Metal-Containing Pesticides

Metals

• Essential* – Zinc– Copper– Iron– Chromium– Phosphorus– Selenium– Cobalt

• *All metals are toxic in excess.

• Neutral or detrimental– Tin– Bismuth– Boron– Barium– Antimony– *Arsenic– *Thallium– *Lead– *Mercury

• * Designates invariably harmful metals

General Considerations• 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

• 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

Barium

• Barium carbonate: BaCO3 – Rodenticide• 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• 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• 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

Trifentin acetate

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– Acute toxicity

• 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