Metallic Poison.pptx

Heavy metal poisoning is caused by the accumulation of certain metals in the body due to exposure through food, water, industrial chemicals, or other sources. While your body needs small amounts of some heavy metals to function normally — such as zinc, copper, chromium, iron, and manganese — toxic amounts are harmful.

1. UNIT 1 METALLIC POISON

2. ARSENIC Metallic arsenic is not poisonous, as it is insoluble in water and is not absorbed from the alimentary canal. When heated, it volatilizes, combines with oxygen and forms arsenic trioxide (As 2 O 3 ), which is poisonous. Toxic Salts of Arsenic Arsenious oxide [Arsenic trioxide, As 2 O 3 ]. Occurrence - Occurs in two forms – (a) powder and (b) porcelain type solid mass. Physical properties - (a) White in color, tasteless and odorless; thus could be easily mixed with foodstuffs for homicide. (b) Sparingly soluble in water. (c) Sublimates on heating. (d) Although heavier than water ( sp gr 3.669), floats on it as a thin film. Legitimate uses - Non-medicinal: Used in artificial flowers, calico printing, fly papers, fruit sprays, as mordant in dyeing, preservation of timber against white ants, rat poisons, Sheep dips [liquid insecticide used by farmers to protect their sheep against ticks and lice], taxidermy, wall papers and weed-killers. Others: Arsenic acid [H 3 AsO 4 ] ] Arsenic trichloride (AsCl 3 )- Butter of arsenic. Colorless poisonous oil Arsenic trisulfide (As 2 S 3 ) Tetraarsenic tetrasulfide (As 4 S 4 )

3. Mechanism of Action Arsenic is absorbed through all portals of entry (oral, nasal, cutaneous). (1) Trivalent arsenic (As 3+ ) has a great affinity for sulfhydryl groups [SH groups] . Binds to mitochondrial membrane SH groups "damages them "Cytochrome c is released from the damaged mitochondria“ activation of caspases "Apoptosis [ arsenic induced apoptosis ]. Because of -er affinity for SH groups [and also RBCs], the trivalent form is mo r e toxic than pentavalent form [same is true of antimony also]. (2) Downregulates gene expression of BCL 2 , a prosurvival protein , that protects against apoptosis (3) Inhibits pyruvate dehydrogenase (PDH) complex leading to disruption of oxidative phosphorylation. Epgp pathshala

4. Toxicokinetics [Absorption, Distribution and Elimination] 1. Absorption (1) Average daily intake - is ½ -1 mg [contained in food and water]. (2) Well absorbed from the GIT (pentavalent As), respiratory tract (arsine), or skin ( arsenite ). (3) Upon absorption, it is bound to the protein portion of Hb and alpha -globulins. 2. Distribution (1) Once absorbed, arsenic is quickly distributed to all organs and tissues. (2) In early stages, arsenic is found maximally in liver [in fatal cases >1mg%] followed by kidneys and spleen. (3) Does not cross blood-brain barrier. Brain has lowest levels (4) Inorganic arsenic can cross placenta (5) In ch poisoning: ( i ) Found in muscles for several days, and in keratin containing tissues [skin, hair, nails] for years. Can appear in hair and nails within hours of ingestion. Attaches itself to –SH groups which are abundant in keratin. In intermittent ch poisoning, there are successive deposits of As in hair and nails, and their sequential analysis can determine even the dates on which As was administered [normal growth of hair 0.4mm/day (ii) Gets incorporated in the bone by replacing P. (6) Normal conc in hair – 2ppm (7) Normal levels in urine <0.03mg/L. 3. Elimination (1) Mainly by kidneys: ( i ) As methylated As. (ii) Found in urine within ½ h of ingestion. Then onwards, elimination is continuous for about 10-12 days. (iii) In acute poisoning 24 h excretion > 100 mg (2) Breast milk – eliminated only in traces (3) Bile, feces, sweat, other secretions – Other routes of elimination (4) Has an enterohepatic circulation – Because of this, As is seen in stomach and intestines, even if given by parenteral routes.

5. Mees' lines  are prominent transverse white lines in finger or toe nails due to arsenic deposition in keratin rich tissues. They take some 3–6 weeks to manifest. The above mentioned skin changes are usually present in chronic arsenic toxicity, but can rarely be seen after acute or subacute exposures.

6. Acute Poisoning: Occurs within 24 h of ingestion. Signs and symptoms a. Ingestion (1) GIT: ( i ) Odor – Garlicky (ii) Taste – sweetish metallic (iii) Intense thirst, Ptyalism (iv) Nausea, Vomiting [projectile in nature] (v) Throat – feeling of constriction, dysphagia (vi) Burning and colicky pain – in esophagus, stomach and bowels (vii) Abdominal pain (viii) Diarrhea - (a) Accompanied by pain, tenesmus and irritation around the anus. (b) Stools – (I) expelled frequently and involuntarily (II) Color and odor - dark colored, stinking, bloody; later become colorless, odorless and watery resembling rice-water stools of cholera. (2) Liver - Fatty degeneration within 24 h of ingestion. (3) Muscular – Tenderness of muscles (4) CNS: ( i ) Convulsions and tremors (ii) Formication (iii) Giddiness (iv) Headache (v) Vertigo (vi) General paralysis (vii) Delirium (viii) Coma Inhalation [Arsine gas] (1) Hemolysis (2) hemoglobinuria (3) renal failure (4) death is almost instantaneous.

