01 Introduction To Clinical Toxicology[1]-5

Introduction to Clinical Toxicology

History of Toxicology Antiquity 

Earliest humans used animal venoms and plant extracts for hunting, warfare and assassination



Ebers Papyrus (1500 BC) 

Contains information pertaining to many recognized poisons  

 

Hemlock – state poison of the Greeks Aconite – Chinese arrow poison Opium – both poison & antidote Heavy Metals (As, Pb, Sb, Cu)

History of Toxicology Antiquity 

Hippocrates (400 BC) 



Added a number of poisons and clinical toxicology principles pertaining to bioavailability in therapy & overdosage

Book of Job (400 BC)  

Speaks of poison arrows *Book of Homer (Odyssey)

History of Toxicology Antiquity 

Theophrastus  



Student of Aristotle De Historia Plantarum

Pedanios Dioscorides    

Greek physician in the court of Roman Emperor Nero 1st who attempted to classify poisons (plant, animal or mineral) Use of emetics in poisoning Cupping glasses in snakebites

History of Toxicology Antiquity 

Socrates (470 – 399 BC)  



Demosthenes (385 – 322 BC) 



Best known recipient of poison for used as a state method of execution Cup of Hemlock extract

Took poison hidden in his pen

Cleopatra (69 – 30 BC) 

Use of the more genteel method of falling in her asp

History of Toxicology Antiquity 

King Mithridates VI of Pontus   



Discovered the antidote to for every venomous reptile and poisonous substance Regularly ingested a mixture of 36 ingredients (Galen reports 54) as protection to assassination “mithridatic” – antidotal or protective mixture

Nicander of Colophon 

 

Poetic treatise Theriaca “theriac” synonymous to antidote Alexipharmaca – poem about antidotes

History of Toxicology Antiquity 

Sulla (82 BC) 



Issued Lex Cornelia  1st law against poisoning  Became a regulatory statute directed at careless dispensers of drugs

Nero (37 – 68 AD)  

Used poisons to his brother Brittanicus Used his slaves as tasters to different edible mushrooms from more poisonous ones

History of Toxicology Middle Ages 

Moses ben Maimon (1135 – 1204 AD) 

 



Aka Maimonides Wrote, “Poisons and their Antidotes” (1198) Treatise on the treatment of poisonings from insects, snakes and mad dogs Wrote on the subject of bioavailability  Milk, butter & cream delays intestinal absorption

History of Toxicology Middle Ages 

Council of Ten of Venice 



Contains ample testimony on the political use of poisons during the Renaissance period

Lady Toffana  

Prepared arsenic-containing cosmetics known as Agua Toffana Also contains direction on the use of these cosmetics

History of Toxicology Middle Ages 

Hieronyma Spara 





Successor of Lady Toffana Directed towards specific marital and monetary objectives

Borgias 

Most notorious family engaged in poisoning

History of Toxicology Middle Ages 

Catherine de Medici 



Tested toxic concoctions and noted the following:  Onset of action  Potency  Specificity & site of action  Clinical signs & symptoms

Catherine Deshayes  

Midwife sorceress who earned the title “La Voisin” Convicted of poisonings with over 2,000 infant victims

History of Toxicology Age of Enlightenment 

Paracelsus (1943 – 1541)  Aka Philippus Aureolus Theophrastus Bombastus von Hohenheim 

“All substances are poisons; there is none which is not a poison. The right dose differentiates poison from a remedy.”



Promoted the focus on “toxicon”, (primary toxic agent as a chemical entity)



Introduce mercury as the DOC for syphilis

History of Toxicology Age of Enlightenment 

Paracelsus (1943 – 1541) 

Views of Paracelsus  Experimentation is essential in the examination of responses to chemicals  One should make distinction between the therapeutic and toxic properties of chemicals  These properties are sometimes but not always indistinguishable except by dose  One can ascertain the degree of specificity of chemicals and their therapeutic or toxic effects

History of Toxicology Age of Enlightenment 

Ellenbog (1480) 



Warned on the toxicity of the mercury and lead exposures involved in goldsmithing

Agricola  

Published a short treatise on mining diseases (1556) “On the Miners: Sickness and Other Diseases of Miners” (Paracelsus, 1557)

History of Toxicology Age of Enlightenment 

Bernardino Ramazzini 





Contributed to the advancement of occupational toxicology  Midwives, miners, printers, weavers, potters “Discourse on the Diseases of Workers” (1700)

Percival Pott (1714 – 1788) 



With Paracelsus, pointed out the toxicity of smoke & soot Role of soot in scrotal cancer among chimney sweeps – 1st reported example of polyaromatic hydrocarbon carcinogenicity

History of Toxicology Age of Enlightenment 

Orfila (1787 – 1853)  



1st toxicologist to autopsy material and chemical analysis systematically as legal proof of poisoning Published the major work devoted expressly on the toxicity of natural agents

Magendie 

Studied the MOA of emetine, strychnine and arrow poisons

History of Toxicology Age of Enlightenment 

Claude Bernard 





Oswald Schmiedeberg (1838 – 1921) 



MOA of carbon monoxide Treatise: Introduction to the Study of Experimental Medicine

Research focused on the synthesis of hippuric acid in the liver and the detoxification mechanisms of the liver in several animal species

Louis Lewin (1850 – 1929)  

Chronic toxicity of narcotics and alkaloids Toxicity of methanol, glycerol, acrolein, chloroform

History of Toxicology 20th Century 

“Poison Squad” 





Funded by the US Congress ($5,000) Professional tasters under the direction Washington Wiley (mislabeled foods)

of

Harvey

Discovery of Vitamins aka “Vital amines” 

Led to the use of bioassays to determine whether new synthetic chemicals were beneficial or harmful to laboratory animals

History of Toxicology 20th Century 

Paul Ehrlich (Arsphenamine) 





Resulted in acute and chronic toxicity Arsenic remains the major toxicant in many developing nations

Prohibition of Alcoholic Beverages in the US 

Discovery of the following lead to early studies of neurotoxicology  TOCP (Triorthocresyl Phosphate) – “ginger-jake” walk  Methanol – caused blindness  Lead toxicity

History of Toxicology 20th Century 

Mueller’s DDT (Dichlorodiphenyltrichloroethane) 



Lead to the widespread use of insecticidal agents (Hexachlorocyclohexane, Hexachlorobenzene)

1970s: Love Canal  

Led to the major concerns on hazardous wastes, chemical dump sites and disclosure of information about those sites Lead to the creation of Toxic Substances Control Act and Superfund Bill  Created to cover the toxicology of chemicals from initial synthesis to disposal

History of Toxicology 20th Century 

International Congress of Toxicology 



Made up of toxicology societies of Europe, South America, Asia, Africa and Australia

Cellular and Molecular Mechanisms of Toxicity 

Evolved from Gordon Conference (50th anniversary)

History of Toxicology 21st Century 

Judith Stein 



“Genetics loads the gun but the environment pulls the trigger.”

Zebrafish (C. elegans, D. melanogaster) 

New animal models used in toxicology

Definition of Terms Hazard  

Ability of a chemical agent to cause injury in a given situation or setting Primary considerations: use & exposure

Risk 

The expected frequency of the occurrence of an undesirable effect arising from exposure to a chemical or physical agent

Risk Assessment 

Quantitative estimate of the potential effects on human health and environmental significance of various types of chemical exposures

Definition of Terms Toxin 

Generally refers to toxic substances that are produced by the biological systems such as plants, animals, fungi or bacteria

Toxicant 

Toxic substances that are produced by or are a by-product of anthropogenic activities

Areas of Toxicology 

Descriptive Toxicology 



Deals with toxicity tests to obtain information that can be used to evaluate the risk that exposure to a chemical poses to humans and to the environment

Mechanistic Toxicology 

Determine how chemicals exert deleterious effects on living organisms

Areas of Toxicology 

Regulatory Toxicology 



Judge whether a drug or other chemical has a low enough risk to justify making it available for its intended purpose

Forensic Toxicology  

Combines analytical chemistry and fundamental toxicology Deals with postmortem investigations to establish the cause or circumstances of death

Areas of Toxicology 

Clinical Toxicology  



Focuses on diseases that are caused by or are uniquely associated with toxic substances Treatment of patients who are poisoned by drugs and other chemicals and develop new techniques for diagnosis & treatment of such intoxications

Environmental Toxicology 

Deals with the potentially deleterious impact of chemicals, present as pollutants of the environment on living organisms

Areas of Toxicology 

Occupational Toxicology 





Deals with chemicals found in the workplace Major emphasis is to identify the acute and chronic diseases that chemicals cause, conditions where these are used and prevent absorption of harmful amounts of these chemicals

Ecotoxicology 

Concerned with the toxic effects of chemical and physical agents on populations and communities of living organisms within defined ecosystem

Classification of Toxic Agents 

Based on Target Organ 





Liver, hematopoietic, kidney etc.

Based on Use 

Pesticide, additive etc

solvent,

food

Based on Chemical Stability or Reactivity 



Based on Chemical Structure 



Based on Effects 



Cancer, mutation, liver injury

Based on Physical State 

Gas, dust, liquid, size

Explosive, flammable, oxidizer

Aromatic amine, halogenated hydrocarbon etc.

Classification of Toxic Agents 

Based on Poisoning Potential 



Based on Biochemical Mechanisms of Action 



Extremely toxic, very toxic, slightly toxic

Alkylating agents, cholinesterase inhibitor, endocrine disruptor etc.

Based on General Terms 

 

Irritants & corrosives Air pollutants, occupation-related agents etc. Acute & Chronic poisons

Spectrum of Undesired Effects Allergic Reactions 

Chemical Allergy  Immunologically-mediated adverse reaction to a chemical resulting from previous sensitization to that chemical or structurally similar one



Allergic Reaction and Sensitization Reaction  Describe a situation when pre-exposure of the chemical is required to produce the toxic effect

Spectrum of Undesired Effects Idiosyncratic Reactions 

Chemical Idiosyncrasy  Genetically determined abnormal reactivity to a chemical 

Classic Example: Malignant hyperthermia Succinylcholine (butyrylcholinesterase)



May be due to the ability to: Form a reactive intermediate (thru oxidation)  Detoxify the reactive intermediate (thru hydrolysis)  Exhibit differences in immune response to adducted proteins 

from

Spectrum of Undesired Effects Immediate vs. Delayed Toxicity 

Immediate Toxic Effects – occur or develop rapidly after a single administration of a substance



Delayed Toxic Effects – Occur after the lapse of some time

Spectrum of Undesired Effects Reversible vs. Irreversible Toxic Effects 

Reversible – pathological injury to a tissue has the ability to regenerate



Irreversible – pathological injury to a tissue that have cells which cannot divide or be replaced; carcinogenicity; teratogenicity

Spectrum of Undesired Effects Local vs. Systemic Toxicity 

Local Effects  Occur at the site of first contact between the biological system and the toxicant  May result from ingestion or inhalation of irritant materials



Systemic Effects  Require absorption and distribution of toxicant from its entry point to a distant site at which deleterious effects are produced  Elicit major toxicity in 1 or 2 organs

Spectrum of Undesired Effects Interaction of Chemicals 

Mechanisms of Interaction  Alteration in absorption  Protein binding  Biotransformation  Excretion of 1 or both of the interacting toxicants



Types of Interaction  Additive, potentiation, synergism, antagonism

Spectrum of Undesired Effects Interaction of Chemicals 

Types of Antagonism  Functional – occurs when 2 chemicals counterbalance each other by producing opposite effects on the same physiological functions 

Chemical or Inactivation – chemical reaction between 2 compounds that produces a less toxic product

Spectrum of Undesired Effects Interaction of Chemicals 

Types of Antagonism  Dispositional – occurs when the disposition (ADME) is altered so that the concentration and/or duration of the chemical at the target organ are diminished 

Receptor aka blockers – occurs when 2 chemicals that bind to the same receptor produce less of an effect when given together than the addition of their separate effects or when 1 chemical antagonizes the effect of the 2nd chemical

Spectrum of Undesired Effects Tolerance 

State of decreased responsiveness to a toxic effect of a chemical resulting from prior exposure to that chemical or to a structurally related chemical



Mechanisms  Dispositional Tolerance – decreased amount of toxicant reaching the site where the toxic effect is produced  Reduced responsiveness of a tissue to a chemical

Mechanisms of Toxicity

Significance of Determining the Mechanisms of Toxicity 

Information obtained provides a rational basis for: 

  



Interpreting toxicity data Estimating the probability of a chemical to produce harmful effects Establishing procedures to prevent or antagonize toxic effects Designing drugs or industrial chemicals that are less hazardous

