1. November 18, 2003Robert Burr MD1 Toxicology of High Priority Substances Part 2: Metals

2. November 18, 2003Robert Burr MD2 Metals Large, diverse class of elements Large, diverse class of elements Widely distributed in nature Widely distributed in nature Humans are exposed to metals and metallic compounds from environmental and industrial sources Humans are exposed to metals and metallic compounds from environmental and industrial sources Today: Today: Lead, Mercury, Arsenic and Cadmium Lead, Mercury, Arsenic and Cadmium

3. November 18, 2003Robert Burr MD3 Each Metal has Multiple Forms Elemental Elemental Inorganic (minerals and salts) Inorganic (minerals and salts) Organic (e.g., methyl-mercury, tetraethyl lead) Organic (e.g., methyl-mercury, tetraethyl lead)

4. November 18, 2003Robert Burr MD4 Toxic response depends on: Specific target tissues Specific target tissues Concentration in target tissues, which will depend on the amount absorbed and the duration of exposure. Concentration in target tissues, which will depend on the amount absorbed and the duration of exposure. Toxic potency of the specific metallic toxin Toxic potency of the specific metallic toxin

5. November 18, 2003Robert Burr MD5 Toxic Metal Syndromes The particular syndrome associated with any particular metal depends largely on the tissues and organs where the metal is concentrated. Distribution depends on the specific chemical form of the metal: elemental, inorganic or organic. The particular syndrome associated with any particular metal depends largely on the tissues and organs where the metal is concentrated. Distribution depends on the specific chemical form of the metal: elemental, inorganic or organic. Organic metal compounds are usually lipophilic, so can penetrate the blood-brain barrier more efficiently making them more likely to be neurotoxic. Organic metal compounds are usually lipophilic, so can penetrate the blood-brain barrier more efficiently making them more likely to be neurotoxic. Inorganic metal salts are often excreted through the kidneys making them more likely to be nephrotoxic. Inorganic metal salts are often excreted through the kidneys making them more likely to be nephrotoxic.

6. November 18, 2003Robert Burr MD6 Essential Elements Some metals are “essential” elements and required in some amount for normal body function. Some metals are “essential” elements and required in some amount for normal body function. Examples: Iron, Zinc, Manganese, Copper, and Selenium. Examples: Iron, Zinc, Manganese, Copper, and Selenium. However, when present in excess concentrations, even these will have toxic effects. The dose required for toxic effect is usually substantially (orders of magnitude) larger than the required dietary intake needed to prevent deficiency. However, when present in excess concentrations, even these will have toxic effects. The dose required for toxic effect is usually substantially (orders of magnitude) larger than the required dietary intake needed to prevent deficiency.

7. November 18, 2003Robert Burr MD7 Toxic Metals Some metals have no physiologic role: Lead, Arsenic, Mercury, Cadmium are examples Some metals have no physiologic role: Lead, Arsenic, Mercury, Cadmium are examples

8. November 18, 2003Robert Burr MD8 Cell Injury Responses The principle toxic form of the metals is their free ion which binds to specific cell components The principle toxic form of the metals is their free ion which binds to specific cell components Enzymes Enzymes Cell structures (mitochondria, etc.) Cell structures (mitochondria, etc.) DNA-related proteins DNA-related proteins Specific cell injury effects depend on concentration. Specific cell injury effects depend on concentration. High concentrations produce immediate toxic effects with acute damage to exposed tissues. High concentrations produce immediate toxic effects with acute damage to exposed tissues. Lower concentrations produce more subtle changes in cell function and a gradual decline in organ function and/or mutations/carcinogenesis. Lower concentrations produce more subtle changes in cell function and a gradual decline in organ function and/or mutations/carcinogenesis.

9. November 18, 2003Robert Burr MD9 Physiologic Responses Some metals have physiologic effects Some metals have physiologic effects Usually those with some essential physiologic role: for example: K, Na. Usually those with some essential physiologic role: for example: K, Na. Others may mimic essential metals: for example, lithium. Others may mimic essential metals: for example, lithium.

10. November 18, 2003Robert Burr MD10 Allergic Responses Immediate hypersensitivity (Pt, Be) Immediate hypersensitivity (Pt, Be) Delayed hypersensitivity (Ni, Cr, Be, Zi) Delayed hypersensitivity (Ni, Cr, Be, Zi) Bystander reactions and immune complex disease (Au, Hg) Bystander reactions and immune complex disease (Au, Hg)

11. November 18, 2003Robert Burr MD11 Mutagenic Responses Carcinogenesis Carcinogenesis Probably through interaction with DNA constituents. Probably through interaction with DNA constituents. Cr, As, Ni, Be, Cd Cr, As, Ni, Be, Cd

12. November 18, 2003Robert Burr MD12 Teratogenic Responses Methyl mercury (Minamata disease) Methyl mercury (Minamata disease) Lead (cognitive defects) Lead (cognitive defects)

13. November 18, 2003Robert Burr MD13 Residence Time Metals ions can remain in the body for a very long time. Metals ions can remain in the body for a very long time. In some cases (lead, for example), the metal can be incorporated into bone where it can remain sequestered. Circumstances that increase bone breakdown can release the metal and produce acute toxicity. In some cases (lead, for example), the metal can be incorporated into bone where it can remain sequestered. Circumstances that increase bone breakdown can release the metal and produce acute toxicity.

