BASIC INDUSTRIAL TOXICOLOGY PharmDr.Milan Juhás St.Anne`s University Hospital Brno M:\LF MU\OCCUPATIONAL MEDICINE AND TOXICOLOGY\jpeg\toxicology.gif Today`s goal ... (1) •Focus on industrial intoxications – –Lead poisoning (Pb) –Carbon monooxide (CO) –Insecticides (organophosphates) –Hydrogen cyanide (HCN) –Hydrogen sulphide (H2S) – Today`s goal ... (2) •Focus on industrial intoxications – – –Toxicokinetic properties –Toxicodynamic effects –Industrial occurance and health effects Lead (Pb) • M:\LF MU\OCCUPATIONAL MEDICINE AND TOXICOLOGY\jpeg\Lead_electrolytic_and_1cm3_cube.jpg Lead - properties •Heavy soft grey metal •High density and resistance against rust •Forms –„pure“ metal –Organic compund (petrol hydrocarbons) TML, TEL –Inorganic compound (PbS) •Pipes, petrol, ammunition, foil Lead - toxicokinetic parameters •Absorbtion –Lungs (major absorption) –minority via GIT –Presence of other metals in diet increases GIT absoption ! •Distribution –RBC biomembrane –Bone deposits –Extreme long half-time Other metals (calcium, iron) Lead - toxicodynamic parameters (1) Schema author: Boswell, 2012 Lead blocks conversion of D-ALA to protoporfyrinogen and incorporation of iron atom to central position in protoporphyrine IX, which results in lack of haem molecule formation. Lead - health effects •Acute symptoms –Fatigue, Abdominal cramps –Constipation, Myalgia –Encefalopathy, Renal failure (children) •Chronic intoxication –Peripheral neuropathy, –Anemia •Organic forms – psychosis, mania Lead manifests its toxic effects maily by binding to sulfhydryl groups of proteins, which causes „denaturation“ of several protein molecules and loss of its biologic activity. TREATMENT – EDTA, PENICILLAMINE •Lead poisoning (Pb) •Carbon monooxide (CO) •Insecticides (organophosphates) •Hydrogen cyanide (HCN) •Hydrogen sulphide (H2S) • Carbon monooxice (CO) - properties •Incomplete combustion of carbonaceous compounds •Colourless, odourless gas • M:\LF MU\OCCUPATIONAL MEDICINE AND TOXICOLOGY\jpeg\Carbon-Monoxide-Graphic_v2_MED-MESSENGER.jpg CO - toxicodynamics •CO causes tissue hypoxia –Active competition with oxygen at HB binding sites –Decrease of PO2 –Carboxyhaemoglobin (COHb) synthesis –HB vs. CO - high affinity ( 100 – 240 x stronger) • •RESULT: Hb transport capacity for O2 diminishes Po2 – partial gas pressure (parcialny tlak plynu) CO – health effects •Toxicity in corelation with c[COHb] •CO level in acute intoxication –Below 1 % - asymptomatic –Up to 30 % - non specific effects: dizzyness, headache, neusea, vomitus, tachycardia –Above 30 % - hypotension, spasms, – cherry-red skin discoloration, –Above 60 % - generalized weakness, confusion, cardiac and respiratory depression, –Above 90 % - death within few minutes Chronic toxicity manifests headache, organic psychosyndrome, Carbon monooxide intoxication symptoms CO intoxication treatment •Hyperbaric oxygen –Increase PO2 in plasma –Result: decrease of c[COHb] due to chemical competitive shift – •Brain edema –Corticosteroids, diuretic therapy – CO halftime in healthy adults 4-5 hours in atmosphere at sea level •Lead poisoning (Pb) •Carbon monooxide (CO) •Insecticides(organophosphates) •Hydrogen cyanide (HCN) •Hydrogen sulphide (H2S) • • • Organophosphates •Inhibition of AchE, PchE •Insecticides in agriculture (obsolete) •Chemical weapon – war gas • •Route of poisoning –Dermal absorption –Inhalation Pche - pseudocholinesterase Organophosphates M:\LF MU\OCCUPATIONAL MEDICINE AND TOXICOLOGY\jpeg\204px-Phosphate_formula.svg.png Organophosphates •Accumulation of acetylcholine –Synapsis –RBC –Increased c[acetylcholine] affects both central and peripheral nervous system – •Treatment: atropine, AchE-reactivators •Problem: enzyme aging, • respiratory depressant medication Atropinw in high doses. Usually 2-4 