Inorganic Metallic Irritants—Lead 4O Lead (shisha) Is the commonest of heavy metals as far as chronic poisoning is concerned, Physical properties: Heavy, stecl-gray metal. Salts are variously colored. Contrary to many other pure metals, metallic lead Is absorbed through GIT, being soluble in gastric juice Toxic compounds (Table 40.1) Action i. Lead combines with sulfydryl groups and interferes with mitochondrial oxidative phosphorylation, ATPases, calcium-dependent messengers and enhances oxidation and cell apoptosis. This causes defective heme synthesis, proximal renal tubular and osteoblast dysfunction Il, In the CNS, it has deleterious effects on the nerve cells and myelin sheaths and also causes cerebral edema Absorption and Excretion + Lead is absorbed through the GIT, respiratory tract (dust and fumes) and skin (lead tetraoxide). In blood 95-99% of lead is sequestered in RBCs. + Absorption of lead compounds is directly pro- portional to solubility and inversely proportional to particle size. GIT lead absorption is increased by iron deficiency and low dietary calcium and decreased by co-ingestion with food Table 40.1: Toxle compoun ‘Compounds Uses I. Lead acetate Earller used as an astringent (Sugar of lead) and local sedative for sprains Ii, Lead tetraoxide Used as sindoar {fed lead. or vermilion) i Tetraethyl lead iv. Lead sulfide (surma; least toxig! v. Lead carbonate Manufacture of paints (white lead) Antiknock for petrol ‘Appliod on the eyes + It Is @ cumulative poison. In chronic exposure, it deposits in tissues, mostly in the bones (90%), liver and kidneys + Itismainly excreted through the urine (70%), but rate of excretion is low: smaller amounts are eliminated via feces and scant amounts via the hair, nails and sweat Signs and Symptoms (Acute Poisoning) It manifests as GIT or CNS disturbances, + GIT: Metallic taste, dry throat, thirst, vomiting, nausea, burning abdominal pain (colic) and blood- stained diarrhea leading to circulatory collapse. + CNS: Headache, lethargy, arthralgia, myalgia, ano- rexia, insomnia, paresthesia, depression, coma and death. Fatal dose + Lead carbonate: 40 g + Lead acetate: 20 g Fatal period: 1-2 days. Laboratory diagnosis i. Porphyrinuria due to coproporphyrin 111 Ui, Blood lead level > 70-100 j1g/dl. Protoporphyrin > 35 g/dl ill, Urine lead level > 0.15-0.3 mg/I Treatment i. Gastric lavage with 1% solution of sodium or magnesium sulphate (forms insoluble lead sulphate), above salts are also given in the purgative dose. Il, Demulcents, whole bowel irrigation and repeated cathartics ili, Calcium chloride 5 mg as 10% solution IV or calcium gluconate 10 ml of 10% solution IV causes deposition Of lead in bones from blood (to combat acute crisis). iv. Edetate calcium disodium (CaNa;EDTA), 1500 mg/m?/kg/day (50 mg/kg/day) in 4-6 divided doses oF a5 a continuous infusion for 5 days. Some add BAL, 4-5 mg/kg IM every 4 h for 5 days.<=> Fundamentals of Forensic Medicine and Toxicology v. Vitamin C (weak, but natural chelating agent) may be given Vi. Peritoneal or hemodialysis in anuric patients with chronic renal failure Symptomatic treatment Postmortem Findings i. Body appears emaciated, rigor mortis appears early. ii, Stomach wall is swollen, mucous membrane is congested, grayish in color and softened with eroded patches, Chronic Lead Poisoning (Plumbism/Satumism)' + Lead Is a cumulative potson, remains accumulated in bones as phosphate and carbonate. + High calcium level favors storage, while calcium deficiency causes lead to be released into the blood stream. + Other factors promoting release of stored lead: Acidosis, fever, sweating, consumption of alcohol and exposure to sunlight Causes + Leadl is ingested or inhaled. The most common source is ingestion of lead-containing dust. + Lead paint dust is the most common source of lead exposure for children? Children < 3 years are at the Fatigue Headache Metalic taste Retinal tipping 2 Burton's ine Loss of bdo Weight loss (femeles) monetualiegulartoe greatest risk for lead poisoning as they are more likely to put things containing lead into their mouths (pica— persistent eating of non-nutritive material for 1 month ‘or more) and their brains are rapidly developing + Inhalation of lead dust and fumes by makers of white lead, lead paints, plumbers, glass polishers, printers and glass blowers + Absorption from drinking water stored in lead cisterns, from tinned food contaminated with lead from solder, use of hair dyes and cosmetics containing lead. + Percutaneous absorption of tetraethyl lead in persons. who handle petrol and gasoline. ‘+ Absorption of vermilion