Lecture Notes-Pesticides PDF

Toxic Effects of Pesticides LECTURE NOTES WEEK 7 Pesticides - Key Points 1. A pesticide is any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any 2. pest. Chemical insecticides in use today poison...

Toxic Effects of Pesticides LECTURE NOTES WEEK 7 Pesticides - Key Points 1. A pesticide is any substance or mixture of substances intended for preventing, destroying, repelling, or mitigating any 2. pest. Chemical insecticides in use today poison the nervous systems of the target organisms. 3. An herbicide is any compound that is capable of killing or severely injuring plants. 4. A fungicide is a chemical capable of preventing growth and reproduction of fungi. Pesticides - Key Points Pesticide exposures include: Pesticides can be classified as: (1)Accidental and/or suicidal insecticides (insects), poisonings; Herbicides (weeds), (2) Occupational exposure Fungicides (fungi and molds), (manufacturing, Rodenticides (rodents), mixing/loading, application, Acaricides (mites), harvesting, and handling of crops); Molluscides (snails and other mollusks), (3) Bystander exposure to off-target Miticides (mites), drift from spraying operations; and Larvicides (larvae), and (4) The general public who consume Pediculocides (lice) food items containing pesticide Pesticides – Economics, Public Health DDT undergoes bioaccumulation In the past in the environment Introduced in 1942 20 years, Impacts bird reproduction, pesticide DDT was banned in most use countries by the mid-1970s. became Example: more DDT was banned in 1996 in South Africa efficient. By 1996 less than 10,000 cases of malaria Active were reported. ingredients Dichlorodiphenyl By 2000 without DDT 62,000 malaria cases trichloroethane, DDT are used in were reported smaller Reintroduction of DDT in 2000 reduced the cases amounts to 12,500 Benefits: Pesticides allow production of abundant, inexpensive, Pesticides – Economics, Public Health Exposure to pesticides occurs via Highest Risk for Pesticide the oral or dermal routes or by Exposure Workers involved in inhalation. the production, transport, mixing High oral dose is a result of pesticide and loading, and application of ingestion or suicidal intent, or of pesticides, and in accidental ingestion most common harvesting of pesticide-sprayed due to improper storage crops. Dermal exposure Chronic low doses are a result Pesticides deposited on of pesticide residues in food clothing can be absorbed by and contaminants in water the skin consumed by the general population Pesticides – Human Poisoning World Health Organization TABLE 22–1 WHO-recommended classification (WHO) of pesticides by hazard. Reports several million poisonings causing hospital admission  Pesticides – Regulatory Mandate Environmental Protection Agency Federal Food, Drug and Cosmetic (EPA) Regulates pesticide use under Act Registration for use and the Federal Insecticide, Fungicide and establishment of maximum Rodenticide Act allowable levels of pesticide The Food Quality Protection Act residues (tolerances) in mandates EPA to assess risks of foods and animal feeds. pesticides to infants and children All pesticides imilar for the sold or distributed afe Drinking Water Act or the Clean Air Act in the United States Large number of studies (over 140) must be registered by are required, many years and high costs the EPA. $50 and $100 million. Pesticides – Regulatory Mandate Product and residue chemistry, environmental fate, toxicology, biotransformation/degradation, occupational exposure and reentry protection, spray drift, environmental impact on non-target species (birds, mammals, aquatic organisms, plants, and soil), environmental persistence and bioaccumulation, TABLE 22–2 Basic toxicology testing performance and efficacy. requirements for pesticide registration. Pesticides – INSECTICIDES All of the (chemical) insecticides in use today are neurotoxicants. They act by poisoning the nervous systems Organophosphates, of the target organisms are responsible for a large number of human poisonings and deaths each year. TABLE 22–3 Molecular targets of the major classes of insecticides. Pesticides – INSECTICIDES: phosphorothioates phosphorothioate Organophosphorus FIGURE 22–1 Structures of some organophosphorus insecticides and of the nerve agent sarin. Organophosphorus-Biotransformation Only compounds with a P= O Therefore the P = S should become group P= O are effective