Provides better understanding of physiologic and biochemical processes

fundamental

Ultimate Toxicants 

Parent Xenobiotics 



Lead ions, Tetrodotoxin, TCDD, Methylisocyanate, HCN, CO

Xenobiotic Metabolites  

 

 

 

Amygdalin Arsenate Fluoroacetate Ethylene glycol Hexane Acetaminophen Carbon Tetrachloride Benzo-a-pyrene

– – – – – – – –

HCN Arsenite Fluorocitrate Oxalic Acid 2,5-Hexanedione NAPQI CCl3OO (unsat. FA) BP-radical cation

Ultimate Toxicants 

Reactive Oxygen or Nitrogen Species  



Yield Hydroxyl (HO) Radicals : Hydrogen Peroxide, Diquat, Doxorubicin, Nitrofurantoin, Cr (V), Fe (II), Mn (II), Ni (II) Yields Peroxynitrite (ONOO-) : Paraquat

Endogenous Compounds   

Sulfonamides – albumin-bound bilirubin Unsaturated FA – Lipid radicals Hydroxyl – Protein carbonyls

Stages of Development of Toxicity

Interaction with target molecule

Toxicant

Delivery

Cellular dysfunction, injury

Inappropriate repair and adaptation

Alteration of biological environment

Toxicity

Step 1 – Delivery: From Site of Exposure to the Target

Step 1 – Delivery: From Site of Exposure to the Target

Absorption vs. Presystemic Elimination 

Absorption  Transfer of a chemical from the site of exposure into the systemic circulation 

Rate of absorption depends on:  Concentration

of the chemical at the absorbing surface (rate of exposure, dissolution of the chemical)  Characteristic of the absorbing surface  Physicochemical properties of the toxicant

Step 1 – Delivery: From Site of Exposure to the Target

Absorption vs. Presystemic Elimination 

Presystemic Elimination  Aka First Pass Elimination  Advantage:  Reduces

the toxic effects of chemicals that reach the systemic circulation



Disadvantage:  May

contribute to the injury of the digestive mucosa, liver and lungs

Step 1 – Delivery: From Site of Exposure to the Target Distribution To and Away from the Target 

Mechanisms that promote distribution:  Porosity of the Capillary Endothelium – larger fenestrae (50-150 nm in diameter) to permit passage of proteinbound xenobiotics 

Specialized Transport Across the Plasma Membrane – ion channels and membrane transporters contribute to the delivery of toxicants to intracellular targets

Step 1 – Delivery: From Site of Exposure to the Target Distribution To and Away from the Target 

Mechanisms that promote distribution:  Accumulation in Cell Organelles Occurs in amphipathic xenobiotics with a protonable amine group and lipophilic character  Can be lysosomal or mitochondrial accumulation 



Reversible Intracellular Binding Organic & inorganic cations, polycyclic aromatic hydrocarbons – accumulate in melanin containing cells (retina, substantia nigra, skin)  Thiol-reactive metal ions & metalloids – sequestered by cysteine residues in keratin 

Step 1 – Delivery: From Site of Exposure to the Target Distribution To and Away from the Target 

Mechanisms that oppose distribution:  Binding to Plasma Protein – exemplified by DDT & TCDD (dioxin) which bind to high molecular weight proteins or lipoproteins in the plasma 

Specialized Barriers eg. Blood-brain barrier, blood-testis barrier, placenta  Disadvantage: NO BARRIER FOR LIPOPHILIC SUBSTANCES 

Step 1 – Delivery: From Site of Exposure to the Target Distribution To and Away from the Target 

Mechanisms that oppose distribution:  Storage Sites – eg. Adipocytes 

Association with Intracellular Binding Proteins – temporarily reduce the concentration of toxicants by binding to nontarget intracellular sites



Export from Cells – intracellular toxicants transported back to the extracellular space

Step 1 – Delivery: From Site of Exposure to the Target Excretion vs. Reabsorption 

Excretion  Physical mechanism of the removal of xenobiotics from the blood 

Excretory Structures:  Renal

glomeruli, proximal renal tubular cells, hepatocytes, bile canaliculi – for nonvolatile chemicals  Renal transporters – for amphiphilic molecules <300 Da  Hepatic transporter – for amphiphilic molecules >400 Da

Step 1 – Delivery: From Site of Exposure to the Target Excretion vs. Reabsorption 

Excretion  Criteria for Excretion – Hydrophilic, Ionized due to: Only compounds dissolved in the plasma water can be filtered in the renal glomeruli  Transporters in hepatocytes & renal proximal tubular cells are specialized for secretion of highly hydrophilic organic acids & bases  Only hydrophilic chemicals are freely soluble in the aqueous urine & bile  Lipid-soluble compounds are readily reabsorbed by transcellular diffusion 

Step 1 – Delivery: From Site of Exposure to the Target Excretion vs. Reabsorption 

Excretion  Mechanisms of Excretion for Nonvolatile Lipophilic Compounds: By mammary gland after the chemical is dissolved in milk lipids  In bile in association with biliary micelles and/or phospholipid vesicles  Intestinal 



Mechanism of Compounds: 

Excretion

for

Volatile

Nonreactive

Diffusion through the pulmonary capillaries into the alveoli then exhaled

Step 1 – Delivery: From Site of Exposure to the Target Excretion vs. Reabsorption 

Reabsorption  Depends on the lipid solubility and ionization  Favors lipophilic and unionized compounds

Step 1 – Delivery: From Site of Exposure to the Target Toxication vs. Detoxication 

Toxication  Aka metabolic activation  Biotransformation to harmful products  Physicochemical properties that adversely alter the microenvironment of biological processes or structures 

Mechanisms: Formation of Electrophiles  Free Radicals  Nucleophiles  Redox-active reactants 

Step 1 – Delivery: From Site of Exposure to the Target Toxication vs. Detoxication 

Toxication  Formation of Electrophiles – molecules containing an electron deficient atom with a partial or full positive electron-rich atoms in nucleophiles

 Electrophiles

 Usually

produced by insertion of oxygen atom which withdraws the electron from the atom

Toxicant

Metabolite

Toxic Effect

Ethanol

Acetaldehyde

Hepatic Fibrosis

Benzene

Muconic aldehyde

Bone marrow injury

Acetaminophen

NAPQI

Hepatic necrosis

DES

DES-4,4’-quinone

Carcinogenesis

Aflatoxin

Aflatoxin B1 8,9-epoxide

Carcinogenesis

Benzo(a)pyrene

Benzo(a)pyrene 7,8-diol 9,10-oxide

Carcinogenesis

Sulfamethoxazole

Nitroso-sulfamethoxazole

Immune Reaction

Parathion

Paraoxon

Acetylcholinesterase inhibition

Chloroform

Phosgene

Hepatic Necrosis

Halothane

Trifluoroacetylchloride

Immune Hepatitis

Elemental Mercury

Mercury (II) ion

Brain Injury

Cisplatin

Diaquo-diamino platinate (II)

Renal tubular necrosis

Step 1 – Delivery: From Site of Exposure to the Target Toxication vs. Detoxication 

Toxication  Formation of Free Radicals 

By accepting an electron – eg. Paraquat, doxorubicin, nitrofurantoin  oxygen radicals (reductases)



By losing an electron – eg. Phenols, hydroquinone, aminophenols, aromatic amines, hydrazines, thiols  semiquinone, quinones, quinoneimine (peroxidases)



By homolytic fission of a covalent bond – eg. Carbon tetrachloride  trichloromethyl (induced by electron transfer to the molecule)

Step 1 – Delivery: From Site of Exposure to the Target Toxication vs. Detoxication 

Toxication  Formation of Nucleophiles  Uncommon

mechanism  Eg. Cyanide from amygdalin, acrylonitrile after epoxidation and subsequent glutathione conjugation, from sodium nitroprusside by thiol-induced decomposition

Step 1 – Delivery: From Site of Exposure to the Target Toxication vs. Detoxication 

Toxication  Formation of Redox-Active Reactants  Examples

Methemoglobin-producing nitrite from nitrate by bacterial reduction in the intestine  Esters from nitrous or nitric acid in reaction with glutathione  Dapsone hydroxylamine & 5-hydroxyprimaquine to methemoglobin by cooxidation  Reduction of ascorbic acid 

Step 1 – Delivery: From Site of Exposure to the Target Toxication vs. Detoxication 

Detoxication  Pertains to biotransformation that eliminates an ultimate toxicant or prevents its formation  Take place in several pathways 

Detoxication of Toxicants with no Functional Groups Functional group is introduced to the molecule by CYP 450  An endogenous acid (glucuronic, sulfuric or amino acid) is added to the functional group by transferases  Product: inactive, highly hydrophilic, readily excretable organic acids 

Step 1 – Delivery: From Site of Exposure to the Target Toxication vs. Detoxication 

Detoxication  Detoxication of Nucleophiles 

By conjugation of the nucleophilic functional group (sulfation, glucuronidation, methylation) which prevent peroxidase-catalyzed conversion of nucleophiles to free radicals



By oxidation (flavin-containing monooxgenases) – eg. Thiols, amines, hydrazines



By oxidation to carboxylic dehydrogenase) – alcohols

acid

(alcohol

and

aldehyde

Step 1 – Delivery: From Site of Exposure to the Target Toxication vs. Detoxication 

Detoxication  Detoxication of Electrophiles 



Detoxication of Free Radicals 



General mechanism: Conjugation with the thiol nucleophile glutathione (spontaneous or facilitated by Glutathione-Stransferase)

Mediated by SOD (superoxide dismutases)

Detoxication of Protein Toxins 

Mediated by intra- and extracellular proteases (eg. Thioredoxin)

Step 1 – Delivery: From Site of Exposure to the Target Toxication vs. Detoxication 

Detoxication  Rationale for Insufficient Detoxication may overwhelm the detoxication process  saturation of detoxication enzymes  Inactivation of detoxicating enzyme by the reactive toxicant  Reversed conjugation reactions  Detoxication generates potentially harmful by-products  Toxicants

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule

Considerations:   

Attributes of target molecules Types of reaction between ultimate toxicant and target molecules Effects of toxicants on target molecules

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule

Attributes of Target Molecules 

Prevalent targets: nucleic acids & proteins



Properties of Target Molecules  Appropriate reactivity or steric configuration to allow the ultimate toxicant to enter into reactions  Must be accessible to a sufficiently high concentration of the ultimate toxicant  The first target is usually the enzyme that catalyzes the production of the reactive metabolites or the adjacent intracellular structure

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule Types of Reactions 

Noncovalent Bonding  Due to polar interactions or the formation of hydrogen and ionic bonds  Involved in the interaction of toxicants with targets such as membrane receptors, intracellular receptors, ion channels, enzymes  Examples: Strychnine to the glycine receptor on motor neurons  Saxitoxin to sodium channels  Warfarin to Vit K 2,3-epoxide reductase 

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule Types of Reactions 

Covalent Bonding  



Irreversible bonding (permanently alters endogenous molecules) Common in nonionic and cationic electrophiles and radical cations Exhibit selectivity to nucleophilic atoms

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule Types of Reactions 

Hydrogen Abstraction 

Product: Radicals  Examples:  Thiyl  Amino Acids  Carbonyls  Amines  DNA  C-4’-radical (1st step to DNA Cleavage)  Fatty Acids  Lipid Radicals (initiates peroxidation)  Thiols

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule Types of Reactions 

Electron Transfer  Oxidation Reactions (II) in hemoglobin  Fe (III)  methemoglobinemia  Hydrazines, phenolics are cooxidized with oxyhemoglobin  methemoglobin & hydrogen peroxide  Fe

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule Types of Reactions 

Enzymatic Reactions  Ricin & Abrin – N-glycosidases blocks protein synthesis  Botox – Zn-Proteases  Paralysis  Anthrax – Zn-Proteases  cell death (inactivation of MAPKK)

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule Effects of Toxicants on Target Molecules 

Dysfunction of Target Molecule  Activators: – opioid receptors  Clofibrate – PPAR  Morphine



Inhibitors Strychnine, Curare – NMB  Tetrodotoxin, Saxitoxin – inhibit opening of sodium channels  Atropine,

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule Effects of Toxicants on Target Molecules 

Destruction of Target Molecule  Alteration of the primary structure of endogenous molecules by cross-linking & fragmentation  Eg. Alkylating



agents

Spontaneous degradation of target molecule after chemical attack  Eg.