applied to scalp. Chronic lead poisoning results from daily intake of 1-2 mg of lead Signs and Symptoms Chronic poisoning is insidious with fatigue, sleep distur- bance, headache, irritability, slurred speech, stupor, ataxia, convulsions, anemia and renal failure Fig. 40.1) Characteristic features are given below: 1. Anemia: In early stages, there may be polycy- themia with polychromatophilia, but later there Is. anemia with karyorrhexis and dyserythropoiesis. (punctate basophilia, reticulocytosis, poikilocytosis, Aanisocytosis), nucleated red cells and increase In mononuclear cells. However, polymorphonuclear cells and platelets are decreased, RBC count comes Memory problems Deiiium Sleeo disturbance Ria Kidney faiure ‘Weight loss. anemis Conetpation &eale Opaque < iiss or foot crop metanhyseal bands ray > > Early symptoms] Tate symptoms Fig. 40.1: Signs and symptoms of chronic lead poisoningsasopnmc een coc down to 3.5 million/dl and hemoglobin level to 65 9%. Cause of anemia + Impairment in heme synthesis from protoporphyrin and of porphobilinogen from 6-amino-levulinic acid + Increased fragility of RBCs due to loss of intracellular potassium (there is an increased permeability of cell membrane to K") Lead inhibits heme synthesis through inhibition of delta) ALA-dehydratase utilization and ferrochelatase, resulting ! inthe bulldup of aminolevutinic acid, coproporphyrins | and free erythrocyte protoporphyrin. It also Inhibits | enzyme pyrimidine $'-nucleotidase, thus inereasing | erythrocyte fragility.? Karyorrhexis: Rupture of the RBC cell nucleus with | ehyomatin disintegration into granules that are extruded | from the cell | Punctate basophilia/basophilic stippling: Presence of dark i blue colored pinhead sized spots in the cytoplasm ofthe RBCS representing aggregated ribosomes, due to the tox action of lead on porphyrin metabolism (seen in 25% of | patients) (Fig. 40.2)* | + Anisoytosis: Presence of abnormal size erythrocytes. Poikiloeytosis: Presence of abnormal shaped erythrocytes. | 2. Burton’s/Burtonian (lead) line: A stippled blue line is seen on the gingival surface in 50-70% cases.® + Itis due to subepithelial deposit of granules at the Junction of teeth, especially near dirty or carious teeth of the upper Jaw, within a Week of exposure. + It Is due to formation of lead sulphide by the HS formed from decomposed protein in the mouth, + A similar blue line may be seen In cases of poisoning by: + Mercury: + Iron) + copper + silver (Bismuth tipping oo ey Colic: It is usually a late symptom, involving both large and small intestines, ureters and blood vessels. Seen in 85% of cases The pain is spasmodic, paroxysmal, occurs at night and may be very severe (saturnine colic). During pain, the abdomen is tense. Individual attacks last only for few minutes, but may recur after several days and weeks. Pain is slightly relieved by application of pressure over the abdomen Constipation: Common feature and usually precedes colic.” During pain, there is a desire for defecation. Diarrhea and vorniting may occur. Lead palsy (Drops): It is a late and uncommon phenomenon, seen In < 10% of cases. It is common in adults than in children, and males are particularly affected It occurs due to degeneration of nerves and atrophy of muscles as a result of interference with phosphocreatine metabolism, The muscle groups affected are those most prone to fatigue. Sensory nerves are not clinically affected There may be tremors, numbness, hyperaesthesia and cramps before the actual muscle weakness, Later, the extensor muscles of wrist (wrist drop) are affected (Fig. 40.3), but the deltoid, biceps, anterior tibial (foot drop) and rarely muscles of eye or intrinsic muscles of hand and foot are also affected Peripheral neuropathy is also seen in thallium, bismuth and arsenic poisoning Lead encephalopathy: Minor degree of involvement of brain function, commonly in children is present in almost every case. This may be due to inactivation of MAO as a result of combination of lead with -SH radical of the enzyme Fig, 40.3: Wrist drop<=> Fundamentals of Forensic Medicine and Toxicology + Symptoms include changes in personality, rest- lessness, hyperkinetic and aggressive behavior disorders, fatigablity, mental dullness, learning disorders, refusal to play, headache, insomnia, vomiting, raised intracranial pressure papilledema, visual disturbances and irritability, In others, there may be acute conditions, like convulsions, hallucinations, delirium, coma and death 7. Facial pallor: Eariiest sign; seen around the mouth It is due to vasospasm and produced by contraction of the capillaries at the arterial side 8. Effects on reproductive system: Lead may cause sterility in both male and female patients. In males, there may be loss of libido. In females, there may be infertility, menstrual irregularities, such as amenorrhea, dysmenorrhea and menorrhagia. It may result in abortion in pregnant females due to chronic atrophy or spasmodic contraction of uterus 9. Optic atrophy: Few patients may develop blindness due to optic atrophy. 