14. November 18, 2003Robert Burr MD14 Metallothioneins Specific metal binding proteins in tissue and in the circulation. Specific metal binding proteins in tissue and in the circulation. Sequester metal ions and provide protection against their toxic effects. Sequester metal ions and provide protection against their toxic effects. Toxicity occurs when the binding capacity is exceeded or when the metal-protein complex is broken down in a cell and the metal ion released. Toxicity occurs when the binding capacity is exceeded or when the metal-protein complex is broken down in a cell and the metal ion released.

15. November 18, 2003Robert Burr MD15 Excretion of Metals Since the toxic form is an element, metals cannot be removed by metabolism or biotransformation into other chemicals. The only way of removing metal toxins is by excretion. Since the toxic form is an element, metals cannot be removed by metabolism or biotransformation into other chemicals. The only way of removing metal toxins is by excretion. The kidney is the principal route of excretion. This subjects the kidney tubule cells to high levels of metal ions and, consequently, kidney injury is a common consequence of metal toxicity. The kidney is the principal route of excretion. This subjects the kidney tubule cells to high levels of metal ions and, consequently, kidney injury is a common consequence of metal toxicity.

16. November 18, 2003Robert Burr MD16 Chelation Techniques to increase the rate of excretion of metals Techniques to increase the rate of excretion of metals Administration of chemicals that form stable water- soluble complexes the metal ions and increase their rate of excretion Administration of chemicals that form stable water- soluble complexes the metal ions and increase their rate of excretion These chemicals are called “chelators”. These chemicals are called “chelators”. Some of these are toxic per se and some can actually increase the toxic effects of their metal ligand by mobilizing the metal. Some of these are toxic per se and some can actually increase the toxic effects of their metal ligand by mobilizing the metal.

17. November 18, 2003Robert Burr MD17 Lead Ubiquitous Ubiquitous Earliest documented toxic metal: plumbing Earliest documented toxic metal: plumbing Target tissues: Target tissues: Brain and other nerve tissue Brain and other nerve tissue Liver Liver Kidney Kidney Multiple routes of cell injury Multiple routes of cell injury Mutagenic through reduced DNA repair. Mutagenic through reduced DNA repair. Crosses the placenta: embryo/fetus at risk Crosses the placenta: embryo/fetus at risk Half life: ~5-10 years Half life: ~5-10 years

18. November 18, 2003Robert Burr MD18 Lead: Toxic Responses Cell injury: Interferes with a wide variety of cellular processes Cell injury: Interferes with a wide variety of cellular processes Physiologic: none Physiologic: none Allergenic: none Allergenic: none Mutagenic: by reducing DNA repair, increases the net mutation rate Mutagenic: by reducing DNA repair, increases the net mutation rate Carcinogenic Carcinogenic Teratogenic: CNS effects Teratogenic: CNS effects

19. November 18, 2003Robert Burr MD19 Elemental & Inorganic Lead Easily absorbed through inhalation and ingestion Easily absorbed through inhalation and ingestion Primarily in the form of dusts and fume Primarily in the form of dusts and fume The NOAEL has not been defined and keeps getting lower. The NOAEL has not been defined and keeps getting lower. Acutely toxic with a wide variety of symptoms, none that are specific. Acutely toxic with a wide variety of symptoms, none that are specific. Abdominal pain Abdominal pain Neuropsychologic change: memory, cognition, personality Neuropsychologic change: memory, cognition, personality Peripheral nerve injury (weakness) Peripheral nerve injury (weakness) Blood lead levels diagnostic Blood lead levels diagnostic

20. November 18, 2003Robert Burr MD20 Chronic Lead Toxicity Chronic Lead Toxicity Slow, insidious illness Slow, insidious illness Recognition relies on suspicion and lead measurement Recognition relies on suspicion and lead measurement No specific symptoms or signs No specific symptoms or signs Abdominal pain Abdominal pain Neurologic injury Neurologic injury Reproductive toxicity (men and women) Reproductive toxicity (men and women) Hypertension, gout Hypertension, gout Pregnancy can mobilize stored lead. Pregnancy can mobilize stored lead. OSHA standard OSHA standard CDC recommendations for childhood screening CDC recommendations for childhood screening

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22. November 18, 2003Robert Burr MD22 Organic Lead Alkyl lead compounds Alkyl lead compounds Tetraethyl lead Tetraethyl lead Tetramethyl lead Tetramethyl lead Easily absorbed through skin Easily absorbed through skin Lipophilic and potent neurologic toxins Lipophilic and potent neurologic toxins Dwindling problem Dwindling problem