7. Fatal dose (1) As 2 O 3 - 200-300 mg (2) Arsine gas – 25-30 ppm is lethal in 30 min. Fatal period 1-2 days.

8. PM appearances [Ac arsenic] External (1) Signs of dehydration – Eyeballs, s unken; body , shrunken (2) Skin – Cyanosed/ cyanosis : skin become bluish-blackish, due to low oxygen conc. Internal (1) Mouth, pharynx, esophagus – Generally unaffected, but rarely may be inflamed or ulcerated (2) Stomach – displays major findings. ( i ) Mucosa - (a) swollen, edematous and bright red, either diffusely or in patches. (b) Shows erosions and ulcerations (c) Mass of sticky mucus covers mucosa in which particles of arsenic may be seen (ii) Congestion – Most marked along greater curvature, posterior part and cardiac end of stomach. More prominent at the crests of rugae. Lines of redness run along the walls. Rarely there may be no congestion (iii) Red velvety appearance – stomach wall is soft and red like a valvet Groups of petechiae scattered over mucosa. Sometimes large submucosal and subperitoneal hemorrhages . Small intestine: Mucosa – Inflamed, pale violet. Shows submucous hemorrhages along the entire length; Contains large flakes of mucus with very little fecal matter Cecum and rectum – slightly inflamed Liver, spleen, kidneys: ( i ) Congested, enlarged, show cloudy swelling and if survival is for few days, fatty change. (ii) Glomerular nephritis

9. Chronic Poisoning WHO defines chronic arsenic poisoning [syn, arsenicosis ] as a chronic health condition arising from prolonged ingestion [not less than six months] of arsenic above a safe dose, usually manifested by characteristics skin lesions, with or without involvement of internal organs. Some authorities consider the period of onset as within 4 wks of continuous ingestion. Salient features: Occurs in following circumstances: (1) Occupational - due to repeated accidental ingestion of small doses of arsenic by those working with the metal (2) Through contaminated water (3) Arsenophagists ( people who take arsenic daily in the mistaken belief that it is an Aphrodisiac) (4) Homicidal (5) Recovery from single heavy dose.

10. Tests for Arsenic Marsh test – Hydrogen is passed through suspected material (e.g. vomit). Arsenic if present combines with H 2 to form AsH 3 , which is passed through a jet and burnt. A thin film of arsenic over porcelain is formed. Gutzeit test (3) Reinsch test. (4) Neutron Activation Analysis [NAA] and Atomic Absorption spectroscopy [AAS]. Performed currently.

11. ML Importance Postmortem imbibition of arsenic – If high arsenic content is found in the exhumed body, the defense may take the plea that the arsenic had leached into the body from surrounding soil. There are two objections to this argument (a) Solubility - Arsenic is found in an insoluble form in the soil. For it to be able to leach inside the body, it must be in a soluble form (b) Concentration – Concentration of arsenic found in the body cannot be higher than that in the soil, if arsenic has leached. This is frequently the case. ( i ) There is a counter objection to the first (a) Bacterial activity - Some anaerobic bacteria have been demonstrated in grave soil, which can convert insoluble arsenic into soluble arsenic. Furthermore their metabolic activity causes an exchange of soil arsenic with that of sulphur in the hair. Homicidal poison – Most favorite homicidal poison before 1836, when] Marsh test was developed. Safe levels in drinking water: ( i ) 10 parts per billion [ppb] or 10μg/L Arsenic in drugs of addiction: Opium - generally contaminated with arsenic. Arsenic is a minor component of cigarette smoke Seafood – is exceptionally rich in As. May contain from 2mg/kg for freshwater fish up to 22mg/kg for lobsters. Mussels, oysters, prawns, shellfish

12. LEAD Lead is a silvery-gray soft metal, used in construction of buildings, bullets, ceramics, electric cable insulations, fusible alloys, hair dyes, lead-acid batteries, pewter, potteries, radiation shielding, shots, solders, and weights. Lead and its salts are potent poisons. Toxic Salts of Lead Lead carbonate (PbCO 3 , safeda ); Lead chromate (PbCrO 4 )- has a bright yellow color and is insoluble in water. As a result used in paints as “ chrome yellow ”; Lead diacetate [Pb(C 2 H 3 O 2 ) 2 - Commonly known simply as lead acetate ] – Called sugar of lead because of its sweet taste ; Lead monoxide ( PbO )- Occurs in two polymorphs, red ( litharge ) and yellow ( massicot ). Used in the manufacture of lead glasses, ceramic glazes and fine dinnerware ; Lead sulfide ( PbS , Galena) – Insoluble and stable at blood pH. Thus least toxic forms of lead; Lead tetraacetate [Pb(C 2 H 3 O 2 ) 4 ]; Lead tetroxide (Pb 3 O 4 or 2PbO·PbO 2 )-Also known as red lead, sindoor , vermilion .; Tetraethyl lead [CH 3 CH 2 ) 4 Pb; TEL] - Once a common antiknock additive in petrol. Now largely discontinued because of toxicity. Still used as an additive in aviation fuel for piston engine-powered aircraft.

13. Toxicokinetics Absorption: ( i ) oral route is less efficient (10%-15% of total absorbed Pb comes via this route) than by (ii) inhalation (40-50%). Essential trace elements (Fe, Ca, Zn) reduce absorption by competitive absorption. Children have a 3 fold higher lung deposition rates than adults. (iii) Cutaneous absorption is poor (iv) Placenta – Readily crossed. Causes fetal toxicity when mother is poisoned (v) Other routes – Lead bullets or pellets lodged in bones, muscles and joints (souvenir bullets) may get slowly absorbed causing poisoning. Distribution (1) Mostly stored in bone: approx. 95% of the body Pb is stored in bone (70% in children). (a) In bones Pb is stored mainly as insoluble phosphate and carbonate. (b) -Ca ++ l evels favor storage; Ca ++ deficiency causes Pb to be released into blood stream. (ii) Most of the remainder is distributed to the soft tissue pool. (iii) Very little is present in blood ; 99% of that is bound to RBCs (2) Toxicity is associated with soft tissue lead uptake – (3) Toxic Lead levels: ( i ) Normal asymptomatic tissue lead levels are 200-500 parts per billion (ii) Brain lead content in encephalopathy is 1000-2000 ppb. (iii) Blood lead levels (BLLs) of 100 ppb (>10 μg /dL) are considered toxic.