10. Retinal stippling is noticed by ophthalmoscope with presence of grayish glistening lead particles, in the early phase of chronic lead poisoning Lead osteopathy: In children and young adults, lead is deposited beyond the epiphysis of growing tong bones. The deposition is promoted by calcium and vitamin D and is detectable by radiological examination. Deposition of lead at the growing ends may lead to their abnormal development, 12. Effects on circulatory system: Lead causes vascular constriction leading to hypertension and arteriolar degeneration 13. Effect on kidneys: Atherosclerotic nephritis and interstitial nephritis may occur. 14, Effects on liver: Acute or chronic degeneration leading to dyspepsia, anorexia, emaciation, general weakness and foul breath 15. Effect on peripheral nerves: In addition to meningoencephalitis, it may cause degeneration of anterior horn cells and demyelination leading to peripheral neuritis. 16. Hair: There may be alopecia iagnosis + History. + Clinical features: Abdominal pain, irritability, lethargy, anorexia, anemia, Fanconi's syndrome, peripheral neuropathy, pyuria and azotemia in children. Neurodevelopmental delays, convulsions and coma may be seen = In adults, additionally there are headaches, arthalgias, myalgias, depression, impaired short term memory, and loss of libido. The blue line on the gums {s a valuable but variable clue to diagnosis. + Laboratory tests i. Microcytic, hypochromic anemia, ii, Punctate basophilia: > 200 cells/eu rm. lil, Elevated free erythrocyte protoporphyrin or zine protoporphyrin (> 35 pg/dl) level and azotemia iv. Urine lead level > 80 g/dl (in 24 h sample) \. Whole blood tead level is the most useful indicator of lead exposure. Blood lead > 70 yg/dl (severe toxicity) and > 50-70 g/dl (moderate toxicity). In children, > 10 ug/dl of lead in the blood is abnormal vi. Coproporphyrin in urine > 150/mg/| vii, amino levulinic acid in urine > § mg/l" vil. Plasma lead > 0.1 mg/ml ix. X-ray: Radio-opaque bands or ‘lead fines’ at the metaphyseal plate of long bones are seen in children. These growth arrest lines are not pathognomonic, but are associated with lead levels > 40 pg/dl over long period of time. With recovery, the lead line becomes broader and less dense and may eventually disappear. x. Opaque material may be seen in X-ray of stomach and intestines. Treatment i. Remove the patient from the source of exposure. ii, Potassium or sodium fodide 1-2 g TDS orally. lil, Sodium bicarbonate 20-30 g in four or five divided doses orally. iv. MgSO, or sodium sulphate 8-12 g orally. v. CaNa,EDTA in usual doses. vi. BAL: Chelator of choice In case of renal impairment, Succimer (OMSA) is given in mild to moderate toxicity in a dose of 10 mg/kg orally every 8 h for § days, then every 12 h for 2 weeks vil, Correction of dietary deficiencies in iron, calcium, magnesium and zinc lowers lead absorption Vitamin C may be added (natural chelating agent) vii, Ammonium chloride 1 g, 3-4 times given daily. By this, lead deposited in the bones is mobilized into the blood and excreted Ix. Symptomatic treatmentInorganic Metall Postmortem Findings i. A blue line may be seen on the gums, but it is not a constant feature. Paralyzed muscles show fatty degeneration Heart: It may be hypertrophied and there may be atherosclerosis of aorta iv. Stomach and intestines: It may show ulcerative or hemorrhagic changes with contraction and thick: ening, v. Liver and kidneys: Contracted and hard vi. Brain: Pale and swollen. vii. On histology, bone marrow shows hyperplasia of leucoblasts and erythroblasts (‘immature’ white and red blood cells) Medico-legal Aspects + Acute and homicidal poisoning is rare Chronic potsoning is common. There is a risk of fllure to recognize the possibilty of lead poisoning as the symptoms and signs are subtle and easily overlooked, Accidental chronic. poisoning occurs in people working with lead Lead oleate or red lead Is used as a local application for abortion. It is also used alone or mixed with arsenic as cattle poison. ‘A person can develop lead poisoning from retained lead bullets or projectiles Spinal tap performed