DR. SAADI TOXIC METALS 15-01-2025(1).pptx

Helps students in comprehensive understanding of forensic medicine and toxic substances that can cause death

1. Lecture 1 Pat 4206 Forensic Medicine And Toxicology TOXIC METALS,INSECTICIDES AND PESTICIDES POISONING SALAAM MUJEEB ( PhD, MPH . , MSc., AIMLS, DIMATHE,PGD,FMLSCN.,FAIPH) Lecturer, Department of Pathology Islamic University In Uganda Kampala ,Uganda 15 th January, 2 025

2. PERIODIC TABLE

3. Learning Objectives Periodic Table Introduction and Definitions Toxic Metals Table Essential Metals Medicinal Metals Non Metallic Toxicants Treatment of Toxicity Common Chelating Agents Discussions on some specific toxic metals Lecture Outline

4. Learning Objectives At the end of the lecture ,student/learner will be able to: Understand industrial toxicants like Lead, Cadmium, Arsenic, Copper, Mercury and H ydrocarbons with their toxicological effects on health and the environment. Discuss uses of Metals and their toxicity Explain the environmental toxins like Pesticides , Insecticides,Rodenticides, Dichloro -Diphenyl-Trichloroethane ( DDT ) , H erbicides etc

5. Metals are elements in the periodic table that react b y los i ng o n e or m o r e electrons to form cations. They ha v e p rop e r t i e s s u ch as h igh r e fl ec t i v ity(lustre) ,h igh e lec t ric a l conductivity, high thermal conductivity, strength ,malleability, and mechanical ductility In metal toxicology, we discuss metals that have been reported to produce significant toxicity in humans. These i n clude ma j o r toxic m e t a ls ( e.g. L ea d , Cad m ium, Arsen i c, Me r cu r y, Nick e l ) , Essential metals e.g .Iron ,Zinc, Copper Medicinal Metals e.g .Aluminium, Platinium, Bismuth Non-metallic toxicants e .g .Cyanide ,Selenium ,Fluoride Introduction

6. Introduction(2) Not all heavy metals are particularly toxic, and some are essential, such as Iron, and some, such as Bismuth, have a low toxicity The definition may also include trace elements when in abnormally high doses may be toxic e.g. Iron, Copper, Selenium, Chromium, manganese and molybdenum Radioactive metals e.g. Actinium Barium, Bismuth, Radon, Radium, Thorium, Francium, Plutonium, Neptunium, Uranium etc., have both radiological toxicity and chemical toxicity. Metals in an oxidation state abnormal to the body may also become toxic: Chromium(III) is an essential trace element, but Chromium(VI) is a carcinogen

7. Introduction (3) Toxicity is a function of solubility. Insoluble compounds as well as the metallic forms often exhibit negligible toxicity. The toxicity of any metal depends on its ligands. In some cases, organometallic forms, such as methyl mercury and tetraethyl lead, can be extremely toxic. In other cases, organometallic derivatives are less toxic such as the cobaltocenium cation. Metalloid Boron, Silicon, Arsenic,Antimony , Tellurium, Bismuth , Zinc, Tin, Iodine, Radon

8. Toxic Metals table Name Symbol   Arsenal As   Lead Pb   Mercury Hg   Cadmium Cd   Chromium Cr   Aluminium Al   Beryllium Be   Colbalt Co   Copper Cu   Gadolinium Gd   Iron Fe   Manganese Mn   Nickel Ni   Platinium Pt   Selenium Se   Silicon Si   Silver Ag   Titanium Ti  

9. Use of Metals and their toxicity Metal use by humans is inevitable as they form part of the essential elements needed to support life • The use has been also critical to the progress and success of human civilization especially in the emerging technology. • However industrial processes accumulate metals in the environment to higher levels that cause severe toxicity to humans. • H u m an use of m e t a ls can a l s o al t er t h e chemical form or speciation of an element thus making them potentially toxic . • Meta l s are non-biodegradable . Thi s , combined wi t h t heir bioaccumulation contributes to the high concern for metals as toxicants

10. Carcinogenicity and genotoxicity.e.g. Skin and cancer Nephrotoxicity e.g. proteinuria, azotaemia Neur o t o x i city e . g. enc epha l o pat h y, n u m b n ess, neu r o n al Hepatotoxicity e.g.hepatic comma, cirrhosis Cardiotoxicity e.g. arrythmias, heart failure and hypertension Pneumotoxicity e.g. pneumonitis Haematotoxicity e.g. anaemia, leucopenia Skeletal tissue damage e.g. osteoporosis Gastro-intestinal damage e.g. irritation, sloughing General Metal Toxicities