14. Excretion: (1) Retention rate - Adults retain 1-4% and children 33% of ingested lead [because Pb mimics Ca, which is used by growing children]. Rest is excreted. (2) Excreted through urine and bile - Lead is primarily excreted in urine (approx. 65%; normal urinary excretion of Pb =80 μ g /L) and bile (approx. 35%). Negligible amount is lost via sweat, hair, and nails. (3) Biologic half-lives in various body tissues for lead are : (a) blood (adults), 25 days; (b) blood (children), 10 months; (c) soft tissues (adults), 40 days; (d) bone (labile, trabecular pool), 90 days; and (e) bone (cortical, stable pool), 10 - 20 years.

15. Mechanism of Action Inhibition of heme synthesis : Heme is synthesized in 9 steps. Enzymes at step 2-3 [porphobilinogen synthase or ALA dehydratase], 6-7 [coproporphyrinogen oxidase] and 8-9 [ ferrochelatase ] are inhibited by Pb. This causes an overall . in heme synthesis resulting in anemia. Inhibition of –SH groups - Pb interferes with the action of –SH groups, which are components of several enzymes, receptors and structural proteins.

16. Acute Poisoning Signs and symptoms Acute poisoning is characterized by (1) an astringent and metallic taste , (2) headache, (3) dry throat, (4) nausea and vomiting [occasionally diarrhea], (5) thirst, (6) peripheral circulatory collapse [due to loss of water from GIT], (7) neurological signs [( i ) paresthesias (ii) rarely encephalitis (iii) cerebellar ataxia is common in children]. (8) Hemolysis causes anemia and presence of hemoglobin in the urine, (9) decreased urine output (damage to kidneys). (10) Death in severe cases. Fatal dose (1) Lead acetate – 20 g; (2) Lead carbonate – 40 g; (3) Tetraethyl lead – 100 mg/kg. Fatal period 1-2 days.

17. Cause of death: Gastroenteritis"shock . PM appearances (1) Signs of acute gastroenteritis – thickened red mucosa with eroded patches (2) Grayish white deposit on stomach mucosa. Tests To the suspected material, add hydrochloric acid. White ppt of lead chloride will form. It is soluble in boiling water; crystallizes on cooling.

18. Chronic Poisoning Causes Food and drinking water: ( i ) Drinking water stored in lead cisterns. (ii) Ghee stored in brass or copper vessels lined inside with lead. Fat in ghee reacts with lead to form lead oleate which is absorbed (iii) Food cooked in similar vessels (iv) Tinned food – contaminated with lead from solder (v) If water supply to homes is through lead pipes or copper pipes with leadsoldered joints. (2) Use of hair dyes and cosmetics containing lead (3) House dust from deteriorated lead paint (4) Occupational exposure - Common in people who work with lead, e.g. p ainters, p ewters, p lumbers, p otters and p rinters. Other professions who may be affected are enamel workers, glass polishers, glassblowers, glass polishers, makers of white lead and smelters. Poisoning caused by continuous inhalation. (5) Retained lead ammunition – In old gunshot wounds, if some bullet or pellets remain lodged in body [souvenir bullet or pellets] (6) Sindoor - Use of sindoor (red lead) applied to scalp. Lead can combine with oils used on scalp to form lead oleate, which can be absorbed. (7) Smoking: ( i ) Particularly among workers in Pb based industries. (ii) Mechanisms - (a) Tobacco plants absorb Pb from soil (b) lead arsenate is used as a pesticide on tobacco crops"gets deposited on leaves (c) General poor personal hygiene habits among smokers [inadvertent contact and ingestion] (d) Inadvertent touching of lips with contaminated hands during smoking. (iii) Thus lead-handling workers are advised to improve their hygiene by refraining from smoking in the workplace, regularly washing their hands and face, and bathing immediately after their day’s work. (8) Consumption of wildlife killed with lead ammunition - may cause lead intoxication. (9) Children can get poisoned if they continuously chew or lick on leaded objects, eg furniture and walls painted with lead based paints and toys.

19. Signs and symptoms a. Facial pallor: (1) Facial pallor, particularly circumoral pallor is one of the earliest and most consistent signs (2) Causes: (i) anemia (ii) vasospasm Anemia Initially polycythemia with polychromatophilia (2) Other RBC abnormalities: ( i ) Anisocytosis [unequal sized RBCs] (ii) Nucleated RBCs [ sideroblasts ] (iii) Poikilocytosis [abnormally shaped RBCs] (iv) Punctate basophilia (v) Reticulocytosis (3) Other blood cells: ( i ) -Mononuclear cells (ii) .platelets (iii) polymorphonuclears (4) Significant anemia : ( i ) Usually a sign of more chronic poisoning. (ii) Initially it is microcytic, hypochromic [as seen in Fe deficiency anemia], but later changes to normocytic normochromic. (iii) Anemia is not a significant feature in organic lead poisoning. (iv) Causes - (a) Heme synthesis (b) survival time of RBCs.

20. Lead line (1) Morphology - A stippled blue line [ Burtonian line ] is seen on gums in 50-70% cases. (2) Characteristics: ( i ) More common in upper jaw (ii) Appears within a week of exposure (iii) Not seen in edentulous persons (iv) Removal from exposure obliterates line gradually (v) More common in persons with bad orodental hygiene, carious teeth (3) Mechanism: ( i ) Subepithelial deposition of black Pb granules (ii) Bad oral hygiene"food sticking in gums" decomposition " H2S formed “ Reacts with Pb in tissues " forms PbS [black] (4) D/d – similar lines seen in poisoning by bismuth, copper, iron, mercury and silver.