mg in 10 minute interval until some improvement or atropin toxicity (tachycardia, xerostomia). Obidoxime is in order in 250 mg i.v. infusion or slow i.m. injection repeatedly till respiratory functions improve. Obidoxime is indicated only with maximum atropine dose. •Lead poisoning (Pb) •Carbon monooxide (CO) •Insecticides (organophosphates) •Hydrogen cyanide (HCN) •Hydrogen sulphide (H2S) Hydrogen cyanide (HCN) •Colourless gas with bitter smell • •Use in industry –Extraction of gold, silver –Synthetic fibres and plastic matherials –Metallurgy Hydrogen cyanide (HCN) •Toxicity –Inhibition of cytochromeoxidase in mytochondrial oxydative metabolism M:\LF MU\OCCUPATIONAL MEDICINE AND TOXICOLOGY\jpeg\cyanide1.jpg Hydrogen cyanide (HCN) •Route of intoxication –Skin absorbtion –inhalation • •Acute toxicity symptoms –Headache, tachycardia, hypotension, convulsion –Death Hydrogen cyanide (HCN) •Remove contaminated clothing •Wash exposed skin • •Amylnitrite inhalation •25 % sodium thiosulphate sol. i.v. • The nitrites oxidize some of the hemoglobin's iron from the ferrous state to the ferric state, converting the hemoglobin into methemoglobin.Cyanide binds avidly to methemoglobin, forming cyanmethemoglobin, thus releasing cyanide from cytochrome oxidase.^[14] Treatment with nitrites is not innocuous as methemoglobin cannot carry oxygen, and methemoglobinemia needs to be treated in turn with methylene blue. The evidence for sodium thiosulfate's use is based on animal studies and case reports: the small quantities of cyanide present in dietary sources and in cigarette smoke are normally metabolized to relatively harmless thiocyanate by the mitochondrial enzyme rhodanese(thiosulfate cyanide sulfurtransferase), which uses thiosulfate as a substrate. However, this reaction occurs too slowly in the body for thiosulfate to be adequate by itself in acute cyanide poisoning. Thiosulfate must therefore be used in combination with nitrites.^[14] Hydrogen cyanide (HCN) M:\LF MU\OCCUPATIONAL MEDICINE AND TOXICOLOGY\jpeg\cyanide3.jpg The nitrites oxidize some of the hemoglobin's iron from the ferrous state to the ferric state, converting the hemoglobin into methemoglobin.Cyanide binds avidly to methemoglobin, forming cyanmethemoglobin, thus releasing cyanide from cytochrome oxidase.^[14] Treatment with nitrites is not innocuous as methemoglobin cannot carry oxygen, and methemoglobinemia needs to be treated in turn with methylene blue. The evidence for sodium thiosulfate's use is based on animal studies and case reports: the small quantities of cyanide present in dietary sources and in cigarette smoke are normally metabolized to relatively harmless thiocyanate by the mitochondrial enzyme rhodanese(thiosulfate cyanide sulfurtransferase), which uses thiosulfate as a substrate. However, this reaction occurs too slowly in the body for thiosulfate to be adequate by itself in acute cyanide poisoning. Thiosulfate must therefore be used in combination with nitrites.^[14] •Lead poisoning (Pb) •Carbon monooxide (CO) •Insecticides (organophosphates) •Hydrogen cyanide (HCN) •Hydrogen sulphide (H2S) Hydrogen sulphide (H2S) •Colourless gas with characteristic smell •Toxicity similar to HCN •Inhibition of oxidative mitochondrial metabolism (cytochromeoxidase, HbO2) •Sulphmethaemoglobin formation • •Petrol products (fuel gas), ruber factories • Smell of rotten eggs. Hydrogen sulphide (H2S) •Acute poisoning –Lacrimation, photophobia, mucose irritation (low concentration) –Pneumonitis, respiratory centre paralysis (high concentration) – •Chronic exposure –Keratitis, skin vesicles Hydrogen sulphide (H2S) - therapy •Immediate removal of hydrogen sulphide source • •Oxygen •Sodium amylnitrite –conversion of sulphmethaemoglobin –Symptomatic therapy – milan.juhas@fnusa.cz