11. Binding to cellular proteins (ligands) e.g. Mercury and Cadmium bind to S in proteins disrupting their biological roles Inhibiting enzymes by binding at allosteric sites e.g. Lead inhibits enzymes in haeme synthesis Through mimicry, where the toxic metals mimic and replace essential metals. They gain access to, and potentially disrupt a variety of important functions or even critical metal-mediated cellular functions Mechanism of Metal Toxicity

12. Mimicry of Zinc by Cadmium, Copper, and Nickel, Thallium mimics Potassium and Manganese mimics Iron Metals act as catalytic centers for redox reactions with molecular oxygen or other endogenous oxidants generating reactive oxygen species (ROS) that cause oxidative damage to bio-molecules such as proteins and DNA. Thus, being potential carcinogens Metals in their ionic form react and form DNA and protein adducts in biological systems. E.g.Trivalent chromium species form DNA adducts or DNA p r o t e i n cr o s s- l inks Practice Question Describe in details the mechanism of Metal toxicity Mechanism of Metal toxicity(2)

13. An option for treatment of metal poisoning may be chelation therapy. This is a technique which involves the administration of chelation agents to remove metals from the body.. Examples are: Ethylene Diamine Tetra Acetic Acid (E D TA), D i m e r ca pr o l, Succ i m er, Pen i cilla m ine, Deferoxamine. Chelating a gents are ch e m ic al substances with two m o re ele c tr o ne g at i ve g r o u ps t h a t f o r m stable coor d i n at e -c o vale n t bond s with m e tal catio n s he n ce f o r ming c o m p le xes (chelate s) . Treatment of Metal toxicity (1)

14. Tre a t m ent of m e tal tox i ci t y (2) Chelati n g agen t s are used to pr e ve n t t h e eli m i n ation o f t h e m etal fr o m t h e body or to ac c eler a t e o r rev e rse t h e t o x i c eff e cts o f a heavy m e tal on a n enz y m e or o t her cellular target . The chelate -metal complexes formed are then excreted from the body. However, some may require in-vivo biotransformation to become an active complexing agent Complexation prevents the metal ions from reacting with molecules in the body, and enable them to be dissolved in blood and eliminated in urine ,

15. Tre a t m ent of m e tal tox i ci t y(3) NOTE Some chelators redistribute the metal to other organs Most chelators are not specific and will interact with a number of metals, thus eliminating even essential metals in the body. Metal chelation therapy however should be considered a secondary alternative to reduction or prevention of toxic metal exposures . QUESTION: What are the merits and Demerits of Chelating agents in the management of Metal Toxicity?

16. Common chelating age n ts C h e l ator U s e (m e tal che l at e d) Ro u te / d ose Si d e eff e ct 1. ED T A L e ad Par e nt e r a l Nephro t oxi c i t y 2. Dimercaprol Arsenic, mercury Parenteral CVS effects like (Inorganic), lead hypertension. Redistributes Arsenic(AS) to brain 3 . Succimer Lead Oral Gastrointestinal disturbances 4. Penicillamine Copper Oral Hypersensitivity, nephrotoxicity 5. Deferoxamine Iron Parenteral Hypotension, rash, pulmonary complication 6. Pru s sian blue ( Ferr i c Cesium a nd th a l l ium Oral Constip a t i on h e x ac y a no ferra t e ) 7 . Unith i ol Mer c ury , ars e nic Oral Der m a t olog i c a l r e a c t i ons

17. DISCUSSION ON SOME SPECIFIC TOXIC METALS

18. Conditions that involve Metal Toxicity Aluminium Arsenic Cadmium Copper-Zinc Deficiency Dialysis, Encephalopathy, or dementia Bilateral pain radiating from feet to legs, Pheripheral neuropathy, or unexplained impaired renal function Impaired renal function in Aerosol painters , Impaired wound healing Onset of Parkinsonism younger than age 50 years

19. Arsenic Arsenic (As) is a toxic and carcinogenic metalloid. Arsenic has been known and used since ancient times as the Poison of Kings and the King of Poisons . Arsenicals have been used since ancient times as drugs and even today are very effective against acute leukemia. Sources of AS Occupational exposure to arsenic occurs in the manufacture of pesticides, herbicides, and other agricultural products. High exposure to arsenic fumes and dusts may occur in smelting industries Environmental arsenic exposure mainly occurs from arsenic-contaminated drinking water, burning of coal containing naturally high levels of arsenic and perhaps from wood treated with arsenical preservatives . Food, especially seafood, may contribute significantly to daily arsenic intake. •