21. Colic and constipation (1) Also known as colica Pictonum , Devon colic , or painter’s colic (2 intestinal colic associated with obstinate constipation due to chronic lead poisoning . (3) Usually appears late (5) Colic occurs at night (6) Pain is very severe (8) Constipation and diarrhoea ; Lead palsy Weakness of muscles due to lead. Salient features: Muscles affected: ( i ) Those which are most prone to fatigue (a) extensor muscles of wrist. [ wrist drop ] (b) Anterior tibial [ foot drop ]. Occurs in ch arsenic poisoning also (ii) biceps (iii) deltoid (iv) rarely (a) eye muscles (b) intrinsic muscles of hand and foot. Associated neuropathy also occurs making the condition worse. Reproductive system (1) Sterility and impotence [in both sexes]. (2) Menstrual disorders [Amenorrhea, Dysmenorrhea, Menorrhagia] (3) In pregnant females: ( i ) Abortion – generally between 3-6 months [ Mechanism – please see above] (ii) Premature labor (iii) Intrauterine growth retardation. Eye Ophthalmoscopic examination reveals retinal stippling. Glistening grayish lead particles are seen.

22. Retinal stippling: a spotted condition or appearance , such as an appearance of the retina as if dotted with light and dark points, or the spotted appearance of the erythrocytes in basophilia.

23. PM appearances (1) Gums – Burtonian line (2) CNS: ( i ) Brain – (a) pale (b) greatly swollen (c) PAS + ve , pink staining, homogenous material seen in the perivascular spaces (ii) Peripheral nerves – segmental demyelination (3) CVS: ( i ) Heart – hypertrophied (ii) Aorta, aortic valves - atheromatous (4) Stomach and intestines: ( i ) Hemorrhagic and ulcerative changes (ii) Contracted, thickened (5) Liver: ( i ) Contracted (ii) Hepatocytes – Show eosinophilic intranuclear inclusions [EII] (6) Kidneys: ( i ) Contracted (ii) Proximal tubules - Show EII. (7) Muscles – fatty degeneration [paralyzed during life] (8) Bone marrow: ( i ) Hyperplasic of erythroblasts and leukoblasts (ii) . in fat cells.

24. ML importance (1) Abortion – Lead salts used for abortion, eg Diachylon [lead oleate] ( 2) Artificial insemination - Donors with Pb poisoning [↑ seminal plasma Pb levels] have lower fertility rates than donors with no Pb poisoning or low seminal plasma Pb levels. (3) Cattle poison – Red lead alone or mixed with arsenic (4) Drug abusers - Chronic Pb poisoning may sometimes be seen in drug abusers [because of intentional or unintentional adulteration with lead] ( i ) Cocaine – Lead is a contaminant of manufacture in cocaine paste (ii) Marijuana - Lead in marijuana samples is a diluent (5) Employer’s liability to pay compensation in cases of occupational disease due to Pb (6) Lead pellets or bullets - ( i ) Ingestion – Suicide has been attempted by ingesting lead pellets (ii) Souvenir bullets - These are pellets or bullets which remain in the body after a shooting incident, May cause ch lead poisoning. (7) Manner - Suicidal, and homicidal poisoning rare (8) Rapidity of poisoning - ( i ) Acute poisoning – rare (ii) Chronic poisoning is an occupational disease.

25. MERCURY (QUICKSILVER) General: Mercury is a liquid metal, having bright silvery appearance. It is volatile at room temperature. Toxic Salts of Mercury : Mercury occurs in three forms – Metallic mercury, inorganic salt and organic salts. Metallic mercury if swallowed as such is not poisonous, as it is not absorbed from GIT . It is however absorbed in vapor form, and is very toxic , because inhaled Hg vapors readily cross biological membranes. Organic salts Organic salts are most poisonous , especially (1) methyl mercury and (2) dimethyl mercury . Inorganic salts Among inorganic salts, mercuric salts (Hg ++ ) are more poisonous than mercurous salts (Hg + ). Mercurous salts are less soluble in water than mercuric salts, accounting for their lesser toxicity. Mercuric Chloride [HgCl 2 , Corrosive sublimate ] –Before the advent of antibiotics, used to treat syphilis. Mercuric ammonium chloride - ointment containing 10% HgNH 2 Cl is used for eczema. Mercuric cyanide – [Hg(CN) 2 ]- Odorless, toxic white powder with a bitter Mercury sulphide [ cinnabar , red sulphide of mercury, sindoor , vermilion, HgS ] Mercury thiocyanate [Hg(SCN)2] - Best known for its former use in Deewali , as it produces a large, winding “snake” when set on fire.

26. Toxicokinetics Absorption: ( i ) Elemental Hg – (a) GIT [Not absorbed] nonpoisonous orally. (b) inhalation [80% absorption]. (c) Cellular membranes - diffuses rapidly including the blood-brain barrier and placenta. (d) Half life - 60 days. (ii) Inorganic Hg – GIT [10%], skin and mucus membranes. (iii) Organic Hg – Long chain alkyl compounds -GIT [>50%]; short chain alkyl compounds - GIT [90%] Distribution – Mercury distributes widely to all tissues. Major deposition in CNS , kidneys , liver and spleen. Methylmercury concentrates in hair (due to presence of sulfhydryl groups). Its concentration in hair is 250 times more than in whole blood. Within blood, methylmercury concentrates more in RBC than in plasma. RBC:Plasma ratio of methylmercury is 10:1 , while the same ratio for inorganic Hg is 1:1 . Elimination – The total body half life of elemental and inorganic Hg is 30- 60 days . In contrast half life of organic Hg is 70 days (due to its enterohepatic recirculation). Inorganic mercury is excreted both through urine and feces. Excretion of organic Hg is predominantly fecal.