Formation of free radicals

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule Effects of Toxicants on Target Molecules 

Neoantigen Formation  Hapten formation which evokes immune response Mediated: Eg. Penicillin – IgE reaction T-cell Mediated: Eg. Contact Allergens (Nickel), Sulfamethoxazole, Drug-Induced SLE B-cell

Step 2: Reaction of the Ultimate Toxicant with the Target Molecule Toxicity Not Initiated by Rxn with Target Molecule 

Chemicals that alter H+-ion concentrations in aqueous biophase 

Acids, alcohols  dissipate proton gradient



Solvents & detergents that physicochemically alter the lipid phase of the cell membrane & destroy transmembrane solute gradient



Xenobiotics that cause harm by occupying site or space 

 

Ethylene Glycol, MTX, Acyclovir – ppts in the renal tubules Sulfonamides – Bilirubin binding sites Carbon Dioxide – displacement of oxygen in the pulmonary space

Step 3: Cellular Dysfunction and Resultant Toxicities

Step 3: Cellular Dysfunction and Resultant Toxicities Toxicant Induced Cellular Dysregulation 

Dysregulation of Gene Expression – Transcription 

Acting Through Ligand-Gated TFs

Step 3: Cellular Dysfunction and Resultant Toxicities Toxicant Induced Cellular Dysregulation 

Dysregulation of Gene Expression – Transcription  Alteration of Regulatory Region of Genes  By

direct chemical interaction or by changing methylation patterns  Eg. Thalidomide, drug-induced SLE, oncogenes

Step 3: Cellular Dysfunction and Resultant Toxicities Toxicant Induced Cellular Dysregulation 

Dysregulation of Gene Expression – Signal Transduction  Activators of transduction: Growth factors, cytokines, hormones, neurotransmitters 

Chemicals with Proliferative Effects Promotes mitosis and tumor formation  Eg.1. Lead (II) ion – mimics PKC activator calcium ion  Eg.2. Arsenite – mimics epidermal growth factor 



Chemicals with Antiproliferative Effects 

Eg. Glucocorticoids which contribute to apoptosis

Step 3: Cellular Dysfunction and Resultant Toxicities Toxicant Induced Cellular Dysregulation 

Dysregulation of Gene Expression – Signal Production  Inhibition of some hormones that alters feedback mechanism  Eg. Endocrine hormones that are controlled by negative feedback mechanism

Step 3: Cellular Dysfunction and Resultant Toxicities Toxicant Induced Cellular Dysregulation 

Dysregulation of Electrical Excitable Cells  Excitable cells: Neurons, skeletal, cardiac & smooth muscle cells  Basic MOA of drugs that cause toxicities associated with overdosage, pesticides, microbial, plant and animal toxins  Mechanisms: Alteration in neurotransmitter levels  Toxicant-Neurotransmitter receptor interactions  Intracellular signal transduction  Signal-terminating processes 

Step 3: Cellular Dysfunction and Resultant Toxicities Toxicant Induced Cellular Dysregulation 

Dysregulation of Electrical Excitable Cells  Alteration in Neurotransmitter Levels – Norepinephrine, serotonin, dopamine  Botulinum toxin – acetylcholine  Organophosphates & carbamates insecticide – acetylcholinesterase  TCAs & MAOIs – catecholamines  Reserpine

Step 3: Cellular Dysfunction and Resultant Toxicities Toxicant Induced Cellular Dysregulation 

Dysregulation of Electrical Excitable Cells  Toxicant-Neurotransmitter Receptor Interactions  Agonists

that associate with the ligand-binding site on the receptor and mimic the natural ligand  Antagonists that occupy the ligand-binding site but cannot activate the receptor  Activators and inhibitors that bind to a site on the receptor that is not involved in ligand binding

Step 3: Cellular Dysfunction and Resultant Toxicities Toxicant Induced Cellular Dysregulation 

Dysregulation of Electrical Excitable Cells  Toxicant-Signal Transducer Interactions – overexcitation of voltage-gated sodium ion channels

 DDT



Toxicant-Signal Terminator Interactions (nephrotoxic) – blockade of calcium and potassium ion channels  Astemizole, Terfenadine, Cisapride – blocks voltagegated potassium ion channels  TdP  Cyclosporine

Step 3: Cellular Dysfunction and Resultant Toxicities Toxicant Induced Cellular Dysregulation 

Dysregulation of the Activity of Other Cells  Pertains to the signaling mechanisms operated by non-excitable cells  Eg.

Exocrine secretory cells, pancreatic beta cells, Kupffer cells in the liver

Step 3: Cellular Dysfunction and Resultant Toxicities Toxic Alteration of Cellular Maintenance 

Impairment of Cellular Maintenance  Toxic cell death may result from the disruption in: Synthesis of endogenous molecules  Assembly of macromolecular complexes, membranes, cell organelles  Maintenance of the intracellular environment  Production of energy for operation 



Biochemical Disorders: ATP Depletion  Calcium Ion Accumulation  ROS/RNS Generation 

Step 3: Cellular Dysfunction and Resultant Toxicities Toxic Alteration of Cellular Maintenance 

Impairment of Cellular Maintenance  ATP Depletion Class A – interfere with the delivery of hydrogen to the ETC (eg. Fluoroacetate which inhibits citric acid cycle)  Class B – inhibits transfer of electrons along the ETC to oxygen (eg. Cyanide)  Class C – interfere with oxygen delivery to terminal electron transporter, cytochrome oxidase (eg. Agents that cause hypoxia)  Class D – inhibit activity of ATP synthase  Class E – impairs synthesis of specific proteins encoded by the mitochondrial genome 

Step 3: Cellular Dysfunction and Resultant Toxicities Toxic Alteration of Cellular Maintenance 

Impairment of Cellular Maintenance  Accumulation of Intracellular Calcium Ion  Mitochondria

are equipped with a low-affinity calcium transporter  sequestration of calcium  Accumulation of calcium  deposition of calcium phosphate  Results of sustained elevation of calcium: Depletion of energy stores  Dysfunction of microfilaments  Activation of hydrolytic enzymes  Generation of ROS and RNS 

Step 3: Cellular Dysfunction and Resultant Toxicities Toxic Alteration of Cellular Maintenance 

Mitochondrial Permeability Transition (MTP): Necrosis  Thought to be caused by misfolded proteins from inner and outer membranes which aggregare and open a proteinaceuous pore known as “megachannel” 

Necrosis (Worst Outcome)  cell lysis

Step 3: Cellular Dysfunction and Resultant Toxicities Toxic Alteration of Cellular Maintenance 

Mitochondrial Permeability Transition (MTP): Apoptosis  Apoptosis (Alternative Outcome)  shrinking of cells  apoptotic bodies  Causes are similar to necrosis  “cascade-like” activation of catabolic processes that disassemble the cell



*Form of cell death depends on the severity of insult on the cells

Step 3: Cellular Dysfunction and Resultant Toxicities Toxic Alteration of Cellular Maintenance 

Impairment of External Cellular Maintenance  Toxicants that interfere with cells that are specialized to provide support to other cells, tissues or whole organisms  Eg. Hepatocytes

Step 4: Inappropriate Repair Mechanisms of Repair

Step 4: Inappropriate Repair Mechanisms of Repair 

Molecular Repair  Repair of Proteins – thioredoxins and glutaredoxins  Repair of Lipids – series of reductants with glutathione peroxidase and reductase  Repair of DNA Direct – use of enzymes that directly reverse the damage  Excision – base or nucleotide excision (removal of the lesions that may damage the DNA helix)  Recombinational (Postreplication) – crossover of the appropriate strands of the homologous duplexes 

Step 4: Inappropriate Repair Mechanisms of Repair 

Cellular Repair  Strategy for peripheral neurons  For central neurons, damage is irreversible  In most tissues, injured cells eventually die

Step 4: Inappropriate Repair Mechanisms of Repair 

Tissue Repair  Apoptosis Initiated by a Tissue Repair  Intercept

the process leading to necrosis  Intercept the process leading to neoplasia by eliminating the cells with potentially mutagenic DNA damage 

Proliferation (Regeneration of Tissue)  Replacement

of loss cells by mitosis  Replacement of extracelluar matrix which is composed of proteins, glycoprotein conjugates

Step 4: Inappropriate Repair Mechanisms of Repair 

Tissue Repair  Side Reactions to Tissue Injury that may contribute to repair: – leukocyte invasion  Inflammation – ROS & RNS production  Acute Phase Proteins – cytokines released by the macrophages which has diagnostic and repair value  Generalized reactions  Inflammation

General approaches in the management of poisoning

Drugs used in the Treatment of Poisoning Antidote

Indication

N-acetylcysteine

Acetaminophen

Aminophylline

Propranolol

Ammonium Chloride

Phenyclidine, Amphetamine

Amyl Nitrite

Cyanide

H1 Antihistamine

Bee Sting

Polyvalent Anti-snakebite serum

North American Snakes

Botulism Antitoxin

Botulism

Calcium EDTA

Lead

Calcium gluconate

Fluoride, Black Widow Spider

Activated Charcoal

Adsorbent (Universal Antidote)

Dantrolene

Malignant Hyperthermia (Succinylcholine)

Drugs used in the Treatment of Poisoning Antidote

Indication

Deferoxamine

Iron

50% Dextrose

Cerebral Edema

D5W, D5NS

Fluid replacement

Diazepam

Anticonvulsant

Dimercaprol (BAL)

Heavy Metals

Diphenhydramine

Bee Sting, Anaphylaxis

Epinephrine

Analphylaxis, Hypersensitivity Reaction

95% Ethanol, 5% Ethanol in NS

Methanol

Fluorescein solution (Sterile)

Eye contamination

Furosemide

Diuretic

Glucagon

Propranolol

Drugs used in the Treatment of Poisoning Antidote Ipecac Syrup Isoproterenol Mannitol Methylene Blue Evaporated Milk Morphine Sulfate Milk of Magnesia Naloxone, Naltrexone Norepinephrine Paraldehyde Penicillamine

Indication Emetic Propranolol Cerebral Edema Methemoglobinemia Acids Pain Acids Opioids Cardiac Arrest Acute Alcoholic Mania Lead, Copper

Drugs used in the Treatment of Poisoning Antidote Phenobarbital Phenytoin Physostigmine Potassium Chloride Pralidoxime Prednisolone Propranolol Pyridoxine Sodium bicarbonate Isotonic Sodium Chloride Sodium Nitrate

Indication Anticonvulsant Anti-arrhythmic Atropine (Anticholinergics) Electrolyte Replacement Organophosphates Cerebral Edema Anti-arrhythmic INH, mushrooms, sulfides Acidosis Fluid, Electrolyte replacement Cyanide

Drugs used in the Treatment of Poisoning Antidote Sodium Sulfate Sodium Thiosulfate Starch Succinylcholine Thiopental Urea Vitamin K

Indication Barium, Cathartic Cyanide, Bleaching solution Iodine Anticonvulsant Anticonvulsant Sulfides Dicumarol, Warfarin

Supportive Management Pain 





Severe pain causes vasomotor collapse and reflex inhibition Administer Morphine sulfate  ADRs: N/V, CNS depression, respiratory depression  CI: CNS depression, respiratory difficulty, hyperexcitability, hepatic disease Administer Meperidine  Causes less nausea and vomiting

Supportive Management Fluid Imbalance 

Water loss of 10-15mL/kg/day – replaced by the administration of water without electrolytes or 5 or 10% dextrose in water or just per orem intake of water

Electrolyte Imbalance   

“maintenance requirements” and replacements of deficits & concomitant losses via IV or PO Water excess – 3% sodium chloride Potassium deficits – reestablish urine flow, add 30 meq of K+ per liter of fluid

Supportive Management Acidosis 

Poisoning mechanisms associated with acidosis:  Increase in the production of hydrogen ions (eg. methanol to formic acid)  Loss of body buffering capacity due to renal losses or prolonged diarrhea



Approaches:  Ventilation (for respiratory acidosis)  Administration of sodium bicarbonate

Supportive Management Body Temperature Regulation 

Hyperthermia  Body temperature up to 40°C – wet towels with adequate air circulation or a cooling blanket  Body temperature above 40°C – frequent application of towels wet with water at 10°C or immersion of the extremities in water at approximately 25°C



Hypothermia  Body temperature below 35°C – immersion of the entire body or of the extremities in water not to exceed 42°C  Apply blankets to avoid unnecessary chilling after patient leaves the water  Humidify area; do not use heating pads, heat lamps or hot water bottles

Supportive Management Nutrition 



Supply metabolic needs during acute poisoning Intravenous Feeding 



 

3 L of 5 or 10% glucose for few days 1 L of 5% glucose provides 200 kcal

Gastric Feeding – commercially available or blended TPN preparations Oral Feeding – 50 to 100g each of protein & lipids, and sufficient carbohydrates

Supportive Management Convulsions 

    

Administer anticonvulsants. Maintain hydration by oral administration or IV fluid. Urine output should be 1-3 L/day Maintain adequate airway. A mouth gag may occasionally be necessary. Oxygen may be administered. Treat hypoglycemia by administering glucose. Reduce elevated body temperature by tepid sponges. Remove secretions from the pharynx by suction.