inhibitors of AChE. Catalytic and non catalytic Oxidative desulfuration (leads to the formation of an “oxon,” hydrolysis or oxygen of phosphoesters leads analog of the parent to detoxification insecticide). Thioether oxidation Followed by leads to the formation of a the formation of a sulfoxide, S= sulfone, O, (O= S= O) Catalysis by P450 The oxidations are catalyzed by converts S cytochrome P450s. to sulfoxide and sulfone Organophosphorus-Toxicity OP insecticides have high acute toxicity. Oral LD50 values in rat often below 50 mg/kg. Symptoms: “cholinergic syndrome” Increased sweating, salivation, bronchial secretion, bronchoconstriction, miosis, increased gastrointestinal motility, diarrhea, tremors, muscular twitching, and various central nervous AChE inhibition system by OPs causes effects, including respiratory failure accumulation of acetylcholine at cholinergic synapses, TABLE 22–4 Signs and symptoms of with overstimulation of muscarinic acute Organo phosphorus Toxicity Scheme of hydrolysis of acetylcholine by acetylcholinesterase (AChE) and reaction of chlorpyrifos oxon with AChE Organophosphorus-Toxicity In case of dermal exposure, contaminated clothing should be removed, and the skin washed thoroughly with alkaline soap. In case of ingestion, procedures to reduce absorption from the gastrointestinal tract do not appear to be very effective. Atropine, a muscarinic receptor antagonist, prevents the action of accumulating acetylcholine on these receptors. Administration of pralidoxime (2-PAM) also recommended Diazepam may be used to relieve anxiety in mild cases,  Organophosphorus-Intermediate Syndrome Manifested in 20% to 50% of Symptoms: acute weakness of OP poisoning respiratory, Usually develops cases. neck, and 1 to several days proximal limb after the muscles. poisoning, Hypothesis: Muscle weakness may result from nicotinic receptor desensitization Mortality due to due to prolonged cholinergic respiratory stimulation paralysis and Underlying mechanisms are unknown. complications,  Organophosphorus-Polyneuropathy Organophosphate -induced Delayed Polyneuropathy Occurs 2 to 3 weeks (OPIDP) after a single exposure, its occurrence in humans is now rare. Symptoms: tingling of the hands and feet, NTE is followed by sensory loss, progressive Neuropathy muscle weakness and flaccidity of the Target distal skeletal muscles of the lower Esterase and upper extremities, and ataxia. Primary lesion is a bilateral degenerative change in Exact mechanisms distal levels of axons and their terminals, primarily involved in affecting larger/longer myelinated central and phosphorylation peripheral nerve fibers, leading to breakdown of and aging of NTE and neuritic segments and the myelin sheaths leading axonal degeneration Organophosphorus-Long Term and Developmental Toxicity Long term toxicity in long-lasting Experimental data indicate adverse that young animals are more health effects (particularly in the CNS) sensitive to the acute toxicity of has been shown in animals, and OPs. humans. Low exposure to OPs, Because of their lower at doses that produce no detoxication abilities Studies in rodents indicate that OPs cholinergic can affect various cellular processes signs, also may lead to long-term (e.g., DNA replication, neuronal adverse health effects, survival, neurite outgrowth) and Particularly in the central and noncholinergic peripheral nervous systems. pathways (e.g., serotoninergic synaptic functions, the adenylate cyclase system), and cause various Carbamates Carbamate insecticides are biotransformation derivatives of carbamic acid. reactions, most are N-methylcarbamates. and the principal Acute oral toxicity ranges from low to pathways moderate toxicity, such as carbaryl, to involve oxidation and Carbamate hydrolysis. mechanism of toxicity: extremely high toxicity, such as by inhibition of AChE, which is rapidly aldicarb. Dermal skin penetration by reversible carbamates is increased by organic solvents and when given before a neuropathic emulsifiers present in most organophosphate, carbamates Carbamate poisoning symptoms: offer protection against OPIDP, formulations. miosis, urination, diarrhea, but when salivation, muscle ascicculation, given after, they can promote and CNS effects OPIDP. Embryotoxicity or fetotoxicity is observed only at maternally Methylcarbamates are not Carbamates Toxicity FIGURE 22–3 Structures of some carbamate insecticides, with indication