on the patients with lead encephalopathy and increased intracranial pressure can precipitate cerebral herniation and death, ‘Mnemonics for signs and symptoms of chronic lad poisoning |. Anemia/Anorexia/Arthralgia/Abortion/Atrophy of optic nerve Basophilic stippling/Burtonian line Colle/Constipation/Coproporphyrin excess in urine/ Cerebral edema Drop (wrist, foo!) Encephalopathy/Emaciation Facial pallor/Foul smell of breath/Fallure of kidneys/ Fanconi syndrome Gonadal dysfunction/Gout like picture Hypertension/Headache/Hallucination/Hyperaesthesla Impotence/Infertility/Insomnia/Irritability vill Peasy that the following criteria should be used as border values for ‘safe exposure: blood lead—80 yig/dl (0 in some countries), urinary lead—150 jg/1, urinary | coproporphyrin—500 g/l, and urinary ALA—20 mg/l. | + Tho Ist, 2nd, 3rd) and 6th hazards on the list in Toxic] Substances and Diseases Registry of US are heavy metals: lead, mercury, arsenic and cadmium + Now methods for moasuring lead in biologicalmedia were! developed in the late 1960s. First, the dithizone method | and later atomic absorption spectrophotometry. i + Leline-X-ray fluorescence (LXRF) is belng used to make in vivo measurements of lead levels In eortieal bone which reflct cumulative exposure over many years in contrast to blood levels, which reflect recent exposure MULTIPLE CHOICE QUESTIONS 1. Plumbism is due to chronic poisoning with: PGI 09 A. Arsenic B. Lead ©. Mercury D. Copper 2. Commonest source of lead to cause increased blood level in children is from: CMC (Vellore) 07 A. Air B. Lead paint dust ©. Water D. Fruits 3. Lead inhibits which enzymes in the heme synthesis pathway: ‘CME (Vellore) 07 A. Aminolevulinate synthase B. Ferrochelatase and 8-ALA dehydtratase €. Porphobilinogen deaminase D. Uroporphyrinogen decarboxylase 5. Punctate basophilia is seen in poisoning with: AIMS 03: TN 06 A. Lead B. Mercury ©. Cadmium D. Potassium 6. Burton’s line Is seen in: AI 07; Rajasthan 17 ‘A, Lead poisoning B. Arsenic poisoning . Phosphorus poisoning. Zine poisoning 7. All are features of lead potsoning, except: PGI 03 A. Diarrhea B. Abdominal pain ¢. Encephalopathy D. Nephropathy In case of chronic lead poisoning, the levels of which of the following Is elevated: NIMHANS 17 4. Basophille stippling Is seen which of the following ‘A. Porphobilinogen cells: ‘Manipal 03; UPSC 11; UP 17 B. S-amino levulinic acid A. Neutrophils B. REC's ©. Bilirubin . Basophils D. Eosinophils B. Urobilinogen 18 2.68 38 468 BA 6A 7A 6.8Inorganic Metallic Irritants—Copper Copper (tamta) as a metal Is not poisonous. The human body copper content is about 100-150 mg which is present as an integral and functional moiety of proteins and enzyme systems including catalase, cytochrome C oxidase, dopamine B-hydroxylase and serum cerulop- Jasmin. However, as the body cannot synthesize copper, the human diet must supply regular amounts for absorption Toxic Compounds and its Uses i. Copper sulphate (Blue vitriol, Bluestone, nila tutia, CuSO): It occurs as large blue crystal, freely soluble in water and having a styptic taste. It is used as algicide, molluscicide and plant fungicide, as mordant in electroplating, as an agent for leather tanning and hide preservation and can be used as an emetic. li, Copper subacetate (verdigris): It occurs as a powder Cr as bluish-green masses and is frequently used in the field of arts and external medicine. ili, Copper carbonate is a blue-green compound forming part of the verdigris patina that is found on weathered brass, bronze and copper. It is used as fungicide, Action Toxicity of copper is exerted on enzymes whose activities depend on sulfhydryl and amino groups because it has high affinity for ligands containing nitrogen and sulfur donors (as in other heavy metals). Besides, nucleic acid may also be targets of copper toxicity. Absorption and Excretion + The principal route of exposure is through ingestion, but inhalation of copper dust and fumes occurs in industrial settings and in miners + After ingestion, maximum absorption of copper occurs in the stomach and jejunum, Absorbed copper is initially bound to albumin and is transported from the GIT to the liver where it is transferred to ceruloplasmin + Copper is eliminated mostly through the feces after excretion into the bile. Urinary excretion of copper is low in humans. Adults have urinary excretion of 25 g/24 h, Signs and Symptoms (Acute Poisoning) Acute ingestion: Symptoms appear in 15-30 min after swallowing. System Signs and symptoms GIT Metallic taste, ptyalism (increased salivation), burning pain in stomach, thirst, colicky