Supportive Management Coma 

       

Treat shock via IV drip of medications at a rate of 50-100 mL/hr if renal function is adequate. Avoid excessive fluid administration. Maintain adequate airway. Aspirate mucus, vomitus, saliva, blood etc. Insert endotracheal tube or do tracheotomy if necessary. Give artificial respiration. Perform gastric lavage of activated charcoal within 4 hours of poisoning. Catheterize the patient if necessary (for urine output). Turn the patient every 30 minutes and massage skin. Maintain adequate nutrition.

Supportive Management Hyperactivity, Delirium & Mania 

 

Protect the patient from physical injury. Avoid strange sensory stimuli. Hydrotherapy – tub baths at 33-36°C for 30 minutes or longer if well tolerated; observe vital signs every 15 minutes.

Supportive Management Hypoxia Physiologic Classification

Type of Poisoning

Treatment

1) Normal Lung and Blood Oxygen Transport Deficient Atmospheric O2  Natural gas suffocation  High nitrogen or methane conc in air

Resuscitation in air or with oxygen

Airway Obstruction

Edema of the tongue, pharynx, larynx due to irritants or corrosives

Ensure adequate airway

Muscular paralysis

Curare, botulism, anesthesia, hemlock

Resuscitation

Respiratory Center Paralysis

Phosphate esters

Resuscitation

Supportive Management Hypoxia Physiologic Classification

Type of Poisoning

Treatment

2) Normal Lung with Impaired Blood Oxygen Transport Inactive Hemoglobin

 Carbon monoxide  Sulfhemoglobin formers  Methemoglobin formers

 100% Oxygen by artificial respiration  Hyperbaric Oxygen  Methylene blue for methemoglobinemia

Impaired Oxygen Exchange

Carbon dioxide

Artificial respiration in air

Low Blood Pressure

Substances causing shock

 Oxygen  Positive-Negative pressure resuscitation

Supportive Management Hypoxia Physiologic Classification

Type of Poisoning

Treatment

3) Normal Lung and Blood Oxygen Transport but Impaired Tissue Uptake Cellular Enzyme Poisoning

Cyanide, fluoride, hydrogen sulfide

 100% oxygen by artificial respiration  Hyperbaric oxygen  Treat cyanide poisoning

Supportive Management Hypoxia 

Equipments and Techniques to Maintain Airway 

Oropharyngeal Airway  Aka

Oral Airway, OPA, Guedel pattern airway  Consists of a curved and flattened plastic rubber-covered metal tube that fits over the curve of the tongue and allows air to pass freely in the pharynx

Supportive Management Hypoxia 

Equipments and Techniques to Maintain Airway  Laryngoscopes – used for the placement of endotracheal airways

Supportive Management Hypoxia 

Equipments and Techniques to Maintain Airway 

Endotracheal airways

Supportive Management Hypoxia 

Equipments and Techniques to Maintain Airway  Suction Device – mechanical suction machine with tubing and traps (Stericath) or hand-operated aspirator

Supportive Management Hypoxia 

Equipments and Techniques to Maintain Airway 

Mouth Gag – used during suction or placement of an endotracheal tube

Supportive Management Hypoxia 

Equipments and Techniques to Maintain Airway  Tracheostomy or Tracheotomy – a sharp scalpel or razor blade is used to divide the skin of the neck downward from the cricoid cartillage to the suprasternal notch

Supportive Management Hypoxia 



Equipments and Techniques to Maintain Airway Manual Artificial Respiration by Direct Inflation (15x / min)  Mouth-to-mouth Insufflation  Direct Inflation Using Anesthesia Mask

Supportive Management Hypoxia 



Equipments and Techniques to Maintain Airway

Oxygen Therapy  

May have an adjunct soda-lime canister as carbon dioxide absorber Adverse Effects: 

 

Depression of respiratory centers Irritation from improperly humidified oxygen Circulatory embarrassment from positive-pressure oxygen therapy

Supportive Management Hypoxia 

Equipments and Techniques to Maintain Airway 

Oxygen Therapy  Devices:

– supplied with tight-fitting face mask and breathing bags

 Inhalators

Supportive Management Hypoxia 

Equipments and Techniques to Maintain Airway

 Oxygen



Therapy

Devices: 

Automatic Cycling Positive Pressure Oxygen Resuscitators – used for intermittent administration of oxygen at pressures as high as 25 mmHg at a rate of 10-30 times per minute

Supportive Management Hypoxia 



Equipments and Techniques to Maintain Airway Oxygen Therapy  Devices: 

Automatic Cycling Positive-Negative Pressure Oxygen Resuscitators – utilize a cycling device operated by oxygen pressure from 15 mmHg positive to 10 mmHg negative

Special Considerations in Pediatric Patients 

Consider the most common causes among pediatric patients:  

Nontoxic or minimally toxic household products Nontoxic doses of potentially toxic drugs (iron supplements, TCAs, digitalis, beta-blockers, calcium channel blockers, salicylates, hydrocarbons

Special Considerations in Pediatric Patients High Risk Populations 

Ingestion in Toddlers and Young Children  Usually results from unintentional ingestion in children under 6 months of age or between the ages of 5



Adolescents and Young Adults  Usually suicidal or a results from drug abuse or experimentation

Special Considerations in Pediatric Patients Clinical Evaluation 

Vital Signs

Age

RR (/min)

HR (/min)

Newborn

30 – 80

1 month

BP (mmHg) Lower Limit

Average

Upper Limit

Severe

110 – 190

52/25

50 – 55

95/72

110/85

30 – 50

100 – 170

64/30

85/50

105/68

120/85

6 months

30 – 50

100 – 170

60/40

90/55

110/72

125/85

1 year

20 – 40

100 – 160

66/40

90/55

110/72

125/88

2 years

20 – 30

100 – 160

74/40

90/55

110/72

125/88

4 years

20 – 25

80 – 130

79/45

95/55

112/75

128/88

8 years

15 – 25

70 – 110

85/48

100/60

118/75

135/92

12 years

15 – 20

60 – 100

95/50

108/65

125/84

142/95

Special Considerations in Pediatric Patients Clinical Evaluation 

Vital Signs - BP  Low BP in the context of poisoning should be regarded as normal only if the child is alert, active, appropriate and has normal peripheral perfusion  Elevated BP should be assumed as an acute condition

Special Considerations in Pediatric Patients Neonates 

Pharmacokinetics  Have high ratio of surface area to body weight  poisoning via percutaneous absorption  Prolonged drug elimination (underdeveloped enzymes)



Neonatal Drug Withdrawal  Occur in infants with prenatal exposure to illicit or therapeutic drugs

Special Considerations in the Evaluation of DrugFacilitated Assault High Risk Populations 

 

Single women or men Traveling or new to area People without companions

Drugs Utilized: “Date-rape drugs” 

Benzodiazepines, other sedative-hypnotics, skeletal muscle relaxants, anticholinergics, hallucinogens, ethanol

Special Considerations in the Evaluation of DrugFacilitated Assault “Date-Rape Drugs” 

Flunitrazepam (Rohypnol®) Imparts blue color to clear beverages and haziness in other colored beverages

Special Considerations in the Evaluation of DrugFacilitated Assault “Date-Rape Drugs” 

GHB (Gamma-hyroxybutyric Acid) aka Sodium Oxybate (Xyrem®) – the fluorescent

GHB Orange GHB sensor developed in the National University of Singapore which can detect GHB in beverages in 30 seconds. Source: Royal Society of Chemistry

Special Considerations in the Evaluation of DrugFacilitated Assault Laboratory Procedures 

Blood Sampling  Collect specimen as soon as possible within 24 hours  Centrifuge the specimen and freeze the plasma or serum at – 80°C  Perform pharmacokinetic evaluation



Urine Sampling  Collect specimen within 72 hours of suspected ingestion and freeze for analysis  *Flunitrazepam (Rohypnol®) – detected up to 96 hours

Special Considerations in the Evaluation of DrugFacilitated Assault Laboratory Procedures 

Substances Detected in the Urine of Victims Drug

Duration (days)

Drug

Duration (days)

Amphetamines

1–3

Clonidine

1–2

Barbiturates

2–7

Cyclobenzaprine

1–2

Benzodiazepines

2–7

Diphenhydramine

1–2

Benzoylecgonine

1–2

Ethanol

<1

Cannabinoids

2–5

GHB

<1

Carisoprodol

1–2

Ketamine

1–2

Chloral Hydrate

1–2

Meprobamate

1–2

Opioids

2–3

Scopolamine

1–2

Toxic agents: pesticides

Pesticides 

Any substance or mixture of substances intended for preventing, destroying, repelling or mitigating pests.



Major Classes: 

   

Insecticides Herbicides Fungicides Rodenticides Others (Acaricides, Larvicides, Pediculicides)

WHO-Recommended Classification of Pesticides Based on Hazard Class

Example/s

LD50 in Rat (mg/KBW) Oral

Dermal

Solids

Liquids

Solids

Liquids

Ia

Extremely Hazardous

5 or less

20 or less

10 or less

40 or less

Ib

Highly Hazardous

5 – 50

20 – 200

10 – 100

40 – 400

II

Moderately Hazardous

50 - 500

200 – 2,000

100 – 1,000

400 – 4,000

III

Slightly Hazardous

Over 500

Over 2,000

Over 1,000

Over 4,000

IV+

Unlikely to present hazard in normal use

Over 2,000

Over 3,000

Over 4,000

Over 6,000

Insecticides (organophosphates) Rodenticides (warfarin)

•Herbicides (paraquat) •Organophosphates (Dimethoate, Fenthion, Chlorpyrifos) •Pyrethroid (Deltamethrin) •Phenylpyrazole (Fipronil)

Pesticides – Insecticides Molecular Targets of Major Classes of Insecticides Target

Insecticide

Effect

Acetylcholinesterase

Organophosphates Carbamates

Inhibition

Sodium Channels

Pyrethroids (Type I & II), DDT

Activation

Dihydropyrazoles

Inhibition

Nicotinic ACh Receptors

Nicotine, Neonicotinoids

Activation

GABA receptor-gated Chloride Channels

Cyclodienes, Phenylpyrazoles, Pyrethroids (Type II)

Inhibition

Glutamate-gated Chloride Channels

Avermectins

Activation

Octopamine Receptors

Formamidines

Mitochondrial Complex I

Rotenoids

Inhibition

Ryanodine Receptors

Diamides

Activation

Pesticides – Insecticides Organophosphorus Compounds Chemistry



Subclasses: Phosphorothioates, Phosphoramidates, Phosphonates

Pesticides – Insecticides Organophosphorus Compounds Chemistry

Organophosphorothioates – requires metabolic activation to inhibit AChE leading to the formation of “oxon” or oxygen analog of the insecticide

Pesticides – Insecticides Organophosphorus Compounds Chemistry

Organophosphates with P = O bond which do not require metabolic activation.