of acute oral and dermal toxicity in the rat, and of water solubility. Note that carbofuran has been banned in recent years in several countries. Pyrethroids Pyrethrins were first developed as insecticides from extracts of the flower heads of Chrysanthemum cinerariifolium, High insecticidal potency, low mammalian toxicity, lack of environmental persistence, and low tendency to induce insect resistance, they account for 15% to 20% Change the normal function of insect of the global nerves insecticide by modifying the market. kinetics of voltage-sensitive sodium channels, Pyrethrin from which mediate the transient increase Chrysanthemum in the sodium permeability of the cinerarifolium nerve membrane that underlies the Pyrethroids They decompose rapidly on exposure to light, Two major biotransformation routes: hydrolysis of the ester linkage, catalyzed by hepatic and plasma carboxylesterases, and oxidation of the alcohol by cytochrome P450s. Pyrethrin from Chrysanthemum cinerariifolium Medicine for the topical treatment Pyrethroids Type I compounds produce a syndrome consisting of marked behavioral arousal, aggressive sparring, increased startle response, and net body tremor progressing to whole-body tremor and Type II compounds produce profuse prostration salivation, coarse tremor progressing to choreoathetosis, and clonic TABLE 22–5 Classification of pyrethroid seizures Insecticides based on toxic signs Occupational exposure, the primary adverse effect resulting from dermal in rats. contact with pyrethroids is paresthesia. Symptoms include continuous tingling or pricking or, when more severe, burning. The condition reverses in about 24 h, and topical application of vitamin E Organochlorine Compounds Chlorinated ethane DDT and Its Analogs—DDT is derivatives, effective against a wide variety of such as DDT and its agricultural pests, and insects that analogs; transmit some the cyclodienes of the world’s most serious diseases, chlordane, aldrin, dieldrin, such as typhus, malaria, and yellow heptachlor, endrin, and ever. toxaphene; In insects and in mammals, DDT interferes with the sodium The hexachlorocyclohexanes, channels in the axonal lindane; and the caged membrane structures mirex, chlordecone. by a mechanism similar to that of type I pyrethroids. Organochlorine Compounds FIGURE 22–4 Structure and acute toxicity (oral LD50 in rat) of selected organochlorine insecticides of different chemical classes. Organochlorine Compounds Acute exposure to high doses of Low Toxicity from dermal DDT causes motor unrest, increased exposure On absorption, DDT distributes in frequency of spontaneous all tissues. The highest movements, abnormal concentrations susceptibility to ear, and hyper are found in adipose tissue. susceptibility It is excreted through the bile, to external stimuli (light, touch, and urine, sound). In humans, the earliest symptom and of milk. This is followed by the development of tremors, progressing to coarse poisoning by DDT is hyperesthesia tremors, of the mouth and lower part of the Chronic exposure increases liver face, followed by paresthesia of and eventually tonic–clonic weight convulsions. the and causes hepatic cell hypertrophy same area and the tongue. Death is typically and necrosis dueand by DDT to respiratory DDE failure. Dizziness, tremor of the (metabolite)  Organochlorine Compounds exachlorocyclohexanes and Cyclodienes Toxic to the central nervous system. Lindane and cyclodienes have induces hepatic drug- moderate to high acute oral toxicity metabolizing enzymes, and They are readily absorbed through the skin. causes hepatosplenomegaly The exact mechanism of chlordecone in rats and humans. The Stockholm Convention on neurotoxicity has not been elucidated, Persistent Organic Pollutants, but it ratified in 2004 by 50 states, is believed to involve inhibition of outlawed ATPases (both Na ,K - and Mg - + + 2+ the use of 12 industrial ATPases), catecholamines. chemicals Yet, an exemption clause allows malaria-endemic nations to continue utilizing (the “Dirty Dozen”), including DDT for indoor residual wall spraying. The DDT United Nations Environment Program Neonicotinoids Nicotine is a systemic insecticide effective toward a wide range of insects, including aphids, thrips, and whiteflies. Pharmacological and toxic effects in mammals and insects by activating nAChRs (CNS). At high doses, parasympathetic stimulation and ganglionic and neuromuscular blockade predominate. FIGURE 22–5 Structures of nicotine and of neonicotinoid insecticides with indication of their acute oral toxicity in rat and their octanol/water partition (P). (Adapted from Tomizawa M, Casida JE. Neonicotinoids  Signs and symptoms of poisoning include: nausea, vomiting, muscle weakness, respiratory effects, headache, lethargy, and tachycardia. Nicotin  Most cases of poisoning with nicotine occur after exposure to e tobacco products, or gum or patches.  