Metal-Containing Pesticides

Metals Neutral or detrimental Tin Bismuth Boron Barium Antimony *Arsenic *Thallium *Lead *Mercury * Designates invariably harmful metals Essential* Zinc Copper Iron Chromium Phosphorus Selenium Cobalt *All metals are toxic in excess.

General Considerations Toxicology For most metal-containing pesticides, the toxicity is due to the metal Example: As-containing herbicide, fungicide will have similar toxicities despite very different structures Exception: Dithiocarbamate fungicides Elements do not degrade Environmental accumulation is a significant risk of continuing use As in soil of old orchards? Bioaccumulation may occur if metal is in a form that can be taken up by plants Most metals are excluded by most plants Cadmium is taken up by some plants Environmental presence in soil implies risk of transport into water Movement from soil to air, air to soil also occurs Environmental transformations may occur Hg ---> MeHg

Barium Barium carbonate: BaCO3 Rodenticide Human poisoning? 20-25% active ingredient in baits Neurotoxicant Human poisoning? 1 case of mass poisoning Substituted for flour in pastry

Chromium Sodium dichromate: Na2Cr2O7•2H2O Cotton defoliant Wood preservative Toxicity: Bronchiogenic cancer suspected May require inhalation Chromium is also an essential element

Copper Copper sulfate: CuSO4 Also known as blue vitriol Fungicide, algicide Bordeaux mixture: CuSO4 and Ca(OH)2 Fungicide and seed treatment Very alkaline Toxicology Acute: Renal failure Chronic: Fatty degeneration of kidneys, liver Pneumoconiosis from occupational exposure to Bordeaux mixture Granulomas of lung, liver , kidney

Zinc Zinc chloride: ZnCl2 Wood preservative LD50 : po, rat: 2,200 to 19,000 mg/kg Ip, mouse: 31 mg/kg Zinc compounds tend to be emetic Zinc phosphide: Zn3P2 Rodenticide Toxicity is due to production of phosphine (PH3) by stomach acid Phosphine causes pulmonary and cerebral edema :

Cadmium No known biological function Cadmium chloride: CdCl2 Turf fungicide Toxicity Acute Salivation, diarrhea, vomiting Chronic Poor growth, anemia, kidney damage Itai-itai from dietary exposure May be aggravated by Ca and/or vitamin D deficiencies High blood pressure? Accumulates in kidneys Human poisoning with CdCl2 has not been reported

Mercury Toxicology Major concern for all forms is chronic toxicity Elemental Hg: Little absorption through GI tract Not absorbed through skin Vapors are primary danger Dyspnea, fatigue, gingivitis, loss of teeth, tremors, irritability Depression, despondency, lethargy, weakness, coma, death Inorganic Hg: Mercuric chloride: HgCl2 Fungicide LD50 37 mg/kg, po, rat

Organic Mercury Compounds 1915: Phenylmercury salts HgC6H6 1929: Alkylmercury salts Methylmercury, HgCH3 LD50 ca 30 mg/kg NOAEL = 0.5 mg/kg/day for 150 days 1960s-1970s - Hg-containing pesticides banned by most countries

Organic Mercury Compounds Toxicology Absorbed through skin, GI tract Crosses blood/brain barrier Little excretion from CNS Neurological damage is 1st symptom CNS Tremors, loss of peripheral vision, irritability progressing to dementia Some improvement if exposure ends Most damage is permanent Pregnant women excrete Hg to fetus Congenital Minamata disease No repair possible Arylmercury compounds Acrodynia or “pink disease”

Thallium Rodenticide Home uses banned in US in 1975 Toxicology Crosses skin, GI tract Mechanism of action not well understood Interferes with intracellular K? Thallium sulfate, Tl2SO4 LD50 10.6 mg/kg, rat po 1/50 of LD50 per day: Depilation in 4 months Death in 6 months

Arsenic Fungicide Chromated copper arsenate Insecticides Paris Green Copper acetoarsenite Cu(C2H3OO)2 •3Cu(AsO2) used against Colorado potato beetle, 1865 Scheele’s Green Copper arsenite, CuHAsO NaAsO2 still used in poison bait against grasshoppers PbHAsO4 used on apples against codling moths Used against gypsy moth 38,000,000 kg in 1942 LD50 in rats, po: 800 mg/kg Herbicide Cacodylic acid: (CH3)2AsO(OH) LD50 in rats, po: 830 mg/kg Fungicide Chromated copper arsenate wood treatment introduced 1940s phased out 2003 12x2x6” board contains 27 g arsenic 5 Tbs ash contains enough As to kill a 1,100 lb cow tastes salty

Human Toxicity of Arsenic Acute toxicity GI tract symptoms Cumulative toxicity (rats) 1.6 mg/kg/day is NOAEL of arsenites 3.2 mg/kg/day is NOAEL of arsenates Mechanism Increases permeability of capillaries Decreases blood pressure ---> shock, death Skin lesions Also used therapeutically to clear skin Polyneuropathy Cancer Skin Following ingestion, not topical application Lung Following inhalation only? Evidence is epidemiological People living downwind from copper smelters

Tin Trifentin acetate Trifentin acetate Introduced 1954 as fungicide Inorganic tin does not enter body Organic tin compounds RSnX3 RSn2X2 RSn3X RSn4X X = Simple ion Complex ion R = Alkyl Aryl Trifentin acetate Introduced 1954 as fungicide Also used as molluscicide, algicide Bioaccumulates in harbor ecosystems Neurotoxic Banned for environmental reasons

Summary All metals are toxic in excess As, Hg, Cd, Pb have no useful function in living organisms Toxicity of metal-containing pesticides is usually that of the metal Exceptions: Dithiocarbamate fungicides Zinc phosphide

Dithiocarbamate Fungicides Ethylenebisdithiocarbamates Maneb Nabam Zineb Dimethyldithiocarbamates Ferbam Ziram

Ethylenebisdithiocarbamates Zineb: Acute toxicity LD50 po rats: 1,850-8,900 mg/kg Mice: 7,600-8,200 mg/kg Rabbits: 4,450 mg/kg Maneb LD50 po > 5,000 mg/kg in rats and mice M M = Zn, Zineb = Mn, Maneb = Na, Nabam = Zn+Mn, Mancozeb

Ethylenebisdisdithiocarbamate fungicides: an alternative structural form

Dimethyldithiocarbamates Ziram LD50 po rats: 1400 mg/kg Mice: 480 mg/kg Guinea pigs: 100-150 mg/kg

Common Features of Dithiocarbamates Acute toxicity is low Depress thyroid function Common metabolite: Ethylenethiourea Interact with alcohol consumption Blocks oxidation of EtOH at acetaldehyde step Acetaldehyde accumulates Disulfiram (Antabuse) Used to prevent EtOH consumption by alcoholics Disulfiram

ETHYLENETHIOUREA

Developmental toxicity of ethylenethiourea Severe developmental toxicity in rats Craniofacial malformations Little activity in mice Similar pharmacokinetics in both species

Summary Toxicity of most metal-containing pesticides depends on the metal Toxicity of dithiocarbamates does not depend on the identity of the metal Dithiocarbamates are Thyrotoxic Suspect carcinogens Their metabolite, ethylenethiourea, Is a developmental toxic in rats but not in mice Many dithiocarbamates were voluntarily withdrawn by their manufacturers rather than carrying out currently required safety testing