Pesticides – Insecticides Organophosphorus Compounds Metabolites

Organophosphate Methylparathion Methylchlorpyrifos Dichlorvos Trichlorfon Parathion Diazinon Chlorpyrifos

Metabolite Dimethylphosphate (DMP)

Azinphos-methyl (Guthion) Fenitrothion

Dimethylthiophosphate (DMTP)

Diethylphosphate (DEP) Diethylthiophosphate (DETP)

Pesticides – Insecticides Organophosphorus Compounds Mechanism of Toxicity  Inhibits AChE found in synaptic junctions, RBCs and butyrylcholinesterases found in plasma which leads to the accumulation of excessive ACh at the muscarinic receptors, nicotinic receptors and CNS 

Permanent inhibition is occur through covalent bonding known as “aging”

Pesticides – Insecticides Organophosphorus Compounds Clinical Manifestations 

Cholinergic excess  Delayed, often permanent peripheral neuropathy  “Jamaican

Ginger Paralysis” – outbreak from drinking rum contaminated with thiocresyl phosphate

Pesticides – Insecticides Organophosphorus Compounds Clinical Manifestations  Intermediate Syndrome 

Results from the redistribution of the pesticide or inadequate oxime therapy



Proximal muscle weakness 2-4 days after the resolution of acute cholinergic crisis which may last 1-2weeks and do not respond to additional treatment with oximes or atropine



Neck weakness, progressing to proximal limb weakness and cranial nerve palsies  respiratory muscle weakness  respiratory arrest

Pesticides – Insecticides Organophosphorus Compounds Diagnosis  Solvent odor, strong garlicky odor  Measurement of specific levels 

 

Decrease in plasma pseudocholinesterase and RBC acetylcholinesterase – 50% or greater depression from baseline; PChE falls before AChE and recovers faster

CXR if pulmonary edema or aspiration of hydrocarbon solvent is suspected (Hydrocarbon Pneumonitis) Observe asymptomatic patient for at least 8-12 hours to rule out delayed-onset symptoms, especially after extensive skin exposure or ingestion of a highly fat-soluble agent

Pesticides – Insecticides Organophosphorus Compounds Treatment  Atropine – 0.5 – 2mg IV initially, then double the dose every 5 minutes until signs of atropinization are present 

Pralidoxime (PAM, 2-PAM, Protopam) and Other Oximes (DAM or diacetylmonoxime) Must be given immediately before irreversible phosphorylation of the enzyme  1-2g initial bolus dose or 20-40 mg/kg in children IV over 5-10 minutes followed by continuous infusion up to 24 hours until patient becomes asymptomatic 

Pesticides – Insecticides Carbamates Chemistry  Derived from carbamic acid (N-methylcarbamate)  Less lipophilic than organophosphates  Eg. Carbaryl, Aldicarb (“Tres Pasitos” poisoning in New York due to watermelons contaminated with Aldicarb)

Pesticides – Insecticides Carbamates Mechanism of Toxicity & Manifestations  Similar to organophosphates, BUT: Less CNS effects (more difficulty in crossing the BBB)  Do not undergo “aging” (faster reactivation of AChE) 

Diagnosis  Based on symptoms  Measurement of specific levels are not very useful

Treatment  Short-lived and reversible toxicity  Empirical treatment with Pralidoxime

Pesticides – Insecticides Pyrethrins & Pyrethroids  

Pyrethrins – naturally occurring insecticide derived chrysanthemum plant (Chrysanthemum cinerariaefolium) Pyrethroids – synthetically derived compounds

from

Mechanism of Toxicity  Binds to the α-subunit of the sodium channel  slow the activation and inactivation of the channel  hyperexcitable state

Pesticides – Insecticides Pyrethrins & Pyrethroids

Pesticides – Insecticides Pyrethrins & Pyrethroids 

Chemistry

Pesticides – Insecticides Pyrethrins & Pyrethroids Clinical Manifestations Syndrome

Signs & Symptoms

Examples

Type I (T Syndrome)

Aggressive sparring Increased sensitivity to stimuli Whole-body tremors Prostration

Allethrin Bioallethrin Resmethrin Phenothrin

Type II (CS Syndrome)

Pawing and burrowing Profuse salivation Coarse tremor Choreoatetosis Clonic seizures

Deltamethrin Fenvalerate Cypermethrin Cyhalothrin

Pesticides – Insecticides Pyrethrins & Pyrethroids Clinical Manifestations (Chronic Exposure)  

 

Anaphylactic reactions to hypersensitive individuals Precipitates asthma attack if inhaled Burning, tingling, numbness, edema, paresthesia via skin exposure Corneal injury (keratitis, denudation) during accidental eye exposure

Toxic Doses  



Greater than 100-1000 mg/kg Lethal acute oral dose: 10 – 100 g

No specific antidote

Pesticides – Insecticides Organochlorine (Chlorinated Hydrocarbons) Low Toxicity (LD50 >1g/kg)

Moderate Toxicity (LD50 >50 mg/kg)

High Toxicity (LD50 <50 mg/kg)

Ethylan (Perthane)

Chlordane

Aldrin

Hexachlorobenzene

DDT

Dieldrin

Methoxychlor

Heptachlor

Endrin

Kepone

Endosulfan

Lindane

Mirex Toxaphene

Pesticides – Insecticides Organochlorine (Chlorinated Hydrocarbons) Mechanism of Toxicity  Neurotoxins that interfere with transmission of nerve impulses especially in the brain  Sensitize the myocardium to arrythmogenic effects of catecholamines  Generate toxic metabolites

Diagnosis  Can be measured in the serum (but levels are not routinely available)  Others (electrolytes, glucose, BUN, creatinine, hepatic transaminases, prothrombin time, ECG)

Pesticides – Insecticides Organochlorine (Chlorinated Hydrocarbons) Clinical Manifestations  Recurrent or delayed-onset seizures  Arrythmias  Metabolic acidosis  Signs of hepatitis or renal injury  Hematopoietic dyscrasias 

No specific antidote

Pesticides – Insecticides Organochlorine (Chlorinated Hydrocarbons)

*Mueller’s DDT  1,1,1-trichloro-2,2-bis(4-chlorophenyl) ethane  Metabolites: DDE, DDD, DDA which distributes well in all tissues (highest concentration in adipose)  Banned in 1972 BUT:  2004

Stockholm Convention on Persistent Organic Pollutants – “Dirty Dozen”  Malaria-endemic areas can continue utilizing DDT for indoor residual wall spraying

Pesticides – Insecticides Other Insecticides Rotenoids – Rotenone  Agricultural insecticide/acaricide in organic farming  Have the ability to inhibit (nanomolar concentrations) the mitochondrial respiratory chain  S/Sx: Initial increased respiratory and cardiac rates  Clonic and tonic spasms  Muscular depression  respiratory depression 

 

*Acute intoxication in humans is rare Currently investigated as a potential cause of Parkinson’s

Pesticides – Insecticides Other Insecticides

Nicotine  Minor insecticide in Asian countries (fumigants)  Acts by activating nicotinic acetylcholine receptors (initial depolarization  protracted depolarization  receptor paralysis)  Associated with high acute toxicity (LD50 <50 mg/kg)  S/sx: nausea, vomiting, muscle weakness, respiratory effects, headache, lethargy, tachycardia  *Green Tobacco Sickness

Pesticides – Insecticides Other Insecticides Neonicotinoids  Chemically-modified nicotine (nitromethylene, nitroimine, cyanoimine)  Prototype: Nithiazine Highly toxic to insects, low toxicity to mammals  Light unstable  Similar mechanism and manifestations with nicotine 

 

Other Compounds: Imidacloprid, Nitenpyram, Acetamipid, Thiacloprid Widely used due to selectivity

Pesticides – Insecticides Other Insecticides Formamidines  Similar structure to norepinephrine  Activates octopamine-dependent adenylate cyclase  S/sx: sympathomimetic effects (activates alpha adrenoceptors)  Chlordimeform (withdrawn – probable human carcinogen) 



Metabolites: Desmethylchlordimeform (400x more potent, 4-chlorotoluidine & N-formyl-4-chloro-toluidine (causes hemangioendothelioma)

Amitraz Widely used for ectoparasites  Acute toxicity similar to clonidine (not associated with deaths) 

Pesticides – Insecticides Other Insecticides Avermectins 

Isolated from Streptomyces avermitilis  Compounds: B1a – highest antiparasitic activity  Abamectin – 80% Avermectin B1a and 20% Avermectin B1b  Emamectin, Ivermectin – seminsynthetic derivatives of Avermectin B1a  Avermectin

Pesticides – Insecticides Other Insecticides Phenylpyrazoles 

Fipronil  Blocks GABA-gated chloride channels & glutamate-activated chloride channels (in insects)  Broad spectrum insecticide  Poisoning is due to accidental ingestion; no evidence of eye or skin irritant, carcinogenic, mutagenic effects

Pesticides – Insecticides Other Insecticides Diamides 

Fubendiamide, Chlorantraniliprole  Activates ryanodine receptors  release of stored calcium  muscle contraction 

*Ryanodine – alkaloid from Ryania speciosa which blocks calcium channels

Pesticides – Insecticides Other Insecticides Bacillus thuringiensis 

A microbial pesticide  Other

biopesticides: plant-incorporated biochemical pesticides (eg. pheromones)



protectants,

Produces proteins that are selectively toxic to certain insects  AE: infrequent allergic reactions & infections

Pesticides – Insect Repellents DEET  



 

N,N –diethyl-m-toluamide or N,N-diethyl-3methylbenzamide Applied directly to the skin or clothing MOA still unknown  Direct detection and avoidance of mosquitoes to DEET vapors S/sx: Neurotoxic (seizures) Recommendation:  Max concentration for children (<12 y/o): 10%  Max concentration for adults: 30%

Pesticides – Insect Repellents Picaridin    

1-piperidinecarboxylic acid or 2-(hydroxyethyl),1methyl-propyl ester Alternative to DEET MOA: interaction with specific olfactory receptors of the arthropod Unremarkable toxicological profile

Pesticides – Herbicides Methods of Classification 

By chemical classes



By the time of application  Preplanting – applied to soil before crop is seeded  Preemergent – applied to soil before the appearance of unwanted vegetation  Postemergent – applied to soil after germination



By the manner of application  Contact – affects the plant that was treated  Translocated – applied to soil or above-ground parts that are absorbed & circulated to distant tissues

Pesticides – Herbicides By Chemical Classes – Chlorophenoxy Compounds 

Compounds  2,4-dichlorophenoxyacetic acid (2,4-D) – widely used 

2,4,5-trichlorophenoxyacetic acid (2,4,5-T) – became the source of TCDD (2,3,7,8-tetrachlororodibenzo-p-dioxin)  withdrawn 



*Agent Orange – 50:50 mixture of N-butyl esters of 2,4-D and 2,4,5-T which was contaminated by TCDD

4-chloro-2-methylphenoxyacetic acid (MCPA)

Pesticides – Herbicides By Chemical Classes – Chlorophenoxy Compounds 

Mechanisms of Toxicity  Cell membrane damage  Interference with metabolic pathways coenzyme A  Uncoupling of oxidative phosphorylation

involving

acetyl



Acute Poisoning Symptoms:  Vomiting, burning of the mouth, abdominal pain, hypotension, myotonia, coma



Management:  Urine alkalinization with sodium bicarbonate

Pesticides – Herbicides By Chemical Classes – Bipyridyl Compounds Paraquat  1,1’-dimethyl-4-4’-bipyridilium dichloride  Mechanism of Toxicity Strong cations in aqueous and concentrated solutions  Extremely potent  Reacts with NADPH  produces reactive free radicals (superoxide anion)  cell death and tissue destruction  Selectively taken up and concentrated by pulmonary alveolar cells  cell necrosis  connective proliferation  pulmonary fibrosis 

Pesticides – Herbicides By Chemical Classes – Bipyridyl Compounds Paraquat  Pharmacokinetics Rapidly absorbed in the GIT, peak within 2 hours of ingestion  Poor absorption in the skin, but absorbed through abraded skin or prolonged contact  Food prevents absorption 



Clinical Manifestations Pain, swelling in the mouth & throat, oral ulcerations  Nausea, vomiting, abdominal pain  Corrosive GI injury, renal failure, myonecrosis, shock, death (usually due to pulmonary fibrosis 

Pesticides – Herbicides By Chemical Classes – Bipyridyl Compounds Paraquat 

Diagnosis  Clinical

signs & symptoms (especially oral mucosal burns)  Confused with diphtheria  Plasma & urine levels 



Fatal plasma levels: 2 mg/L at 4 hours, 0.9 mg/L at 6 hours, 0.1 mg/L at 24 hours

Treatment: NO specific antidotes  Note:

avoid excessive oxygen administration because this may aggravate lipid peroxidation reactions in the lungs

Pesticides – Herbicides By Chemical Classes – Bipyridyl Compounds Diquat 

Mechanism of Toxicity  Similar

to paraquat, but not selectively taken by pulmonary alveolar cells



Clinical Manifestations  Similar

to paraquat, but do not cause pulmonary fibrosis  Can cause cerebral and brainstem hemorrhagic infarctions

Pesticides – Herbicides By Chemical Classes – Bipyridyl Compounds Diquat 

Diagnosis  Similar

to paraquat  Plasma levels obtained through Sygenta 

No specific antidote.