Workers who cultivate, harvest, or handle tobacco may experience green tobacco sickness,  caused by dermal absorption of nicotine.  Neonicotinoids include nithiazine, imidacloprid, nitenpyram, Other Old and New Insecticides Rotenoids agricultural insecticide/acaricide particularly in organic Inhibit, at nanomolar farming Rotenone concentrations, mitochondrial respiration by Poisoning symptoms include blocking initial increased respiratory electron transport at NADH– and ubiquinone reductase, the cardiac rates, clonic and tonic energy conserving enzyme spasms, and muscular complex, depression, known as complex I. followed by respiratory depression. Other Old and New Insecticides Avermectins Streptomyces avermitilis The semisynthetic derivatives of avermectin B1a, emamectin benzoate, and ivermectin are used as insecticides, and for parasite control in human and Avermectin B1a veterinary medicine. symptoms of intoxication include eight individual hyperexcitability, tremors, and avermectins incoordination, by Streptomyces followed by ataxia and coma-like avermitilis sedation. that have antiparasitic activity. Other Old and New Insecticides Avermectins Abamectin is used primarily to control mites, emamectin benzoate is effective at Avermectin B1a controlling lepidopterian species in various crops and emerald ash borer in trees. Ivermectin is used as an In insects and nematodes antihelmintic and they are binding to, and antiparasitic drug in veterinary activating, medicine. glutamate-dependent In humans it has proven to be an chloride channel. effective treatment for infection of Exerting their toxic INSECT REPELLENTS mosquitoes alone transmit disease to more than 700 million persons annually DEET (N,N-diethyl-mtoluamide or N,N-diethyl-3- methylbenzamide) is very effective at repelling insects, flies, fleas, and ticks. Protection In childrentime DEETincreases with is possibly increasing responsible concentrations. or neurotoxic effects Children should only be exposed to products with less than 10% DEET. Insect repellent formulations (cream, aerosol, wipe) containing 5% to 20% picaridin are highly effective against a variety of arthropod pests, especially mosquitoes, ticks, and flies. INSECT REPELLENTS DEET (N,N-diethyl- interaction with specific olfactory mtoluamide or receptors of the arthropod. N,N-diethyl-3- methylbenzamide) In humans it is absorbed through the skin to a limited degree, and is metabolized via hydroxylation and glucuronidation, Picaridin before excretion in the urine. HERBICIDES chemicals that are capable of either killing or severely injuring plants preplanting herbicides are applied to the soil before a crop is seeded, preemergent herbicides are applied to the soil before the time of appearance of unwanted vegetation, postemergent herbicides are applied to the soil or foliage after the germination Contact o the cropaffect herbicides: and/or weeds. the plant that was treated, translocated herbicides are applied TABLE 22–6 Some mechanisms o to the action Chlorophenoxy Compounds Auxin, a plant growth Acute poisoning in hormone, humans, Is critical to the growth of Results in vomiting, many burning of the mouth, broad-leaved plants, but is abdominal pain, not Auxin hypotension, used by grasses, myotonia, and CNS involvement Chlorophenoxy compounds Including coma. can Suppress the growth of Dermal exposure is weeds the major route of (e.g., dandelions) without unintentional exposure affecting the grass. to 2,4-D in humans.  Chlorophenoxy Compounds 2,4-dichlorophenoxyacetic acid (2,4-D). Reports suggest an association between exposure to 2,4-D and neurologic effects like peripheral neuropathy, demyelination and ganglion degeneration in the CNS, reduced nerve conduction velocity, myotonia, and behavioral alterations. 