abdominal pain, nausea, eructalion and repeated vomiting. Vomited matter Is blue or green Diarrhea with much straining, Motions are liquid brown, rarely bloody. Oliguria, hematuria, hemoglobinuria, album nuria and uremia’ Hopatic Jaundice Is common in severe cases. MS Cramps ar spasms of legs, paralysis of limbs. Renal CVS Breathing dificult, cold perspiration, hypotension and symptoms of circulatory collapse CNS Frontal headache, drowsiness, insensibility, irreversible coma and death occurs + Hemolysis and hemoglobinuria are present in severe cases. Individuals with G-6-phosphate deficiency may be at increased risk of hematologic effects of copper. Multi-organ dysfunction syndrome may occur and death due to hepatic or renal fallure or both occurs after a few days Acute inhalation of large doses of copper dusts or furnes + Upper respiratory tract irritation resulting in sore throat and cough, + Conjunctivitis, palpebral edema and sinus irritation may occur. + Nasal mucous membrane may show atrophy with perforation. Exposure of skin to copper compounds may cause irritant contact dermatitis and severe exposure may cause a greenish-blue discoloration of skiney ae <> Fatal dose + Copper subacetate: 18 g + Copper sulphate: 20 g (0.15-0.3 g/kg) Fatal period: 18-24 h, but it may extend to 1-3 days. Treatment i. No need to use emetics as vomiting occurs in 5-10 min after ingestion. ii, Gastric lavage with 1% potassium ferrocyanicle which acts as antidote by forming cupric ferrocyanide (insoluble) ili, Demullcents: Egg white or milk (form insoluble alouminate of copper). iv. Castor oll is given to remove poison from the intestines. v. D-penicillamine given in usual doses is very effective vi. EDTA or BAL in usual doses? vil. Allay pain by injecting morphine and use diuretics, if urine is suppressed villi, Symptomatic treatment to maintain electrolyte and fluid balance ix. For severe cases associated with anorexia and hematuria, cortisone 80-100 mg IM thrice daily Is recommended. Postmortem Findings i. Skin may be yellow due to jaundice, ii, Greenish-blue froth from the mouth and nostrils, Ill, Mucous membrane of the mouth and tongue may have bluish or greenish-blue tinge. iv. Internally, some discoloration is present in the mucous membrane of the esophagus and stomach v. Stomach: Gastric mucosa is congested with desquamation and hemorrhage at places. vi, Small intestine: Mucosa (upper part) shows signs of moderate irritation vii. Liver: Soft and fatty. It shows centrilobular necrosis and biliary stasis vill, Kidneys: It may show degenerative changes in proximal tubules. Hemoglobin casts may be seen. Chronic Copper Poisoning Cause: It occurs among workers using copper and its, salts due to inhalation of copper dust or fumes—welders, may develop metal fume fever. It may also occur from food being contaminated with verdigris from dirty copper vessels. Signs and Symptoms i. Green or purple tine on the gums, a constant metallic taste, nausea, dyspepsia, vomiting and diarrhea ith colicky pain. li, Giddiness and headache. iii, Laryngitis and bronchitis. iv. Renal damage. v. General signs of progressive emaciation, viz. anemia, malaise and debility, vi. Peripheral neuritis with wrist drop or foot drop. and atrophy of muscles vii, Copper dust may cause inflammation of the conjunctiva and ulceration of the cornea. vill, Skin becomes jaundiced. Urine and perspira- tion become green. ix. Bronzed diabetes may be present Treatment i. After removing the cause, patient should be given ‘a massage and a warm bath. Patient should be exposed to fresh air. ii, Attention should be paid to his diet and dyspe- psia iil, Symptomatic treatment Postmortem Findings + Liver: Fatty degeneration, + Kidneys: Degeneration of the epithelial cells. Medico-legal Aspects + Suicidal cases are common. + Accidental poisoning results from eating food contaminated with verdigris (formed from action of ‘vegetable acids on copper cooking vessels) + Toxicity may develop from the copper absorbed systemically from the wire used in certain intra-uterine contraceptive devices or from the tubing used in hemodialysis equipment + Rarely, itis used for homicide because of its color and taste. + Poisoning may be caused by ingestion of food to which copper has been added to keep the color of vegetables green + Children may swallow copper sulphate crystals attracted by its color. + Rarely, It Is used as cattle poison. + Copper occurs in small medicinal doses in tablets with sulphate of iron and manganese + Copper sulphate was used as an antidote in phosphorus poisoning and in wound debridement.