Pesticides – Herbicides By Chemical Classes – Chloroacetanilides 

Alachlor, Butachlor, Propachlor



MOA: inhibits synthesis of lipids, alcohols, fatty acids and terpenoids



Clinical Manifestations  Alachlor – “Progressive Uveal Degeneration Syndrome” in rats but not an eye irritant in humans; skin sensitizer

Pesticides – Herbicides By Chemical Classes – Triazines 

Atrazine, Simazine, Propazine



MOA:  inhibits photosynthesis (herbicide)  posed no harm in the US general population  Endocrine effects: action on the pituitary luteinizing hormone regulated by the hypothalamic gonadotropinreleasing hormone

Pesticides – Herbicides By Chemical Classes – Phosphonomethyl AA Glyphosate  N-phophonomethyl glycine 

Mechanism of Toxicity Presence of surfactants  impair cardiac contractility and increase in pulmonary vascular resistance  Presence of surfactants  uncoupling of mitochondrial oxidative phosphorylation  Phosphorus-containing compound but does not inhibit acetylcholinesterase 

Pesticides – Herbicides By Chemical Classes – Phosphonomethyl AA Glyphosate  Clinical Manifestations Ocular – mild conjunctivitis, superficial corneal injury  Inhalation – nasal discomfort, throat irritation  Ingestion – GI corrosive effects, myocardial depression to cardiogenic shock, ventilatory insufficiency secondary to pulmonary aspiration, renal & hepatic impairment 



Diagnosis: serum & urine glyphosphate levels (not so significant)



No specific antidote

Pesticides – Herbicides By Chemical Classes – Phosphonomethyl AA Glufosinate  MOA: irreversibly inhibit glutamine synthase  increased levels of ammonia & deficiency of glutamine 

*mammals have metabolic systems that cope with glutamine deficiency



Poisoning cases are associated with suicidal intent or accidental misuse



Manifestations: GI effects, impaired respiration, neurologic disturbance, cardiovascular effects, reduction in cholinesterases

Pesticides – Fungicides Captan, Folpet, Captafol  Very toxic at IP exposure  Metabolite: Thiophosgene  Potent eye irritants but only mild skin irritants  Structurally similar with Thalidomide  Contains carbon, chlorine, sulfur (chloroalkylthio fungicides)

Pesticides – Fungicides Dithiocarbamates 

  

Nomenclature is associated with cation moiety  Maneb (Mn), Ziram, Zineb (Zn), Mancozeb (Mn, Zn), Thiram Structurally-related with Disulfiram Metabolite: Ethylenethiourea (ETU) Clinical Manifestations:  s/sx depend on the moiety on chronic exposure  Thyroid hypertrophy due to ETU  Neurotoxicity (due to thyroid effects, moiety)

Pesticides – Fungicides Chlorothalonil 

Highly toxic at IP and inhalational route



Clinical Manifestations  Severe irreversible eye irritations  Skin irritation at repeated exposures

Pesticides – Fungicides Benzimidazoles – Benomyl 



 

Methyl-1-butylcarbamoyl-2-benzimidazolecarbamate Mildly irritating to eyes & skin  Causes allergic contact dermatitis Low systemic toxicity in all routes Possibly teratogenic – associated with anophthalmia

Pesticides – Fungicides Inorganic & Organometal Fungicides 

Soluble Copper Salts – Bordeaux Mixture  Copper sulfate and calcium hydroxide  Low toxicity



Organic Mercury – Methylmercury



Organotin – Triphenyltin Acetate, Tributyltin  Antifouling agents  Banned in 2008 due to ecological AE  Associated with moderate to high acute toxicity  Replaced by copper + “booster” biocides 

Chlorothalonil, Zineb, Diuron

Pesticides – Rodenticides Criteria  

 

The poison must be very effective in the target species once incorporated into bait in small quantities Baits containing the poisons must not excite bait shyness The manner of death must be such that survivors do not become suspicious of its cause It should be species-specific

Pesticides – Rodenticides Fluoroacetic Acid and Its Derivatives Fluoroacetate (Compound 1080)  Sodium monofluoroacetate (SMFA), sodium fluoroacetate  Mechanism of Toxicity 



Metabolized to the toxic compound fluorocitrate  inhibits aconitase enzyme within the Krebs cycle  blockade of cellular metabolism

Clinical Manifestations Onset of effect is 30 minutes to several hours  delayed effects  Diffuse cellular poisoning – N/V, diarrhea, lactic acidosis, shock, renal failure, confusion, seizures, coma, respiratory arrest, pulmonary edema, ventricular dysrhythmias 

Pesticides – Rodenticides Fluoroacetic Acid and Its Derivatives Fluoroacetate (Compound 1080)  Diagnosis 



Mimics poisoning caused by cellular toxins (cyanide, hydrogen sulfide)

Treatment No available antidote  Monoacetin (Glyceryl monoacetate) – decreases conversion to toxic metabolite; tested on monkeys but not yet on humans 

Fluoroacetamide (Compound 1081)  Similar to fluoroacetate

Pesticides – Rodenticides Thioureas – ANTU  



α-naphthylthiourea Well absorbed by skin contact & inhalation Manifestations:  Pulmonary edema, liver injury – from ingestion  Hypothyroidism due to injury to thyroid & adrenals  Possible slight contamination with α2napthylamine (bladder carcinogen)

Pesticides – Rodenticides Anticoagulants 

Coumarins  Dicoumarol  Warfarin  Superwarfarins (Brodifacoum, Diphacinone, Bromadiolone, Chlorophacinone, Difenacoum, Pindone, Valone)



Mechanism of Toxicity  Inhibition of the hepatic synthesis of vitamin K-dependent coagulation factors  Duration of action: Warfarin – 2 to 7 days; Superwarfarins – up to several months

Pesticides – Rodenticides Anticoagulants 

Clinical Manifestations  Generally toxic even at small doses (1mg for superwarfarins)  Ecchymoses, subconjunctival hemorrhage, bleeding gums, internal hemorrhage (hematematesis, melena, hematuria)



Diagnosis  Blood levels (greater than 4 – 10 ng/mL)  Baseline PT & INR which elevates 1-2days after ingestion

Pesticides – Rodenticides Anticoagulants 

Treatment  Vitamin K1 (Menadione)

(Phytonadione)

but

not

Vitamin

K3

If prophylactic dose is given – monitor PT for a minimum of 5 days after Vitamin K1 administration  Oral Vitamin K1 – administer every 6 hours up to 800mg daily  IV route not recommended – vitamin K-mediated reversal of anticoagulation 



Fresh Frozen Plasma or Fresh Whole Blood

Pesticides – Rodenticides Other Compounds 

Norbormide  Lethal to rats only  No cases of human intoxication



Zinc Phosphide  Toxicity is associated with phosphine (PH3)  Causes widespread cellular toxicity with necrosis of the GIT and injury to liver and kidney

Pesticides – Fumigants Methyl Bromide 

Mechanism of Toxicity  Potent, nonspecific alkylating agent  Direct alkylation of cellular components (glutathione, proteins, DNA)  Forms toxic metabolites from methylated glutathione  3-fold heavier than air

Pesticides – Fumigants Methyl Bromide 

Clinical Manifestations  Acute irritant effects on the eyes, mucous membranes, upper respiratory tract attributed to chloropicrin 

Chemical burns



Delayed acute systemic effects (24-hour delay) – flu-like symptoms which may lead to death due to fulminant respiratory failure with noncardiogenic pulmonary edema or complications of status epilepticus



Neurologic & psychiatric problems (chronic sequelae)

Pesticides – Fumigants Methyl Bromide 

Treatment  NAC or BAL – offers reactive sulfhydryl group to bind free methyl bromide  Remove contaminated clothing & wash affected skin with soap and water (can penetrate clothing)

Pesticides – Fumigants 1,3-Dichloropropene 

 



1,3-dichloropropylene, Telone Well absorbed dermally Vapors irritating to the eyes & respiratory tract Has chloroform-like odor

Metam Sodium  



Sodium methyldithiocarbamate Skin, eye, mucous membrane, respiratory tract irritant Olive green to light yellow liquid with fairly string sulfur odor

Pesticides – Fumigants Sulfur Compounds 

Oldest of all pesticides



Sulfur Dioxide  Pungent, suffocating odor with a taste  Strongly irritating to eyes & skin, may lead to burns



Sulfuryl Fluoride  Chloropicrin is also added  Irritating to eyes & respiratory tract, causes fatal pulmonary edema  Chronic exposure: kidney & liver injury, elevated fluoride

Toxic Agents: Metals

Essential vs. Non-essential Metals Essential Metals 



Metals that have biologic roles and considered necessary for good health but overdoses or overexposure to these metals lead to toxic effects Eg. Copper, Zinc, Manganese, Selenium, Iron, Molybdenum, Cobalt

Non-essential Metals  

Have no known beneficial role to play in biological functions Eg. Beryllium, Cadmium, Lead, Mercury, Thallium, Titanium, Uranium

Speciation of Metals Non-Biological Factor 

Ionization 

Tendency to give up electrons to become a cation which will form complexes with other compounds

Biological Factor 

Biotransformation 



Circumstances in the environment that create hazardous compounds Eg. Yeasts reduce ionic mercury to elemental mercury  vapors of elemental mercury diffuse more easily to cell membranes

Sources of Exposure Natural Sources 



Metals are naturally-occurring elements in the earth’s crust Found in soils, sediments, surface & groundwaters, air

Sources of Exposure Anthropogenic Sources  

Caused by humans thru mechanisms like mining, dredging, construction & manufacturing Examples  Lead in gasoline, paints, pipes  Minamata Disease  Occupational exposure

Biomarkers of Exposure 

A biomarker is any measurable biological parameter that indicates exposure to a toxic substance



Blood, urine, hair and fingernails are the most accessible tissues for measuring metal exposure

Major Toxic Metals Arsenic (As)  

 

From the Persian word “Zarnikh”, Greek work “arsenikon” which means “yellow orpiment” Known as the poison of kings and king of poisons Occurs as a gray-colored metal and naturally found in rocks Industrial Uses:  Wood preservative (2/3 of domestic consumption) but voluntarily banned in 2003  Herbicide  Feed additive in swine & poultry

Major Toxic Metals Arsenic (As) 

Pharm’l Uses  



Arsenic Trioxide – reintroduced in USP 2000 as a chemotherapeutic agent Inorganic arsenic – folk remedy & tonics in Asian countries

Mechanism of Toxicity 

Ionization (pentavalent, trivalent forms):   

 

Inhibits enzymatic reactions for cellular metabolism Increase oxidative stress Alters gene expression & signal transduction

Arsenite is 10 times more acutely toxic than Arsenate Metabolites: MMA (monomethylarsinic), DMA (dimethylarsinic)

Major Toxic Metals Arsenic (As) 

Clinical Manifestations : Acute Exposure 

Diffuse capillary damage  minutes or hours of delay (usually 1 to 12 hrs)  hemorrhagic gastroenteritis  subside for 24 to 48 hours  continuous multisystemic effect



Cardiovascular Effect Phase 1 – shock secondary to fluid loss due to gastroenteritis Cardiovascular Effect Phase 2 – after 1- 6 days of delay – congestive cardiomyopathy, pulmonary edema, TdP



Major Toxic Metals Arsenic (As) 

Clinical Manifestations: Acute Exposure 

Neurologic: 2-6 days – altered mental status; 5 weeks after acute exposure – painful distal dysesthesia (feet)  ascending weakness & paralysis  respiratory failure



Hematologic: After 2 weeks of acute exposure – leukopenia & anemia



Dermal: after 2 weeks – desquamation of palms & soles, maculopapular rash, periorbital edema, herpes  after months – Aldrich-Mees Lines

Major Toxic Metals Arsenic (As) 

Clinical Manifestations: Chronic Exposure  Multisystemic effects 

Skin Lesions – period of 1 to 10 years: characteristic pattern of spotted “raindrop” pigmentation on the torso & extremities  hyperkeratotic changes on the palms & soles  skin cancer



Cancer – may also result from chronic inhalation (lung cancer)

Major Toxic Metals Arsenic (As)

Major Toxic Metals Arsenic (As) 

Diagnosis  Spot Urine Analysis: > 1000 mcg/L 2 to 4 hours of urinary arsenic excretion (appear during the first 2 to 3 days after acute symptomatic poisoning)  *Ingestion of seafoods – false elevations for up to 3 days (arsenobetaine, arsenosugars) 



Elevated concentrations in nails or hair – greater than 1ppm

Major Toxic Metals Arsenic (As) 

Specific Antidotes  Unithiol (2,3-dimercaptopropanesulfonic acid aka DMPS) Water-soluble analog of BAL  Has the most favorable pharmacologic profile for the treatment of acute arsenic intoxication  MOA: Chelation  AE: self-limited, reversible dermatologic reactions  *Drug-Lab Interaction – may contribute to the increase levels of total urinary arsenic  *chelation challenge test  Note: once stable, shift to oral unithiol 