2,4-D does not appear to have Genotoxic or carcinogenic properties in rats, mice, Bipyridil Compounds Paraquat is a fast-acting, nonselective contact herbicide, used to control broad- leaved weeds and grasses in plantations and fruit orchards, and for general weed control. on absorption, independent of the N,N′-dimethyl-4,4′-bipyridinium dichloride route of exposure, paraquat Paraquat accumulates in the lung and the kidney. is very poorly metabolized, and is excreted almost unchanged in the urine. no genotoxic activity, is not 6,7-dihydrodipyrido[1,2-a:2′, 1′-c]pyrazine-5,8-diium dibromide carcinogenic in rodents, has no effect Diquat on fertility, is not teratogenic, and only produces fetotoxicity at maternally toxic doses.  Bipyridil Compounds (1) Redox cycling of paraquat utilizing NADPH; (2) Formation of hydroxyl radicals leading to lipid peroxidation (3); (4) Detoxication of H2O2 via glutathione reductase/peroxidase couple, utilizing Damage to alveolar epithelial cells NADPH occurs within 24 h after acute exposure to lethal doses of paraquat. Damage progresses in the following 2 to 4 days with loss of the alveolar epithelium, alveolar edema, extensive infiltration of inflammatory cells into the IGURE 22–6alveolar interstitium, Mechanism and of toxicity of paraquat. Bipyridil Compounds The second phase is characterized by attempts by the alveolar epithelium to regenerate and restore normal architecture, and presents as an N,N′-dimethyl-4,4′-bipyridinium dichloride intensive fibrosis. Paraquat On chronic exposure, target organs for toxicity are the gastrointestinal tract, the kidney, and particularly the eye 6,7-dihydrodipyrido[1,2-a:2′, Human clinical symptoms include 1′-c]pyrazine-5,8-diium dibromide nausea, vomiting, diarrhea, ulceration Diquat of mouth and esophagus, decline in renal functions, and neurologic effects, Chloroacetanilides alachlor, acetochlor, and metolachlor , (corn, soybeans, and peanuts). Alachlor, acetochlor, and butachlor are probable human carcinogens (Group alachlorB2). in well water led to cancellation of its registration in some alachlor, countries, Triazines 2-Chloro-N-(2,6-diethylphenyl)- The family of triazine herbicides comprises N-(methoxymethyl)acetamide several compounds (atrazine, simazine, and propazine) studies indicate primarily decreased body weight ga Atrazine exposure to atrazine through residues in food commodities is very low, 6-Chloro-N2-ethyl-N4-(propan-2-yl)- contamination of ground water and drinking 1,3,5-triazine-2,4-diamine water is common.  Phosphonomethyl Amino Acids Glyphosate (N-phosphonomethyl glycine) and Glufosinate (N- phosphonomethyl homoalanine). 2-Amino-4-[hydroxy(methyl N-(Phosphonomethyl)glycine phosphonoyl)]butanoic acid Glyphosate exerts its herbicidal action by broad-spectrum nonselective inhibiting the enzyme 5- systemic enolpyruvylshikimate -3- phosphate herbicides used for post-emergent synthase, responsible for the synthesis of control of annual and perennial They do not inhibit AChE. an intermediate in the biosynthesis of plants. various amino acids Although important in plant growth, this metabolic pathway is not present in mammals. Phosphonomethyl Amino Acids N-(Phosphonomethyl)glycine 2-Amino-4-[hydroxy(methyl phosphonoyl)]butanoic acid Glufosinate is a nonselective contact herbicide that acts by irreversibly inhibiting glutamine synthetase. Plants die as a consequence of the increased levels of ammonia Although important in plant growth, this metabolic pathway is not present in mammals. Phosphonomethyl Amino Acids N-(Phosphonomethyl)glycine 2-Amino-4-[hydroxy(methyl phosphonoyl)]butanoic acid Mild intoxication results mainly in Developmental toxic effects transient gastrointestinal were found in rabbits symptoms. (premature deliveries, abortions, and dead Moderate or severe poisoning fetuses). presents with gastrointestinal Humans experience bleeding, gastrointestinal effects, hypotension, pulmonary impaired respiration, dysfunction, neurologic disturbance, FUNGICIDES Captan and Folpet are broad-spectrum fungicides; Captan potent eye irritants, but only mild Folpet skin irritants. Captan and folpet, and thiophosgene, are found mutagenic in vitro tests; induce the development of duodenal tumors in mice, and on this basis, no evidence of they are classified by the US EPA as teratogenicity probable human carcinogens. has been found FUNGICIDES-Dithiocarbamates low acute toxicity by the oral, dermal, and respiratory routes. Ethylenethiourea These compounds are metabolized to a common metabolite, Ethylenethiourea. Dithiocarbamates It is