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)
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)
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
Antiquity
Socrates (470 399 BC)
Best known recipient of poison for used as a state method of
execution
Cup of Hemlock extract
Demosthenes (385 322 BC)

Took poison hidden in his pen
Cleopatra (69 30 BC)

Use of the more genteel method of falling in her asp
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
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
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
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
Middle Ages
Hieronyma Spara
Successor of Lady Toffana
Directed towards specific marital and monetary objectives
Borgias
Most notorious family engaged in poisoning
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
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
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
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)
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
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
Claude Bernard
MOA of carbon monoxide
Treatise: Introduction to the Study of Experimental Medicine
Oswald Schmiedeberg (1838 1921)

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
20th Century
Poison Squad
Funded by the US Congress ($5,000)
Professional tasters under the direction of Harvey
Washington Wiley (mislabeled foods)
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
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
20th Century
Muellers 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
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)
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 Based on Chemical Stability
Liver, hematopoietic, kidney or Reactivity
etc.
Explosive, flammable, oxidizer
Based on Use
Pesticide, solvent, food Based on Chemical
additive etc Structure
Aromatic amine, halogenated
Based on Effects hydrocarbon etc.
Cancer, mutation, liver injury
Based on Physical State

Gas, dust, liquid, size
Classification of Toxic Agents
Based on Poisoning Potential
Extremely toxic, very toxic, slightly toxic
Based on Biochemical Mechanisms of Action

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
Idiosyncratic Reactions
Chemical Idiosyncrasy
Genetically determined abnormal reactivity to a chemical
Classic Example: Malignant hyperthermia from

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

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
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
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
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
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
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
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 fundamental

physiologic and biochemical processes
Ultimate Toxicants
Parent Xenobiotics
Lead ions, Tetrodotoxin, TCDD, Methylisocyanate, HCN, CO
Xenobiotic Metabolites
Amygdalin HCN
Arsenate Arsenite
Fluoroacetate Fluorocitrate
Ethylene glycol Oxalic Acid
Hexane 2,5-Hexanedione
Acetaminophen NAPQI
Carbon Tetrachloride CCl3OO (unsat. FA)
Benzo-a-pyrene 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 Cellular Inappropriate
dysfunction, repair and
Toxicant Delivery injury adaptation
Alteration of
biological
environment
Toxicity
Step 1 Delivery:
From Site of Exposure to the Target
Step 1 Delivery:
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:
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:
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 protein-
bound xenobiotics
Specialized Transport Across the Plasma Membrane ion

channels and membrane transporters contribute to the
delivery of toxicants to intracellular targets
Step 1 Delivery:
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:
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:
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:
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:
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:
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 Excretion for Volatile Nonreactive

Compounds:
Diffusion through the pulmonary capillaries into the alveoli then
exhaled
Step 1 Delivery:
Reabsorption
Depends on the lipid solubility and ionization
Favors lipophilic and unionized compounds
Step 1 Delivery:
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:
Toxication
Formation of Electrophiles
Electrophiles molecules containing an electron
deficient atom with a partial or full positive electron-rich
atoms in nucleophiles
Usuallyproduced 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:
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:
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:
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:
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:
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 acid (alcohol and aldehyde

dehydrogenase) alcohols
Step 1 Delivery:
Detoxication
Detoxication of Electrophiles
General mechanism: Conjugation with the thiol nucleophile
glutathione (spontaneous or facilitated by Glutathione-S-
transferase)
Detoxication of Free Radicals

Mediated by SOD (superoxide dismutases)
Detoxication of Protein Toxins

Mediated by intra- and extracellular proteases (eg. Thioredoxin)
Step 1 Delivery:
Detoxication
Rationale for Insufficient Detoxication
Toxicants 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
Step 2: Reaction of the Ultimate Toxicant with the
Target Molecule
Target Molecule
Considerations:
Attributes of target molecules
Types of reaction between ultimate toxicant and
target molecules
Effects of toxicants on target molecules
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
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

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
Target Molecule
Types of Reactions
Hydrogen Abstraction
Product: Radicals
Examples:
Thiols Thiyl
Amino Acids Carbonyls Amines
DNA C-4-radical (1st step to DNA Cleavage)
Fatty Acids Lipid Radicals (initiates peroxidation)
Target Molecule
Types of Reactions
Electron Transfer
Oxidation Reactions
Fe (II) in hemoglobin Fe (III) methemoglobinemia
Hydrazines, phenolics are cooxidized with
oxyhemoglobin methemoglobin & hydrogen
peroxide
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)
Target Molecule
Effects of Toxicants on Target Molecules
Dysfunction of Target Molecule
Activators:
Morphine opioid receptors
Clofibrate PPAR
Inhibitors
Atropine,Strychnine, Curare NMB
Tetrodotoxin, Saxitoxin inhibit opening of sodium
channels
Target Molecule
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
Target Molecule
Neoantigen Formation
Hapten formation which evokes immune
response
B-cell Mediated: Eg. Penicillin IgE reaction
T-cell Mediated: Eg. Contact Allergens (Nickel),
Sulfamethoxazole, Drug-Induced SLE
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
Toxicities
Toxicant Induced Cellular Dysregulation
Dysregulation of Gene Expression Transcription
Acting Through Ligand-Gated TFs
Toxicities
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
Toxicities
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
Toxicities
Dysregulation of Gene Expression Signal Production
Inhibition of some hormones that alters feedback
mechanism
Eg. Endocrine hormones that are controlled by negative
feedback mechanism
Toxicities
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
Toxicities
Alteration in Neurotransmitter Levels
Reserpine Norepinephrine, serotonin, dopamine
Botulinum toxin acetylcholine
Organophosphates & carbamates insecticide
acetylcholinesterase
TCAs & MAOIs catecholamines
Toxicities
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
Toxicities
Toxicant-Signal Transducer Interactions
DDT overexcitation of voltage-gated sodium ion
channels
Toxicant-Signal Terminator Interactions