27. Mechanism of Action (1) Mercury binding to ( i ) sulfhydryl (ii) phosphoryl (iii) carboxyl and (iv) amide groups - results in widespread dysfunction of enzymes, transport mechanisms, membranes and structural proteins (2) Direct oxidative effect of mercuric ions - results in PCT necrosis. Mercury ion accumulates predominantly in the renal cortex (3) Immune mechanism – results in membranous glomerulonephritis and acrodynia associated with Hg (4) Methylmercury inhibits astrocyte uptake of cysteine - Results in production of glutathione (a major antioxidant).

28. Acute Poisoning Signs and symptoms differ according to the type of Hg ingested [elemental, inorganic or organic]. Signs and symptoms Elemental mercury : Inhalation - Usually occurs following gold refining in a closed room. (1) General – Headache, blurring of vision, Fever, chills [metal fume fever], conjunctivitis, salivation (2) Pulmonary – chest pain, cough, dyspnea, interstitial pneumonitis,, necrotizing bronchiolitis, pulmonary edema, pulmonary failure, (3) GIT – Metallic taste, deep red oral mucosa, gingivitis, stomatitis, strawberry tongue, swelling of salivary glands, teeth [loosened] (4) Miscellaneous – Reddened palms and soles, manifestations similar to Kawasaki disease (mucocutaneous lymph node syndrome) especially in children

29. Ingestion : Absorption is minimal [<0.01% is absorbed]. Large quantities can be ingested without obvious toxic manifestations. In 1515 , an English nobleman on his honeymoon drank a large amount of elemental Hg by mistake, but did not suffer any harm. Injection (1) S/c or IM (INTRAMUSCULAR) - Abscess formation, ulceration [exuding tiny droplets of Hg]. (2) IV (INTRAVEINAL) – [generally suicidal, or taken with a false belief that it acts as an aphrodisiac] bloody sputum, dry cough, granuloma, pulmonary embolism, tachypnea , thrombophlebitis. (3) Intra-arterial – Can occur inadvertently from arterial blood gas sampling with syringes containing Hg as anaerobic seal. Peripheral embolization with ischemia and gangrene. X-ray in all cases reveals Hg globules.

30. Inorganic mercury: Manifestations occur in 2 phases. First phase (1) Immediately after ingestion of corrosive mercury salts – Hot burning pain, sense of constriction, ashen discoloration of the mucous membrane in mouth and throat. Burning pain extends down to stomach and abdomen. (2) Within a few minutes - Intense epigastric pain, followed by diffuse abdominal pain. Nausea, retching and almost continuous vomiting of mucoid material, which frequently contains blood and shreds of mucous membrane. Hoarse voice. (3) Mouth, tongue and faeces – are corroded, swollen and show a grayish white coating. (4) Acrid metallic taste, excessive salivation and thirst. (5) Severe purging, with liquid, bloody feces and considerable tenesmus. (6) Rapid, weak pulse; breathing shallow and difficult; Pallor; Prostration, circulatory collapse, and death. (7) Above Signs and symptoms are not seen with mercury compounds of low irritancy or with portals of entry other than the mouth.

31. Second phase If death does not intervene, phase 2 begins in 1-3 days in untreated cases (unless vomiting effectively removed most or all poison). (1) Oral - Marked salivation, mercurial stomatitis, glossitis and ulcerative gingivitis within 24-36 hr. Loosening of teeth, necrosis of the jaw. (2) Renal - PCT Necrosis in 2-3 days, transient polyuria, albuminuriahematuria , anuria, azotemia and renal acidosis. Recovery may occur within 10-14 days, but death may also occur in some cases. (3) Late - After many days after the original exposure (especially in untreated cases), a membranous colitis may appear; dysentery, tenesmus, ulceration of the colonic mucosa, and hemorrhage. Liver necrosis sometimes develops. [ Tenesmus is the feeling that  you need to pass stools , even though your bowels are already empty.] Fatal dose: 1-4 g of HgCl 2 Fatal period: 3-5 days

32. PM appearances (1) Lips, mouth, tongue and esophagus - Mucous membrane more or less whitened, swollen and soft. (2) Stomach and esophagus: ( i ) congestion (ii) corrosion (iii) inflammation (iv) severe hemorrhagic necrosis (3) Large intestines – Mucus membrane inflamed, swollen, corroded and hemorrhagic [lesions seen if person survived for a few days. Due to reexcretion of Hg in the large intestines] – Necrotic areas. Small intestine is also affected but to a lesser degree. (4) Heart – subendocardial petechial hemorrhages [ Petechiae are formed when tiny blood vessels called capillaries break open. ] (5) Lungs – Thrombosis in capillaries. (6) Liver – congested. Shows cloudy swelling and fatty change. (7) Kidney – Interstitial nephritis (8) H/P (Hepatic portal) ( i ) Severe proximal convoluted tubule (PCT) necrosis, hemorrhagic glomerular nephritis (ii) Mercury deposition in renal cortex and renal macrophages (iii) Neuronal necrosis and glial proliferation in cerebral cortex [seen in Minamata disease].