20. Arsenic (As) toxicity The dominant basis of arsenic poisoning is from ground water that naturally contains high concentrations of arsenic. A 2007 study found that over 137 million people in more than 70 countries are probably affected by arsenic poisoning from drinking water. Acute Poisoning : Ingestion of large doses (70–180 mg) of inorganic arsenic can damage mucous membranes of the gastrointestinal tract, causing irritation, vesicle formation, and even sloughing, Sensory loss, encelopathy, anaemia and leucopenia, garlic breath odor Chronic poisoning : Mee’s line syndrome(Leukonychia or Alderich-Mees’lines),Skin cancer(spotted hyper pigmentation), liver injury (jaundice),Peripheral neuropathy (pin and needles pain), interference with heme synthesis (increased porphyrin excretion)

21. Me c hanism of tox i c i ty of Arsenic The trivalent compounds of arsenic are inhibiting enzymes or alter proteins by reacting with proteineous thiol groups. Pentavalent arsenate mimics and replaces inorganic phosphate in the formation of adenosine triphosphate. In carcinogenicity, Arsenic and its metabolites produce oxidants that causes oxidative DNA damage, genomic ins t ab i li t y, Impaired DNA repair and enhan c ed ce l l pro l ifer a tion

22. Treatment of Arsenic Poisoning Acute arsenic poisoning, treatment is symptomatic, with particular attention to fluid volume replacement and support of blood pressure. Penicillamine is given orally in four divided doses to a m ax i m um of 2 g/day for 4 hours. Di m erc a pro l : 3 to 4 m g/kg int r a m uscula r l y every 4 to 12 hours Chronic Arsenic poisoning can be prevented by reducing Arsenic exposure.

23. 2. Lead Environmental lead comes mainly from human activity and is listed as a top toxic substance Inorganic lead compounds are used as pigments in paints, dyes, and ceramic braces. Organo-lead compounds were used as gasoline additives. Lead alloys are used in batteries, shields from radiation, water pipes, and ammunition, jewelry making. Herbal medicines could be potential sources of lead exposure. Poisoning is also higher in urban centres than rural centres Le a d po i s o ni n g is m ore c o mm on in c h i l dr e n b e c a use t h e m a j or way of exposure is food and water.

24. Lead poisoning (Plumbism) Neurological, Neurobehavioral, and Developmental Effects in Children e.g. encelopathy, low IQ Peripheral neuropathy is a classic manifestation of lead toxicity in adults. Nephrotoxicity consisting of proximal tubular dysfunction, interstitial fibrosis, progressive nephron loss, azotemia and renal failure In bones, lead causes osteoporosis and dental caries. Lead colic is a major gastrointestinal symptom of severe lead poisoning, and is characterized by abdominal pain, nausea, vomiting, constipation, and cramps Carcinogenicity especially stomach and lung cancers. •

25. Sources of Lead Homes that have cracked and peeling old lead paint on their walls. •Home renovations that disturb old lead paint can spread invisible lead dust. •Lead from old lead paint may contaminate household dust and nearby soil.

26. Lead Poisoning cont’d Most lead exposure in the U.S. today occurs in older homes with deteriorated leaded paint. •Children are at greatest risk of lead poisoning from their homes. Most children are exposed to lead in dust (not by eating paint chips).

27. How Does Lead Enter the Body? Ingestion Adults absorb about 6% of ingested lead. Fasting adults absorb more. Children absorb much more lead (30-50% if well fed, and more, if fasting or malnourished). It takes >10 years to turn over one half the body’s stored lead. Bone source slowly leaches into the blood.

28. Lead Exposure in utero Lead crosses the placenta in plasma. •Pregnancy (and lactation) causes lead release from bone stores into plasma •Plasma lead is about 10% of circulating blood lead. •Epidemiologic effects on CNS have been documented. •Peak transfer is at 12-14 weeks gestation

29. What happens when lead enters the body ? Lead is stored for long periods in mineralizing tissue such as teeth and bones. Lead can be released again into the bloodstream from these sources during times of bodily stress, such as ~ pregnancy ~ breastfeeding ~ calcium deficiency ~ osteoporosis (thinning of the bones)

30. Treatment of acute lead poisoning Antidote: Succimer, EDTA, Dimercaprol Succimer is the first orally active lead chelator available for children, with a safety and efficacy profile that surpasses that of D- Penicillamine. Succimer usually is given every 8 hours (10 mg/kg) for 5 days and then every 12 hours for an additional 2 weeks . Dimercaprol. Given intramuscularly at a dose of 4 mg/kg every 4 hours for 48 hours, then every 6 hours for 48 hours, and finally, every 6 to 12 hours for an additional 7 days. CaNa 2 EDTA is initiated at a dose of 30 to 50 mg/kg per day in two divided doses either by deep intramuscular injection or slow intravenous infusion for up to 5 consecutive days. NOTE: The combination of Dimercaprol and CaNa 2 EDTA is more effective than is either chelator alone