Major Toxic Metals Arsenic (As) 

Specific Antidotes  Dimercaprol (2,3-dimercaptopropanol aka BAL, British Anti-Lewisite) 2nd line for arsenic poisoning  MOA: Chelation  CI: peanut allergy (dispensed in peanut oil); G6PD deficiency  AE: dose-related tachycardia (onset of 15-30 minutes, duration of 2 hours); redistribution of arsenic in the brain; forms toxic complex with iron 

Major Toxic Metals Arsenic (As) 

Specific Antidotes  Succimer (meso-2,3-dimercaptosuccinic acid aka DMSA) Oral form  Suggested if patient is already stable after parenteral unithiol or BAL  MOA: Chelation  AE: Mercaptan-odor to the urine (no clinical significance)  *Note: not recommended as 1st line for arsenic due to impaired GI absorption 

Major Toxic Metals Beryllium (Be) 

  

“the most toxic metal” From Greek word “beryllos” meaning mineral beryl Hard, grayish metal that occurs as a chemical component of rocks, coal, oil, volcanic dust Primary route of exposure: Lungs

Major Toxic Metals Beryllium (Be) 

Clinical Manifestations  Acute Chemical Pneumonitis  Fulmination

inflammatory reaction of the entire respiratory tract  Occurs immediately following inhalation of aerosols of soluble beryllium compounds (BeF2)  Recovery after several weeks or months

Major Toxic Metals Beryllium (Be) 

Clinical Manifestations  Chronic Beryllium Disease (CBD)  Aka

Berylliosis, Chronic Granulomatous Disease  First discovered in fluorescent lamp workers exposed to insoluble Beryllium compounds (BeO)  Typical Features: granulomatous inflammation of the lungs, dyspnea on exertion, cough, chest pain, weight loss, fatigue, general weakness, hypertrophy of the right heart  *Beryllium-induced lung tumor

Major Toxic Metals Cadmium (Cd) 

 

From the Latin word “Cadmia” Discovered as an impurity of calamine (ZnCO3) Mechanism of Toxicity:  Inhaled form is 60x more toxic than ingested form Threshold-Limit Value – 0.01 (inhalable) to 0.002 (respirable) mg/m3 as an 8-hour time-weighted average  5 mg/m3 inhaled for 8 hours may be lethal 



Ingested form – bound to metallothionein  renal damage 15 mg/L induces vomiting  Lethal dose : 350 to 8900mg 

Major Toxic Metals Cadmium (Cd) 

Clinical Manifestations 

Inhalation Acute – cough, wheezing, headache, fever, chemical pneumonitis, noncardiogenic pulmonary edema within 12 to 24 hours  Chronic – lung cancer 



Ingestion Acute – GI adverse effects within minutes; death due to shock & renal failure  Chronic – “itai-itai” or “ouch-ouch” disease in bones; renal and liver disease 

Major Toxic Metals Cadmium (Cd)

Major Toxic Metals Cadmium (Cd) 

Diagnosis  Whole-blood Cadmium Levels > 1 mcg/L  Urine cadmium levels > 1mcg/g of creatinine  Measure for kidney damage: beta-microglobulin, retinolbinding protein, albumin, metallothionein



*There is no evidence that chelation therapy with BAL, EDTA & Penicillamine is effective. Vitamin D for Itai-itai disease



Major Toxic Metals Chromium (Cr) 

From the Greek word “Chroma” meaning color



Sources  Trivalent Chromium – naturally found in chromite ores which are refined to ferrochromium or metallic chromium; essential trace nutrient for glucose metabolism  Hexavalent Chromium – by-product of industrial processes; carcinogen

Major Toxic Metals Chromium (Cr) 

Mechanism of Toxicity  Hexavalent is 10 to 100-fold more toxic than trivalent  Hexavalent – powerful oxidizing agents which have corrosive effects to the airways, skin, mucous membranes and GIT



Diagnosis  Urine levels > 1mcg/L  Blood levels are not useful  History of exposure

Major Toxic Metals Chromium (Cr) 

Clinical Manifestations  Inhalation – acute irritant effects; chronic exposure lead to pulmonary sensitization, asthma, cancer 

Skin & Eyes – acute contact may cause severe corneal injury, deep skin burns, oral/ esophageal burns; chronic exposure is associated with 8% of contact dermatitis cases



Ingestion – acute hemorrhagic gastroenteritis; oxidizes hemoglobin but methemoglobinemia is uncommon

Major Toxic Metals Chromium (Cr)

Major Toxic Metals Chromium (Cr) 

Specific Antidotes  Chelation therapy is not effective 

Ascorbic Acid MOA: assists the conversion of the hexavalent chromium to less toxic trivalent compound  2 to 4 grams of ascorbic acid per gram of hexavalent chromium 



N-acetylcysteine 

Used for dichromate poisoning

Major Toxic Metals Lead (Pb) 

From the Latin word, “plumbum”



Lead Compounds:  Primarily exists in the divalent form  Metallic lead (Pb0) – resistant to corrosion, combine with metals to form alloys  Inorganic lead – used as pigment in paints, dyes & ceramic glazes  Organolead (Pb+4) – gasoline additives

Major Toxic Metals Lead (Pb) 

Mechanisms of Toxicity  Inactivation or alteration of enzymes & other macromolecules by binding to sulfhydryl, phosphate or carboxyl ligands  Interaction with essential cations (Ca, Zn, Fe)  Alterations in cellular, mitochondrial membranes, neurotransmitter synthesis & function, heme synthesis, cellular redox status, nucleotide metabolism

Major Toxic Metals Lead (Pb) 

Clinical Manifestations  Acute Ingestion – abdominal pain, anemia (hemolytic), toxic hepatitis, encephalopathy 

Subacute or Chronic (more common) Constitutional effects – malaise, irritability, anorexia, arthralgia, myalgia, hypertension  GI effects – Lead colic, constipation  CNS – impaired concentration to encephalopathy; age-related decline in cognitive function in children  Peripheral Neuropathy – “wrist drop”  Hematotoxic, nephrotoxic effects 



*Fanconi-like aminoaciduria in children

Major Toxic Metals Lead (Pb)

Major Toxic Metals Lead (Pb)  Diagnosis  Whole-blood levels – most useful indicator mcg/dL – without occupational or specific environmental exposure  5 – 25 mcg/dL – subclinical decreases in intelligence & impaired neurobehavioral development in children exposed in utero or in early childhood  10 – 25 mcg/dL (adults) – risk for HTN; contributes to decline in cognitive function  <5

Major Toxic Metals Lead (Pb) 

Diagnosis  Whole-blood levels – most useful indicator – 60 mcg/dL – neuropsychiatric effects  60 – 80 mcg/dL – GI symptoms, subclinical renal effects  > 80 mcg/dL – serious overt intoxication  > 100 mcg/dL – encephalopathy & neuropathy  25

Major Toxic Metals Lead (Pb) 

Diagnosis  FEP (Free Erythrocyte Protoporphyrin) or ZPP Protoporphyrin)

(Zinc

> 35 mcg/dL – lead-induced inhibition of heme synthesis  Elevated whole blood, normal FEP or ZPP – very recent exposure  Not sensitive for blood levels <30 mcg/dL  *False positive for iron deficiency 

 

Urinary Lead Excretion Xray Fluorescence Measurement of Lead in Bone

Major Toxic Metals Lead (Pb) 

Treatment  Encephalopathy Calcium EDTA  Single dose BAL followed 4 hours later by concomitant administration of calcium EDTA & BAL 



Symptomatic without Encephalopathy Parenteral Calcium EDTA (for px with lead colic)  Oral Succimer  Unithiol – alternative to succimer 

Major Toxic Metals Lead (Pb) 

Treatment  Asymptomatic children with elevated blood levels 



Asymptomatic Adults 



Succimer for blood levels greater than 45 mcg/dL

Succimer for markedly elevated levels (80 mcg/dL)

Alternative Treatment – Penicillamine

Major Toxic Metals Mercury (Hg) 

 



Aka Quicksilver Named after the Greco-roman god known for swift light Derived from the Latin word “Hydrargyrum” meaning water and silver

Primary Forms:  Elemental / Metallic (Hg0) – vapor is more hazardous than the liquid form  Inorganic Salts – eg. Mercuric Chloride  Organic (alkyl & aryl) – eg. Methylmercury (CH3Hg+ or MeHg)  toxicologically most important organic form

Major Toxic Metals Mercury (Hg)

Major Toxic Metals Mercury (Hg) 

Mechanism of Toxicity : reacts with sulfhydryl groups resulting to enzyme inhibition & pathologic alteration of cellular membranes



Clinical Manifestations  Acute inhalation of metallic form – severe chemical pneumonitis, noncardiogenic pulmonary edema, acute gingivostomatitis

Major Toxic Metals Mercury (Hg) 

Clinical Manifestations  Chronic inhalation of metallic form – Triad symptoms (tremor, neuropsychiatric disturbances, gingivostomatitis) stages: tremors  choreiform movements  Neuropsychiatric: insidious onset  Acrodynia: rare idiosyncratic reaction which occurs mainly in children (pain in the extremities, “pink disease”, hypertension, profuse sweating, anorexia, insomnia, erethism  Early

Major Toxic Metals Mercury (Hg) 

Clinical Manifestations  Acute Ingestion of Inorganic Salts – abrupt onset of hemorrhagic gastroenteritis & abdominal pain (HgCl2) 

Organic Mercury Compounds – symptoms first become apparent after a latent interval of several weeks or months

Major Toxic Metals Mercury (Hg)

Major Toxic Metals Mercury (Hg) 

Diagnosis  Follows biphasic elimination rate (rapid then slow) – excreted in the urine & feces mercury – mass of metal per volume of urine or mass of metal per gram of creatinine

 Urine



Metallic & inorganic - whole-blood levels rise faster than urine levels  Organic – 90% undergo enterohepatic recirculation  fecal excretion; whole-blood halflife is 50 days; hair levels

Major Toxic Metals Mercury (Hg) 

Treatment  Metallic – oral succimer & unithiol; alternative tx with penicillamine 

Inorganic – IV unithiol, IM BAL, follow-up with oral succimer



Organic – oral succimer, NAC (both reduces tissue & brain levels of mercury

Major Toxic Metals Nickel (Ni) 

First isolated form the ores of kupfenickel (niccolite)



Clinical Manifestations  Contact Dermatitis – most common adverse effect; Type IV hypersensitivity reaction  Nickel Carbonyl Poisoning – in combination with carbon monoxide N/V, epigastric & chest pain  cough, hyperpnea, cyanosis, GI symptoms, weakness, fever, leucocytosis  pneumonia, respiratory failure  cerebral edema, death

 Headache,

Major Toxic Metals Nickel (Ni) 

Treatment  Sodium diethylcarbodithioate (DDTC) – Drug of choice MOA:

Chelation

 Alternative

chelators: penicillamine, DMPS

Disulfiram,

Essential Metals with Potential for Toxicity Cobalt (Co)  



Came from the German word, “kobalt” derived from “kobold” meaning goblin By-product of copper and nickel mining

Essential Form: Cobalamin  Critical component of Vit B12 required for the production of RBC & pernicious anemia

Essential Metals with Potential for Toxicity Cobalt (Co) 

Clinical Manifestations  “Hard Metal” pneumoconiosis – progressive form of pulmonary interstitial fibrosis due to inhalation of high cobalt concentrations 

Intake due to anemia therapy – leads to goiter, cardiomyopathy with signs of CHF

Essential Metals with Potential for Toxicity Cobalt (Co)

Essential Metals with Potential for Toxicity Copper (Cu) 

Previously known as cerium because it was mined in Cyprus



Essentiality & Deficiency  Component of metaloenzymes: Type A oxidases, Type B monoamine oxidases (cytochrome C oxidase)  Deficiency in humans (rare) – result of malnutrition or overdose of molybdenum  hypochromic, mycrocytic anemia refractory to iron supplementation  Biomarkers of Deficiency: low serum & urine levels, ceruloplasmin concentration, copper-dependent enzyme activity

Essential Metals with Potential for Toxicity Copper (Cu) 

Clinical Manifestations  Oral ingestion – GI distress, hepatic necrosis, death 

Menkes Disease Rare sex-linked genetic defect in copper metabolism  copper deficiency in male infants  CM: peculiar hair, failure to thrive, severe mental retardation, neurologic impairment, connective tissue dysfunction, osteoportic skull, death by 3 to 5 years of age  Mgt: Copper-histidine supplementation 

Essential Metals with Potential for Toxicity Copper (Cu) 