33. Chronic Poisoning ( Hydrargyrism ) Clinical pictures are different in inorganic and organic mercury toxicity. Inorganic mercuric chloride mainly affects the renal and gastrointestinal systems . The characteristic neurological feature is a fine tremor, particularly of the hands and fingers.. Signs and symptoms May result from (1) External application of Hg as ointment (2) occupational exposure (3) recovery from a large dose (4) excessive therapeutic use of Hg. General (1) Anemia (2) anorexia (3) loss of weight (4) Inflammation of gums (5) blue line at the junction of teeth and gums (6) Sore mouth and throat (7) loosening of teeth (8) GIT disturbances (9) chronic nephritis with progressive uremia. Ptyalism [ overproduction of saliva]

34. Mercurial tremors Mercurial tremors (syn. Danbury tremors or shakes, Glassblowers tremors or shakes, Hatter’s shakes ) are static and intentional tremors seen in chronic mercury poisoning (1) Tremors – Two types are seen ( i ) Static or resting tremor - occurs when the muscle is at rest. It is a fine trembling motion, most evident in the upper extremities (ii) Intentional or ataxic tremor – (a) occurs when there is purposeful movement of an extremity, or (b) as an aggravation of an established static tremor. Concussion mercurialis ( Tetanus mercurialis ) refers to the last stage where tremors are so intense that they prevent daily activities. (2) Predisposing factors – Alcohol predisposes to tremors. Severe shakes are never seen in teetotalers. (3) Glassblower’s shakes - Glassblowers often blow colored mercury compounds in ornamental glass. May get poisoned. [M ad hatter disease is  a form of chronic mercury poisoning . ] Mercurial erethism Mercurial erethism (or erythism ) is the name given to neuropsychiatric manifestations seen in chronic mercury poisoning . . The classical triad of chronic mercury poisoning is ( i ) gingivostomatitis (ii) mercurial tremors and (iii) mercurial erethism. Main symptoms seen in erethism are – Anorexia, emotional instability, fatigue, insomnia, loss of memory, mood changes [anxiety, shyness, withdrawal, depression, loss of confidence, nervousness, irritability, timidity], resentment at being observed, rough temper, delusions, hallucinations, suicidal melancholia, manic depressive psychosis ( mad hatter ). The Mad Hatter is a character in Alice’s Adventures in Wonderland, a novel written in 1865 by Lewis Carroll. He showed signs of mercurial erethism.

35. Mercuria lentis : discolouration of the capsule of the lens of the eye due to deposition of mercury ,as observed and seen through the slit lamp is one of the earyl symptoms of chronic Mercury poisoning . Salient features: (1) Slit lamp examination demonstrates a matt-brown reflex from anterior lens c apsule (2) It is bilateral and has no effect on visual acuity. In contrast methyl mercury toxicity results in visual blurring and tunnel vision .

36. Acrodynia (pink disease) : Acrodynia (also known as calomel disease, erythredema , Feer’s disease, pink disease, Selter’s disease and Swift’s disease) is a peculiar manifestation of mercury poisoning seen in children. ( Gk acro , extremity; dynia , pain). Salient features: (1) Hands and feet of the child became painful, paresthetic , peeling, perspiring, pink and puffy (2) Anorexia, hypertension, hypotonia, insomnia, irritability, photophobia, rashes [due to excessive perspiration]. (3) Symptoms of catecholamine excess (perspiration, tachycardia, hypertension) occur because mercury blocks the degradation pathway of catecholamines. (4) Acrodynia was relatively common amongst children in the first half of the 20th century, due to the use of calomel in teething powders (analgesic action) and for washing nappies (bactericidal action). Mnemonic for chronic Hg poisoning"TABLE – Tremor, Acrodynia, Blue-Black line on gums, Lentis , Erethism

37. Hunter Russell syndrome : Occurs due to ch exposure to methyl mercury . Most disastrous epidemic occurred in 1953 [Minamata disease]. . Symptoms: (1) CNS – Peripheral neuropathy is a major feature. Major symptoms are akinesia, ataxia, auditory impairment, blurred vision, cerebellar ataxia, constricted vision, dementia, depression, diminished or absent deep tendon reflexes, but up to 40% may have enhanced tendon reflexes, dysarthria, impaired hearing, smell and taste, malaise, memory loss, numbness, olfactory impairment, paresthesia with a peroral and glove and stocking distribution, rigidity, sensory impairments, spasticity, taste impairment, tremors, visual blurring and tunnel vision , and weakness. (2) The immature brain is especially susceptible to the effects of methylmercury and is often damaged in an irreversible and profound manner. (3) Congenital poisoning - mental retardation, deafness, blindness, dysphasia ataxia, microcephaly, and cerebral palsy. However, signs of peripheral neuropathy are not found. (4) Pathology - The symptoms are due to loss of myelinated nerve fibers, autonomic dysfunction, sensory nerve conduction delay, abnormal neuronal migration, and abnormal central nervous system cell division.

38. Tests for Mercury Suspected solution + A piece of copper wire + Few drops of HCl -  A silvery colored coating of mercury on copper wire will form.

39. MLI [1] Blood - Stains of red sulphide of mercury resemble blood stains. They need to be differentiated (2) Blood transfusions - Blood conc of Hg may be higher in persons taking a diet rich in sea food. If blood from such individuals is transfused to premature infants [especially multiple transfusions in a short period], there is a possibility of Hg poisoning. (3) Component of: ( i ) HgCl 2 is a component of cavity fluid for embalming ( art and science of preserving human remains by treating them  ) (4) Criminal abortion – Mercury salts [ eg HgCl2] introduced in vagina for criminal abortion or as contraceptive measures. May cause death. (5) Dentistry – Hg used in dental amalgams. ( i ) Patients - Chronic absorption produces grayish blue mucosal discoloration. (ii) Dentists – Many still knead the amalgam mass in their hands. While squeezing the mass to express out excess Hg, droplets often fall on the floor. Since they are difficult to scoop up, they are allowed to remain their and vaporize causing the Hg conc in the environment to rise. This may cause chronic Hg poisoning in dentists. (6) Manner of poisoning: ( i ) Accident– can occur as a result of (a) thermometers breaking in the mouth. It is usually harmless. (b) as a complication of Hg-sealed syringes for arterial blood drawing. It can give rise to radiopaque shadows in the head (embolization in brain), chest (embolization in lungs) and other areas of the body. D/d of such shadows are (I) embolization of bullet fragments or lead shots, (II) heavy metal and metal salt deposits (bismuth) in gluteal areas and (III) cysticercosis (c) Disk battery ingestions – Mercury oxide may release if battery opens within GIT causing Hg poisoning. (ii) Homicide and suicide – rare.