31. 3. Mercury Atmospheric mercury, is derived from natural degasing of the earth’s crust, volcanic eruption and evaporation from oceans and soils. However, anthropogenic sources significantly contribute to atmospheric mercury. These include emissions from metal mining and smelting, coal-combustion, municipal incinerators, and chloralkali industries. Once in the ecosystem , mercury is either oxidized to form inorganic mercury compounds or methylated by microorganisms to form methylmercury.

32. Mercury Cont’d Organo-mercurial compounds are more toxic than inorganic mercury Methyl mercury enters aquatic food chains through planktons, then herbivorous fish, and finally ascending to carnivorous fish and sea mammals. On the top of the food chain, tissue mercury can rise to levels 1800 to 80,000 times higher than levels in the surrounding water. This bio-concentration results into significantly high toxic levels in humans who feed on contaminated fish. (responsible for the mina mata disease in Japan) Mercury exposure can be dietary (fish consumption), occupational (industrial ), medicinal, accidental or freely from the environment

33. Exposure to Mercury Forms of mercury exposure include metal, vapor, salt, and organic compound Most exposure is from eating fish, amalgam based dental fillings, or exposure at work. In fish, those higher up in the food chain generally have higher levels of mercury. Less commonly poisoning may occur as an attempt to end one's life Human activities that release mercury into the environment include the burning of coal and mining of gold. Tests of the blood, urine, and hair for mercury are available but do not relate well to the amount in the body.

34. Prevention of Mercury Poisoning Prevention includes eating a diet low in mercury, removing mercury from medical and other devices, proper disposal of mercury, and not mining further mercury. In those with acute poisoning from inorganic mercury salts, chelation with either dimercaptosuccinic acid (DMSA) or dimercaptopropane sulfonate (DMPS) appears to improve outcomes if given within a few hours of exposure.

35. Mercury toxicity Mercury vapor - corrosive bronchitis and interstitial pneumonitis, tremor or increased excitability.. Early signs are non-specific, and this condition has been termed the asthenic-vegetative syndrome or micromercurialism . Inorganic mercury- Nephrotoxicity (proteinuria) • Methylmercury - Neurotoxicity paresthesia , ataxia, difficulty in swallowing and articulating words Mechanism of Toxicity Oxidative stress autoimmune N,B: Mercury toxicity causes erethism (abnormal mental excitement) . M ercury b i n ds to sul f hydryl gr o ups of pr o teins i n t h e ce l ls dis r upt i ng th e m produ c ing nonspec i fic ce l l in j ury or even ce l l dea t h. Also m e r cu r y inter r u p ts m i c ro t ub u le for m a t i o n, inhibit enzymes, , interrupts protein and DNA synthesis and stimulates 134

36. Treatment of mercury poisoning Antidote: Dimercaprol , EDTA or unithiol Inorganic mercury severe poising, particularly with acute renal failure, hemodialysis with L- cysteine may be the first measure, along with administration of chelating agents Dimercaprol: 5 mg/kg intramuscularly initially, followed by 2.5 mg/kg intramuscularly every 12 to 24 hours for 10 days. N.B: Dimercaprol should not be used in treatment of exposure to elemental or organic mercury because it redistributes mercury to the brain but instead Unithiol can be used 135

37. Mercury poisoning Mercury poisoning is a type of metal poisoning due to mercury exposure. Symptoms depend upon the type, dose, method, and duration of exposure. They may include muscle weakness, poor coordination, numbness in the hands and feet, skin rashes, anxiety, memory problems, trouble speaking, trouble hearing, or trouble seeing. High level exposure to methylmercury is known as Minamata disease. Methylmercury exposure in children may result in acrodynia (pink's disease) in which the skin becomes pink and peels. Long-term complications may include kidney problems and decreased intelligence. The effects of long-term low-dose exposure to methylmercury is unclear. s

38. 4. Cadmium Cadmium ranks close to lead and mercury as one of the top toxic substances Food is the major source of cadmium for the general populations since many plants readily accumulate cadmium from soil. Inhalation is the dominant route of exposure in occupational settings such as refining zinc and lead ores, iron production, cement manufacture, and industries involving fossil fuel combustion, manufacture of paint pigments, cadmium-nickel batteries, and electroplating Toxicity Severe irritation to the gastrointestinal epithelium (nausea, vomiting, and abdominal pain) acute pneumonitis with pulmonary edema Nephrotoxicity, neurotoxicity, carcinogenicity • • • Treatment: At the present time, there is no effective clinical treatment for cadmium intoxication because chelation therapy results into serious adverse effect but EDTA can be used