Clinical Manifestations  Wilson Disease  Autosomal

recessive genetic disorder of copper metabolism characterized by excessive accumulation of copper in liver, brain, kidneys & cornea  Tx: Penicillamine, Trien (triethylenetetramine 2HCl), Zinc Acetate, Tetrathiomolybdate  Adjunct: NAC (prevents neurodegenerative disorders)

Essential Metals with Potential for Toxicity Copper (Cu) 

Clinical Manifestations  Hereditary Aceruloplasminemia Autosomal recessive disorder of copper-binding protein ceruloplasmin, associated with iron overload syndrome  CM: mental confusion, memory loss, dementia, cerebellar ataxia, altered motor function, retinal degeration, diabetes 



Indian Childhood Cirrhosis (ICC) Occurs in young children, characterized by jaundice  Distinguishing features: widespread brown orcein staining & intralobular hepatic fibrosis  portal cirrhosis & inflammation  Etiology: bottle feeding of milk contaminated with copper 

Essential Metals with Potential for Toxicity Copper (Cu) 

Clinical Manifestations  Idiopathic Copper Toxicosis Childhood Cirrhosis  Similar



or

Non-Indian

to ICC but occurs in Western countries

Treatment: Chelators

Essential Metals with Potential for Toxicity Copper (Cu)

Essential Metals with Potential for Toxicity Iron (Fe)  Derived from the Ethruscan word “aisar” meaning “the gods” 

Essentiality & Deficiency  Essential metal for erythropoiesis & key component of hemoglobin, myoglobin, heme enzymes, metalloflavoprotein & mitochondrial enzymes  Iron deficiency – most common nutritional deficiency worldwide

Essential Metals with Potential for Toxicity Iron (Fe)  Clinical Manifestations  Acute Poisoning – ingestion of dietary supplements  Sx:

abdomina pain, diarrhea, vomiting, pallor or cyanosis, metabolic acidosis, liver damage, cardiac collapse  *Death occur within 24 hours 

Hereditary Hemochromatosis  Autosomal

recessive disorder due to mutation in the hemochromatosis gene  Excessive deposition of iron that causes organ damage resulting to fibrosis

Essential Metals with Potential for Toxicity Iron (Fe) 

Clinical Manifestations  Transfusional Siderosis Iron

overload occur via repeated blood transfusion for some form of refractory anemia Hemosiderosis – increased iron stores in the form of hemosiderin

Essential Metals with Potential for Toxicity Iron (Fe)

Essential Metals with Potential for Toxicity Iron (Fe) 

Treatment: Deferroxamine (Desferrioxamine)  MOA: specific chelating agent for iron – binds to free iron and to some extent, loosely bound iron 

AE: hypotension or anaphylactoid reaction from very rapid IV bolus administration (remedy: 15mg/kg/hr rate)  Yersinia enterocolitica sepsis (siderophore) 



Laboratory Interaction: Falsely low serum iron, falsely elevated total-iron binding capacity

Essential Metals with Potential for Toxicity Magnesium (Mg) 

Name originates from the Greek word “Magnesia”, a district in Thessaly



Essentiality & Deficiency  Cofactor of many enzymes  Deficiency: irritability, frank tetany, convulsions



Clinical Manifestation: Metal fume fever similar to Zn Treatment: Calcium infusion



Essential Metals with Potential for Toxicity Manganese (Mn) 





Named after the Latin word, “magnes” meaning magnet Essential metal for many metabolic & cellular functions Clinical Manifestations  Manganism – chronic manganese-induced neurotoxicity which affects dopaminergic neurons 



Psychiatric & movement disorders(“cock-walk” gait)

Co-accumulation of iron

Essential Metals with Potential for Toxicity Manganese (Mn)

Essential Metals with Potential for Toxicity Molybdenum (Mo) 

   

From Greek word, “molybdos”, meaning “lead-like” Cofactor in enzymatic processes Deficiency is associated with disturbances in uric acid & sulfite metabolism Low toxicity in humans : Gouty-like effects; Molybdenosis (similar to copper deficiency) Tx: supplemental copper

Essential Metals with Potential for Toxicity Selenium (Se) 

From the Greek word “selene” meaning moon



Has antioxidant actions (20 selenoproteins)  Selenoprotein P – major plasma selenoprotein; antioxidant  Selenium W – low molecular weight selenoprotein; redox function



Clinical Manifestations  Keshan Disease Deficiency in selenium characterized by cardiomyopathy  Occurs in children 15 years of age & women in childbearing age 

Essential Metals with Potential for Toxicity Selenium (Se) 

Clinical Manifestations  Kashin-Beck Disease 



Osteoarthropathy found in areas where combined deficiency of selenium & iodine occurs with elevated exposure to mycotoxins & fulvic acids

Selenosis Excessive levels of selenium  S/Sx: hair & fingernail loss, tooth discoloration, numbness, paralysis, hemiplegia 

Essential Metals with Potential for Toxicity Selenium (Se)

Essential Metals with Potential for Toxicity Zinc (Zn) 

Named from the German word “zink” meaning Tin



Therapeutic Uses:  Acute diarrhea in infants with severe zinc deficiency  Treatment of common colds by its antiviral & immunomodulatory effects  Reduce the burden on Wilson ‘s disease  Prevention of blindness in age-related macular degeneration

Essential Metals with Potential for Toxicity Zinc (Zn) 

Clinical Manifestations  Acrodermatitis Enterohepatica  Rare

autosomal recessive disorder involving zinc deficiency that can begin to appear after weaning from breast or formula feeding  S/sx: periorificial & acral dermatitis, alopecia, diarrhea  Tx: Zinc supplementation

Essential Metals with Potential for Toxicity

Zinc (Zn) 

Clinical Manifestations  Metal Fume Fever  s/sx:

fever, chest pain, chills, cough, dyspnea, nausea, muscle soreness, fatigue, leukocytosis

 Neuronal  May

Toxicity

later develop to Alzheimer’s disease

 Pancreatic  May

Toxicity

cause β-cell death in the Islets of Langerhans

Metals Related to Medical Therapy Aluminum (Al) 

3rd most abundant element in the Earth’s crust



Acute toxicity is rare  Lung & Bones – lung fibrosis, osteomalacia (due to alteration in intestinal phosphate absorption)  Neurotoxic – death with status epilepticus  Dialysis Dementia – speech disorder  dementia  convulsions  myoclonus (3 to 7 years after dialysis)



Treatment: Deferoxamine & Deferiprone

Metals Related to Medical Therapy Bismuth (Bi)  Bisemutum is from the German “Wismuth” from the term weiBe Masse for white mass 

Clinical Manifestations: encephalopathy



Treatment  D/C Bismuth therapy  Chelation therapy (BAL, DMSA, DMPS)

Acute

renal

injury,

Metals Related to Medical Therapy Gallium (Ga)

“Gallia” meaning Gaul or France  Clinical Manifestations  Resemble trivalent iron  Lung toxicity  From

Metals Related to Medical Therapy Gold (Au)  

Monovalent salts are used in Rheumatoid Arthritis Clinical Manifestations  Contact dermatitis accompanied by stomatitis  Proteinuria, Nephrotic Syndrome – if used for RA

Metals Related to Medical Therapy Lithium (Li) 

  



Lightest metal From the Greek word, “Lithos” meaning stone DOC for mania & bipolar disorder Clinical Manifestations  Lithium hydride – skin burns  Narrow TI – seizures, coma, cardiovascular disturbances, nephritis Treatment: Amiloride & other diuretics, hemodialysis

Metals Related to Medical Therapy Platinum (Pt) 

Clinical Manifestation: Hypersensitivity reactions  Platinosis – skin & respiratory changes Urticaria,

dermatitis, respiratory distress (irritation to asthmatic syndrome) Hexachloroplatinate & hexachloroplatinic acid  Note:

Toxicity from antitumor complexes (eg. cisplatin)

Minor Toxic Metals Antimony (Sb)  From Greek words “anti and monos”, meaning opposed to solitude  Never exist in pure form  Medicinal uses: schistosomiasis, leishmaniasis  Clinical Manifestations  Rhinitis  pulmonary edema  Transient skin eruptions (antimony spots)  Trivalent form is more toxic – arrhythmias, myocardial damage  *Stibine – toxic gas

Minor Toxic Metals Barium (Ba)   

From Greek word “barys” meaning heavy Medical Use: contrast media Clinical Manifestation:  Baritosis – Benign pneumoconiosis resulting from inhalation of barium sulfate or barium carbonate  Ingestion  Hallmark

symptoms: hypokalemia, muscle weakness progressing to muscle paralysis  Others: vomiting, diarrhea, GI hemorrhage, cardiac arrest

Minor Toxic Metals Cesium (Cs)  From Latin word “caesius” meaning sky blue  Catalyst in inorganic chemistry  Clinical Manifestations  Radioactive exposure – N/V, diarrhea, local skin blistering, bone marrow suppression, infection, hemorrhage, death  Nonradioactive – GI & eye irritation, cardiac arrhythmia (QT prolongation)  Treatment: Prussian Blue

Minor Toxic Metals Fluorine (F)  Compounds:  Fluoride – Essential component for normal mineralization of bones & dental enamel  Fluorosilic Acid & Sodium Fluorosilicate – for water fluoridation 

Clinical Manifestations  Dental Fluorosis – white, opaque areas on the tooth surface to severe form manifested as yellowish brown to black stains & severe pitting of the teeth

Minor Toxic Metals Fluorine (F) 

Clinical Manifestations  Skeletal Fluorosis Manifested

during advanced stage: symptoms similar to arthritis, sporadic pain, back stiffness, burning-like sensation , pricking & tingling in the limbs, muscle weakness, chronic fatigue More advanced stage: osteoporosis, crippling skeletal fluorosis accompanied by kyphosis & lordosis

Minor Toxic Metals Fluorine (F)

Minor Toxic Metals Germanium (Ge)  Exposure mainly comes from the diet (canned foods)  No reports on systemic toxicity  But associated with renal dysfunction, anemia, muscle weakness, peripheral neuropathy  Spirogermanium  2-aza-8-germanospiro(4,5)decane-2-propamine8,8-diethyl-N,N-dimethyl dichloride  Neurotoxic to humans after IV injection for cancer treatment

Minor Toxic Metals Palladium (Pd) 

Named after the asteroid Pallas  Medical Use: has anticancer potential  Associated to allergic reactions even at very low doses

Minor Toxic Metals Silver (Ag) 

Recent use: Silver nanoparticles (AgNP) as antimicrobials  Clinical Manifestations  Argyria – characteristic, irreversible pigmentation of the skin (local & general)  Argyrosis – irreversible pigmentation of the eyes  *Gray-blue patches  No effective treatment

Minor Toxic Metals Silver (Ag)

Minor Toxic Metals Tellurium (Te)

Named after the Latin word for earth “Tellus”  Clinical Manifestations  Tellurites: Sweating, nausea, metallic taste, garlic smelling breath  *Tellurates & Tellurium – low toxicity  Gestational exposure may produce hydrocephalus 

Minor Toxic Metals Thallium (Tl)  From the Greek word “thallos” meaning green shoot or twig  Classic poisoning syndrome: gastroenteritis, polyneuropathy, alopecia  Depilation begins in about 10 days after ingestion and complete hair loss can occur in 1 month  Death is due to renal, CNS, cardiac failure  Consistent & characteristic feature: “burning feet syndrome”  Treatment  DOC: Prussian Blue  Alternative: deferoxamine

Minor Toxic Metals Tin (Sn) 

Relatively nontoxic  Ingestion – acute gastroenteritis  Stannosis – benign nonfibrotic pneumoconiosis resulting from chronic inhalation

Minor Toxic Metals Titanium (Ti) 

Named for the Titans of Greek mythology  Investigated as cancer chemotherapeutic agents (Titanium diketonate & budotitane; Titanocene Dichloride)  Causes mild to severe pulmonary injury

Minor Toxic Metals Uranium (U) 

Named after Uranus  Clinical Manifestations  Nephrotoxicity – Biomarker: enzymuria, increased excretion of low molecular weight proteins, amino acids, glucose  Osteoporosis from chronic intoxication (accumulates in the bones)  Lung cancer

Minor Toxic Metals Vanadium (V)  Named after the Scandinavian mythology “Vanadis” because of its multicolored chemical compounds  Essential trace element in bacteria  Proposed medicinal uses: lowering of chloesterol, TG,glucose, prevent tumor growth  Toxicity increases as valence increases  Characteristic greenish-black discoloration of the tongue due to deposition of vanadium  Bronchitis, pneumonia form pentoxide dust