40. (7) Quacks – Mercury salts are quacks’ favorites. Acute Hg poisoning may result from the external application of some mercurial preparation, or from the injection into the uterus, or into large abscess cavities of a soln of corrosive sublimate. Symptoms of acute Hg poisoning, followed in some cases by death, have resulted from the external application of corrosive sublimate to tumors or ulcers, a method sometimes resorted to by quacks for the destruction of socalled cancer; similar toxic symptoms have resulted from injecting a solution of corrosive sublimate into psoas abscess cavities, and into the uterus after childbirth. [8] Therapeutic use of Hg: ( i ) Mercuric chloride – Strong soln used for washing abscess cavities or irrigating vagina, uterus or rectum. May cause accidental poisoning. (ii) Mercurous chloride – (a) Can cause acrodynia [please see above]. Even today it is sometimes used as a laxative. (b) As an abortifacient, it caused death of pregnant mothers [ ch 26 ] (iii) Metallic mercury is generally not poisonous. At one time oral Hg in doses of 100 to 500 g was given for the treatment of adynamic ileus and bowel obstruction . It usually passed off in the feces harmlessly, but sometimes diarrhea and stomatitis resulted. Occasionally fatal poisoning also occurred. Hg was also put as a weight at the end of a gastroduodenal tubes, which were passed to relive GIT obstructions. Sometimes the Hg containing balloons used to rupture, releasing Hg in the GIT. Generally such events were harmless, but occasionally acute appendicitis used to occur. Sometimes Hg used to escape from a perforated appendix and formed intraperitoneal mercury granulomas ., (9) Thiomersal controversy – Thiomersal, an organomercury compound, is a well established antiseptic and antifungal agent, and has been used as a preservative in vaccines, immunoglobulin preparations, skin test antigens, antivenins, ophthalmic and nasal products, and tattoo inks. Its use in vaccines allows the use of multidose vials instead of single-dose vials, which are more expensive. There have been concerns that its use in vaccines leads to the development of autism and other brain development disorders in children.

41. COPPER Toxic Salts of Copper Copper acetoarsenite – (2) Copper arsenite (3) Copper subacetate : used by Greek artists as a green pigment in their paintings]. (4) Copper sulphate [blue vitriol]

42. Mechanism of Action (1) Effect on SH groups: ( i ) Copper inhibits the sulfhydryl groups on enzymes in important antioxidant systems including G-6-PD and glutathione reductase, reducing their free r adical scavenging activities (ii) Intravascular hemolysis is caused by the inhibition of G-6-PD . (2) Copper - s the permeability of cell membranes by inhibiting the Na + /K + ATPase pump . (3) Copper intoxication can cause rhabdomyolysis , as it damages human skeletal muscle cells .

43. Toxicokinetics (1) Absorption - Copper is absorbed by an active process involving a Cu- ATPase in the small intestinal mucosal cell membrane [also known as the Menkes ATPase] (2) If mucosa is damaged – as in acute overdose, the absorption is significantly higher. (3) Carriers of copper - After absorption, copper is rapidly bound to carriers [albumin, ceruloplasmin, and amino acids eg histidine], for transport to the liver and other tissues. (4) Local release of copper - Copper is released locally [in liver and other tissues] in the reduced form from its carrier (5) Fate of copper - (a) In the hepatocyte, copper may either be incorporated into enzymes or eliminated depending on body’s needs. (b) Cu-ATPase located on trans-Golgi network assists in its incorporation into enzymes. (c) Same Cu-ATPase on pericanalicular lysosomes assists elimination as a metallothionein-copper complex, into the biliary system [final excretion in feces]. Biliary excretion of copper is 2000 μg /24 h. Renal excretion is negligible; about 5-25 μg /24 h (6) Release of copper in plasma - (a) Excess copper is released into the plasma from the liver, bound primarily to ceruloplasmin. (b) 1 Molecule of ceruloplasmin binds 6 atoms of copper. (c) 90-95% of serum copper is bound to ceruloplasmin, and 5-10% to albumin; unbound copper and copper bound to other carriers [amino acids] is <1%. (d) Half life - ( i ) Ceruloplasmin bound copper has a plasma half-life of 24 hours. (ii) Half-life of erythrocyte copper is 26 days. (e) The albumin-copper complex represents the “free” or toxicologically active copper. (f) Following acute poisoning , the excess copper binds only to albumin.

44. Acute Poisoning Signs and symptoms Symptoms appear within 15-30 minutes. In mild cases there is ( i ) a metallic taste in mouth (ii) -salivation (ptyalism) (iii) thirst (iv) nausea, vomiting, eructations and diarrhea (v) burning pain in the stomach with colicky abdominal pain (vi) Vomited matter is bluish-green . In severe cases there may be ( i ) Hepatotoxicity – Acute hepatic necrosis and jaundice (ii) Hemolysis – More common than hepatotoxicity. Seen invariably in those who have undergone liver damage. Manifested by myoglobinuria , hemoglobinuria and hemoglobinuric renal failure (uncommon in patients who receive adequate volume replacement therapy) (iii) hematemesis , melena – Due to ulceration in the GIT (iv) methemoglobinemia , methemoglobinuria (v) Renal and pulmonary toxicity – Due to oxidative effects of copper ions. Renal toxicity is manifested by oliguria (vi) Hypotension and cardiovascular collapse – due to (a) intravascular volume depletion from vomiting and diarrhea and (b) direct effect of copper on vascular and cardiac cells (vii) Neurological – lethargy, seizures, coma. Result from hepatic encephalopathy. In Wilson’s disease, neurological manifestations are prominent.

