain Toxicity varies greatly in different species Very toxic to fish - Used to paralyze fish for capture and consumption Low acute toxicity in humans, but causes allergic reactions Poisoning symptoms: increased respiratory and cardiac rates, muscular depression, followed by respiratory depression