39. 5. Iron Iron is an essential metal for erythropoiesis and a key component of hemoglobin, myoglobin, heme enzymes, metalloflavoprotein enzymes, and mitochondrial enzymes. In biological systems, iron mainly exists as the ferrous (2+) and ferric (3+) forms. Iron deficiency causes anaemia and is the most common nutritional deficiency worldwide, affecting infants, young children, and women of child-bearing age. Oral ferrous sulfate is the treatment of choice for iron deficiency. Despite the essentiality of iron in the body , its overload causes severe iron toxicity • • • •

40. Toxicity of iron Acute iron poisoning from accidental ingestion of iron containing dietary supplements is the most common cause of acute toxicity in children. Symptoms include abdominal pain, diarrhea, vomiting, cyanoses metabolic acidosis, and cardiac collapse. Chronic iron toxicity can arise due to: Hereditary factors- result into excessive absorption of Fe from gut. Excessive intake of iron in the diet Repeated blood transfusion during refractory anaemia Iron overload results into hepatocellular carcinoma, cardiovascular diseases and neurodegenerative diseases

41. Treatment of iron Excess(Toxicity) Deferoxamine Supportive therapy and iron chelation with Deferoxamine should be used as soon as poss i bl e .

42. Chromium(Cr) Chromium is a chemical element with symbol Cr and atomic number 24. It is the first element in group 6 It is a steely-grey, lustrous, hard and brittle metal which takes a high polish, resists tarnishing, and has a high melting point. Trivalent chromium (Cr(III)) ion is an essential nutrient in trace amounts in humans for insulin, sugar and lipid metabolism While chromium metal and Cr(III) ions are not considered toxic, hexavalent chromium (Cr(VI)) is toxic and carcinogenic Abandoned chromium production sites often require environmental cleanup

43. Gadolinium(Gd) Gadolinium is a chemical element with symbol  Gd and atomic number 64. Gadolinium is a silvery-white, malleable, and ductile rare earth metal. It is found in nature only in oxidized form, and even when separated, The kinds of gadolinium(III) ions occurring in water-soluble salts are toxic to mammals. However, chelated gadolinium(III) compounds are far less toxic because they carry gadolinium(III) through the kidneys, and out of the body, before the free ion can be released into the tissues.

44. Zinc Zinc is a chemical element with symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table In some respects zinc is chemically similar to magnesium: both elements exhibit only one normal oxidation state (+2)

45. Zinc deficiency Zinc is an essential mineral perceived by the public today as being of "exceptional biologic and public health importance", especially regarding prenatal and postnatal development. Zinc deficiency affects about two billion people in the developing world and is associated with many diseases. In children, deficiency causes growth retardation, delayed sexual maturation, infection susceptibility, and diarrhoea Enzymes with a zinc atom in the reactive center are widespread in biochemistry, such as alcohol dehydrogenase in humans. Consumption of excess zinc can cause ataxia, lethargy and copper deficiency.

46. Zinc

47. Copper Copper is an essential element widely distributed in nature. • • Food, beve r ages and dr i n k ing wa t er a re m a j o r sou r ces of exposu r e i n the gene r al population. industry is • C o pper e x posure in p r i m ari l y f rom inhaled part i c u lates i n m i n ing o r m e t a l fu m es i n s m elt i ng opera t i o ns, welding, or related activities. Copper is an essential component of several metalloenzymes, • including release c yto c h ro m e c - o x id a se t h at is i m portant in e ne r gy • Copper/ z inc supe r oxi d e dis m ut a se is pr e s e n t in m ost c ells, redu c es supero x ide ra di c a ls to hy d rogen pero x ide p r eve n ti ng oxygen toxicity In mammals, little copper is excreted into the urine but in bile. •

48. References/Further readings Hodgson E , Levi PE.A Textbook of Modern Toxicology. Appleton and Lange.pg 18 .Norwalk ,Connecticut (1987) Alemu Biruh, Wolde Mistire A. Lecture Notes for Medical Laboratory Students Ethiopia Public Health Training Initiative(EPHTI), The Carter Center, the Ethiopia Ministry of Health, and the Ethiopia Ministry of Education. May 2007 Analytical Reference Standards and Supplementary Data for Pesticides and other Organic Compounds.US Environmental Protection Agency,1981 Matsumura,F (1975).Toxicology of Insecticides.New York. Plenum Press

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