45. Fatal dose 0.15-0.3 g/kg (CuSO4), i.e. about 20 g or a 70 kg man. 3. Fatal period 1-3 days.

46. PM appearances (1) Mouth and nostrils – Greenish blue froth (2) Gastric mucosa – Congested, eroded, swollen, inflamed. Color – greenish blue. Contents – greenish blue (3) Liver – Soft, fatty (4) Kidneys – Degenerative changes in proximal tubules (5) Skin – Yellow [due to jaundice] (6) Blood - hemolysis .

47. Chronic Poisoning Causes (1) Occurs in workers engaged in copper factories (inhalation of copper dust) (2) Copper cooking vessels – If copper cooking vessels are not properly tinned on the inside, food cooked in such vessels will cause formation of copper salts [Acids used in cooking (citric acid, tartaric acid, acetic acid) react with copper and form salts]. Their ingestion over a period of time will cause chronic poisoning. (3) Wilson’s disease: Wilson’s disease or hepatolenticular degeneration is an autosomal recessive genetic disorder affecting approx 1 in 40,000 people. Cause is the presence of abnormal allele of ATP7B gene at both loci (located on chromosome 13). A single abnormal copy of the gene is present in 1 in 100 people. They are carriers and do not develop any symptoms. If an abnormal allele is inherited from both parents, Wilson’s disease develops. The normal gene codes for ATPase that transports copper into bile and incorporates it into ceruloplasmin . In the absence of normal gene, copper accumulates in tissues . This manifests as neurological or psychiatric symptoms and liver disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older patients have been described.

48. Signs and symptoms (1) Anemia (2) Green line on gums (3) Colic (4) Peripheral neuritis (5) Degeneration and atrophy of muscles (6) Vineyard’s sprayer’s lung - Bordeaux mixture is copper sulfate (1-2%) mixed with lime [Ca(OH)2]. It is sprayed in vineyards to control fungus on grapes, melons, and berries. It is chronically inhaled by vineyard sprayers, who develop interstitial pulmonary fibrosis and histiocytic granulomas containing copper. Many workers also develop malignancies indicating the carcinogenic effects of copper. (7) Chalcosis lentis - ( Gk chalkos , copper) Chronic poisoning may cause deposition of copper in the cornea or lens turning them greenish-brown . (8) Greenish discoloration of hair: ( i ) Caused due to deposition of Cu over the hair. (ii) Swimming pools - Copper salts [ eg CuSO4] are used in swimming pools as algaecides. Long time swimmers may get green discoloration of hair . (iii) Tap water – Copper leeches from copper fittings by the acidic pH of the water [caused by fluoridation of drinking water]"may turn hair green. (iv) Exhaust gases containing copper and dusts from the copper processing industry cause green discoloration of the hair [ Chalcosis ]

49. ML Importance (1) Abortifacient (2) Cattle poison (3) Cheshunt compound - a mixture of copper sulfate and ammonium carbonate used in horticulture to prevent fungal diseases in seeds. May cause poisoning (4) Manner of poisoning: ( i ) Accident - (a) Children – may often put the crystals in their mouth attracted by their shining green color (b) Coin ingestion – Indian ` 2 and ` 5 coins are made of cupro-nickel. Their accidental ingestion may cause poisoning. (c) Cookware - Copper tea kettles and other copper cookware can be a source of copper toxicity if used frequently over a period of time. (d) Vegetables - Copper salts are used to enhance the green color of vegetables"if vegetables not washed properly before eating, can cause poisoning. Food vendors are liable for punishment under The Prevention of Food Adulteration Act, 1954. (ii) Homicide – Because of their color and taste, salts of copper can not normally be used for homicide. However they can be mixed in blue colored liquids eg sherbets or dark liquids eg Cola drinks (iii) Suicide – Relatively common, as copper salts are used in many cottage industries (5) Medicine - Copper has been used in medicine for a variety of ailments, which can cause iatrogenic poisoning ( i ) Treatment of burns and other wounds (ii) Contraceptive Pills - -es Cu levels in the body, because of close association between estrogen and Cu levels.

50. (iii) Copper is a component of dental casting gold alloys, dental amalgams, and IUDs. It corrodes"releases Cu ions into the surrounding tissue"toxicity . (iv) As an emetic – In the 1960s, copper sulphate (250 mg) was used as an emetic. No more used now because of its toxicity. (v) Hemodialysis - Copper in dialysis heating coils can be released, especially if acidic water is used in hemodialysis. (vi) Phosphorus poisoning – in ingestions as well as topical exposures to phosphorous.

51. Metal fume fever [MFF] - Caused by freshly oxidized metallic fumes (Most commonly with zinc , followed by copper and iron. Cadmium and tin however produce a more severe illness Usually caused by welding or melting of metals, soldering, forging and casting (all involve oxidation of metals. ZnO forms at relatively lower temperatures , accounting for its frequency as a causative factor). Quite common; more than 1000 cases are reported annually. Signs and symptoms [of MFF] - Influenza like syndrome, with sudden onset of chills, fever (104°C), thirst, myalgias and headache within 4-8 hours of inhalation of freshly oxidized metallic fumes. Course is generally benign with symptoms resolving completely within 24-48 hours without any sequelae. Theories of causation (a) release of endogenous pyrogens (b) production of antigenic metal proteinates (c) Delayed hypersensitivity pneumonitis (d) Direct toxic effect on alveolar cells.