responsible for the effects of dithiocarbamates on the thyroid, which include hypertrophy and hyperplasia of thyroid follicular cells that progress to  FUNGICIDES- Metals rganic and Organometallic Fungicides Copper sulfate has overall low toxicity and remains one of the most widely used fungicides. Ph3Sn and Bu3Sn CuSO4 Triphenyltin acetate is used as a Organic mercury compounds, fungicide, whereas tributyltin is such as methylmercury, were utilized as an anti fouling agent. used extensively as fungicides Triphenyltin has moderate to high in the past for the prevention of acute toxicity, but may cause seed-borne diseases in grains and reproductive toxicity and endocrine cereals. disruption. FUNGICIDES- Metals Organic mercury compounds, such as methylmercury, were used extensively as fungicides in the past for the prevention of seed-borne diseases in grains and cereals. RODENTICIDES Rats and mice can cause health To be effective and safe, rodenticides and must satisfy several criteria: economic damages to humans. (1) the poison must be very effective in the target species once Rodents are vectors for several incorporated human into bait in small quantity; diseases, including plague, (2) baits containing the poison endemic rickettsiosis, must not excite bait shyness, so that spirochetosis, and others; the animal will continue to eat it; (3) the manner of death must be such They can occasionally bite that survivors do not become people; suspicious of its cause; and they can consume large (4) it should be species-specific, Toxicologic problems can arise from acute quantities of postharvest stored accidental foods, and can  RODENTICIDES luoroacetic Acid and Its Derivatives the central nervous system and the Their high mammalian toxicity limits heart. their use to trained personnel. Initial gastrointestinal symptoms are followed by severe cardiovascular effects (ventricular tachycardia, fibrillation, and hypotension), and CNS effects (agitation, convulsions, and coma).  RODENTICIDES-Anticoagulants Anticoagulants Coumarin derivatives, including warfarin itself, are used as anticoagulant drugs and have become a mainstay for prevention of thromboembolic disease. Coumarins antagonize the action of vitamin K in the synthesis of clotting actors (factors II, VII, IX, and TheirX). specific mechanism involves inhibition of vitamin K epoxide reductase, which regenerates the reduced vitamin K necessary for sustained carboxylation and synthesis of warfarin relevant clotting factors. hoice for significant number of suicide or homicide attempts FUMIGANTS Compounds used as fumigants are usually nonselective, highly reactive, and cytotoxic. These agents are active toward Inhalation exposure, insects, mites, nematodes, weed and to a minor degree seeds, fungi, or rodents, and have in or dermal exposure common the property of being in the or ingestion, gaseous form at the time they exert in case of solids or liquids. their pesticidal action (e.g., ethylene dibromide methyl bromide, phosphine released by FUMIGANTS Methyl Bromide Methyl bromide is an odorless and broad-spectrum pesticide, used for colorless gas. soil Chloropicrin, with a pungent odor fumigation, commodity treatment, and eye irritation, is often used and structural fumigation. in conjunction with it Acute exposure results in respiratory, gastrointestinal, and neurologic symptoms; the latter include lethargy, headache, seizures, paresthesias, peripheral neuropathy, and ataxia, and are considered to be more relevant than other toxic effects for human risk assessment. FUMIGANTS 1,3-Dichloropropene soil fumigant, extensively utilized for its ability to control soil nematodes. An irritant. Can cause redness and necrosis of the skin. Liver tumors in rats but not in mice, after oral administration Data on genotoxicity are contradictory, and carcinogenicity studies in rodents have found an increase in benign tumors FUMIGANTS Sulfur Elemental sulfur is an effective fumigant for the control of many plant diseases, particularly fungal diseases, and represents the most heavily used crop Exposure to elemental sulfur causes protection chemical in dermatitis. the United States. In ruminants, excessive sulfur ingestion can cause cerebrocortical its major uses in necrosis (polioencephalomalacia), grapes possibly due to its conversion by and tomatoes, microorganisms in the rumen to and can be used in hydrogen sulfide. organic farming.