23. November 18, 2003Robert Burr MD23 Measuring and Managing Lead Exposure Measuring and Managing Lead Exposure Lead levels Lead levels Variable relationship to toxic manifestations Variable relationship to toxic manifestations Best in recent acute exposure Best in recent acute exposure Less helpful in chronic exposure Less helpful in chronic exposure Zinc protoporphyrin levels Zinc protoporphyrin levels Measures lead effect in red blood cells Measures lead effect in red blood cells Useful is assessing unclear situations Useful is assessing unclear situations Medical removal from exposure Medical removal from exposure Pb> 60 Pb> 60 Last three months > 50 Last three months > 50 “Increased risk” from lead exposure “Increased risk” from lead exposure

24. November 18, 2003Robert Burr MD24 Arsenic Ubiquitous, common element Ubiquitous, common element Relatively short half-life (hours) Relatively short half-life (hours) Forms Forms Elemental: non-toxic Elemental: non-toxic Organic: Organic: Dietary, non-toxic arsenobentaine and arsenocholine Dietary, non-toxic arsenobentaine and arsenocholine Military: lewisite, very toxic Military: lewisite, very toxic Inorganic forms are toxic Inorganic forms are toxic Pentavalent (arsenates) Pentavalent (arsenates) Trivalent (arsenites) Trivalent (arsenites) Arsine gas (AsH3) Arsine gas (AsH3)

25. November 18, 2003Robert Burr MD25 Arsenic: Toxic Responses Cell injury: interfere with multiple processes Cell injury: interfere with multiple processes Physiologic: none Physiologic: none Allergenic: none Allergenic: none Mutagenic: interferes with DNA repair Mutagenic: interferes with DNA repair Carcinogenic: skin cancers, lung cancer, angiosarcoma Carcinogenic: skin cancers, lung cancer, angiosarcoma Teratogenic: fetotoxic, congenital malformations Teratogenic: fetotoxic, congenital malformations

26. November 18, 2003Robert Burr MD26 Target Tissues Target Tissues Absorbed through lungs or gi tract Absorbed through lungs or gi tract Distributed by red blood cells to liver, kidney, brain, muscle, skin and hair Distributed by red blood cells to liver, kidney, brain, muscle, skin and hair Acute responses Acute responses Arsine: red blood cells – hemolysis followed by kidney failure Arsine: red blood cells – hemolysis followed by kidney failure Arsenic salts: intestinal cells, kidney, nervous system Arsenic salts: intestinal cells, kidney, nervous system Chronic responses: neuropathy, chronic injury to kidney, liver and lung, skin changes, cancer Chronic responses: neuropathy, chronic injury to kidney, liver and lung, skin changes, cancer

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28. November 18, 2003Robert Burr MD28 Measuring& Managing Arsenic Exposure Blood levels not helpful except early in acute toxic illness Blood levels not helpful except early in acute toxic illness Arsenic can be measured in urine, but must be careful to eliminate non-toxic dietary arsenic Arsenic can be measured in urine, but must be careful to eliminate non-toxic dietary arsenic Hair and nail arsenic can be measured Hair and nail arsenic can be measured Management Management Removal from exposure Removal from exposure Chelation: BAL (dimercaprol); succimer Chelation: BAL (dimercaprol); succimer

29. November 18, 2003Robert Burr MD29 Mercury Forms Forms Elemental: toxic by inhalation, not by ingestion Elemental: toxic by inhalation, not by ingestion Inorganic: mercury salts Inorganic: mercury salts Organic: Organic: Aryl: oxidized to mercury salts Aryl: oxidized to mercury salts Alkyl: methyl mercury, ethyl mercury – extremely toxic Alkyl: methyl mercury, ethyl mercury – extremely toxic Half-life about 2 months Half-life about 2 months

30. November 18, 2003Robert Burr MD30 Mercury: Toxic Responses Cell injury: interfere with multiple processes from divalent mercury ion Cell injury: interfere with multiple processes from divalent mercury ion Physiologic: none Physiologic: none Allergenic: dermatitis Allergenic: dermatitis Mutagenic: not known Mutagenic: not known Carcinogenic: none associated Carcinogenic: none associated Teratogenic: Minamata Disease Teratogenic: Minamata Disease

31. November 18, 2003Robert Burr MD31 Target Tissues Brain Brain Erethism: specific neuropsychologic changes Erethism: specific neuropsychologic changes Loss of coordination Loss of coordination Dementia Dementia Alkyl mercury has particular affinity for brain Alkyl mercury has particular affinity for brain Kidney: acute renal injury Kidney: acute renal injury Lung: acute inhalation injury Lung: acute inhalation injury Oral pathology Oral pathology

32. November 18, 2003Robert Burr MD32 Measuring and Managing Mercury Exposure Measurement Measurement Blood and urine Blood and urine Management Management Removal Removal Chelation Chelation

33. November 18, 2003Robert Burr MD33 ?

34. November 18, 2003Robert Burr MD34 Break