Cyclosporine (nephrotoxic) blockade of calcium and
potassium ion channels
Astemizole, Terfenadine, Cisapride blocks voltage-
gated potassium ion channels TdP
Toxicities
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
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
Toxicities
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
Toxicities
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
Toxicities
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

Toxicities
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
Toxicities
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
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
Cellular Repair
Strategy for peripheral neurons
For central neurons, damage is irreversible
In most tissues, injured cells eventually die
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
Tissue Repair
Side Reactions to Tissue Injury that may
contribute to repair:
Inflammation leukocyte invasion
Inflammation ROS & RNS production
Acute Phase Proteins cytokines released by the
macrophages which has diagnostic and repair value
Generalized reactions
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
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
Antidote Indication
Ipecac Syrup Emetic
Isoproterenol Propranolol
Mannitol Cerebral Edema
Methylene Blue Methemoglobinemia
Evaporated Milk Acids
Morphine Sulfate Pain
Milk of Magnesia Acids
Naloxone, Naltrexone Opioids
Norepinephrine Cardiac Arrest
Paraldehyde Acute Alcoholic Mania
Penicillamine Lead, Copper
Drugs used in the
Antidote Indication
Phenobarbital Anticonvulsant
Phenytoin Anti-arrhythmic
Physostigmine Atropine (Anticholinergics)
Potassium Chloride Electrolyte Replacement
Pralidoxime Organophosphates
Prednisolone Cerebral Edema
Propranolol Anti-arrhythmic
Pyridoxine INH, mushrooms, sulfides
Sodium bicarbonate Acidosis
Isotonic Sodium Chloride Fluid, Electrolyte replacement
Sodium Nitrate Cyanide
Drugs used in the
Antidote Indication
Sodium Sulfate Barium, Cathartic
Sodium Thiosulfate Cyanide, Bleaching solution
Starch Iodine
Succinylcholine Anticonvulsant
Thiopental Anticonvulsant
Urea Sulfides
Vitamin K 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
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
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
Body Temperature Regulation
Hyperthermia
Body temperature up to 40C wet towels with adequate air
circulation or a cooling blanket
Body temperature above 40C frequent application of towels
wet with water at 10C or immersion of the extremities in water
at approximately 25C
Hypothermia
Body temperature below 35C immersion of the entire body
or of the extremities in water not to exceed 42C
Apply blankets to avoid unnecessary chilling after patient leaves
the water
Humidify area; do not use heating pads, heat lamps or hot water
bottles
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
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.
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.
Hyperactivity, Delirium & Mania
Protect the patient from physical injury.
Avoid strange sensory stimuli.
Hydrotherapy tub baths at 33-36C for 30 minutes or
longer if well tolerated; observe vital signs every 15 minutes.
Hypoxia
Physiologic Classification Type of Poisoning Treatment
1) Normal Lung and Blood Oxygen Transport

Deficient Atmospheric O2 Natural gas suffocation Resuscitation in air or
High nitrogen or with oxygen
methane conc in air
Airway Obstruction Edema of the tongue, Ensure adequate airway
pharynx, larynx due to
irritants or corrosives
Muscular paralysis Curare, botulism, Resuscitation
anesthesia, hemlock
Respiratory Center Phosphate esters Resuscitation
Paralysis
Hypoxia
Physiologic Classification Type of Poisoning Treatment
2) Normal Lung with Impaired Blood Oxygen Transport

Inactive Hemoglobin Carbon monoxide 100% Oxygen by
Sulfhemoglobin artificial respiration
formers Hyperbaric Oxygen
Methemoglobin Methylene blue for
formers methemoglobinemia
Impaired Oxygen Carbon dioxide Artificial respiration in

Exchange air
Low Blood Pressure Substances causing Oxygen
shock Positive-Negative
pressure resuscitation
Hypoxia
Physiologic Type of Poisoning Treatment

Classification
3) Normal Lung and Blood Oxygen Transport but Impaired Tissue Uptake
Cellular Enzyme Cyanide, fluoride, 100% oxygen by
Poisoning hydrogen sulfide artificial respiration
Hyperbaric oxygen
Treat cyanide
poisoning
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
Hypoxia
Laryngoscopes used for the placement of endotracheal
airways
Hypoxia
Endotracheal airways
Hypoxia
Suction Device mechanical suction machine with tubing
and traps (Stericath) or hand-operated aspirator
Hypoxia
Mouth Gag used during suction or placement of
an endotracheal tube
Hypoxia
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
Hypoxia
Manual Artificial Respiration by Direct Inflation (15x / min)
Mouth-to-mouth Insufflation
Direct Inflation Using Anesthesia Mask
Hypoxia
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
Hypoxia
Oxygen Therapy
Devices:
Inhalators supplied with tight-fitting face mask and
breathing bags
Hypoxia
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
Hypoxia
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
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
Pediatric Patients
Clinical Evaluation
Vital Signs
Age RR HR BP (mmHg)
(/min) (/min) Lower Limit Average Upper Limit Severe
Newborn 30 80 110 190 52/25 50 55 95/72 110/85

1 month 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
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
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 Drug-
Facilitated 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
Facilitated Assault
Date-Rape Drugs
Flunitrazepam (Rohypnol)
Imparts blue color to clear beverages and

haziness in other colored beverages
Facilitated 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
Facilitated Assault
Laboratory Procedures
Blood Sampling
Collect specimen as soon as possible within 24 hours
Centrifuge the specimen and freeze the plasma or serum at
80C
Perform pharmacokinetic evaluation
Urine Sampling
Collect specimen within 72 hours of suspected ingestion
and freeze for analysis
*Flunitrazepam (Rohypnol) detected up to 96 hours
Facilitated Assault
Laboratory Procedures
Substances Detected in the Urine of Victims
Drug Duration Drug Duration
(days) (days)
Amphetamines 13 Clonidine 12
Barbiturates 27 Cyclobenzaprine 12
Benzodiazepines 27 Diphenhydramine 12
Benzoylecgonine 12 Ethanol <1
Cannabinoids 25 GHB <1
Carisoprodol 12 Ketamine 12
Chloral Hydrate 12 Meprobamate 12
Opioids 23 Scopolamine 12
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 LD50 in Rat (mg/KBW) Example/s
Oral Dermal
Solids Liquids Solids Liquids
Ia Extremely 5 or less 20 or 10 or 40 or less Insecticides (organophosphates)
Hazardous less less Rodenticides (warfarin)
Ib Highly 5 50 20 200 10 100 40 400
Hazardous
II Moderately 50 - 500 200 100 400 Herbicides (paraquat)
Hazardous 2,000 1,000 4,000 Organophosphates (Dimethoate,
Fenthion, Chlorpyrifos)
Pyrethroid (Deltamethrin)
Phenylpyrazole (Fipronil)
III Slightly Over Over Over Over

Hazardous 500 2,000 1,000 4,000
IV+ Unlikely to Over Over Over Over
present 2,000 3,000 4,000 6,000
hazard in
normal use
Pesticides Insecticides
Molecular Targets of Major Classes of Insecticides
Target Insecticide Effect
Acetylcholinesterase Organophosphates Inhibition
Carbamates
Sodium Channels Pyrethroids (Type I & II), DDT Activation
Dihydropyrazoles Inhibition
Nicotinic ACh Receptors Nicotine, Neonicotinoids Activation
GABA receptor-gated Chloride Cyclodienes, Phenylpyrazoles, Inhibition
Channels Pyrethroids (Type II)
Glutamate-gated Chloride Avermectins Activation
Channels
Octopamine Receptors Formamidines
Mitochondrial Complex I Rotenoids Inhibition
Ryanodine Receptors Diamides Activation
Organophosphorus Compounds
Chemistry
Subclasses: Phosphorothioates, Phosphoramidates, Phosphonates

Chemistry
Organophosphorothioates requires metabolic activation to inhibit AChE leading to

the formation of oxon or oxygen analog of the insecticide
Chemistry
Organophosphates with P = O bond which do not require metabolic activation.

Metabolites
Organophosphate Metabolite
Methylparathion Dimethylphosphate (DMP)
Methylchlorpyrifos
Dichlorvos
Trichlorfon
Parathion Diethylphosphate (DEP)
Diazinon Diethylthiophosphate (DETP)
Chlorpyrifos
Azinphos-methyl (Guthion) Dimethylthiophosphate (DMTP)
Fenitrothion
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
Clinical Manifestations
Cholinergic excess
Delayed, often permanent peripheral neuropathy
JamaicanGinger Paralysis outbreak from drinking
rum contaminated with thiocresyl phosphate
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
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
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
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)
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
Pyrethrins & Pyrethroids
Pyrethrins naturally occurring insecticide derived from
chrysanthemum plant (Chrysanthemum cinerariaefolium)
Pyrethroids synthetically derived compounds
Binds to the -subunit of the sodium channel slow the
activation and inactivation of the channel hyperexcitable state
Chemistry
Syndrome Signs & Symptoms Examples

Type I (T Aggressive sparring Allethrin
Syndrome) Increased sensitivity to Bioallethrin
stimuli Resmethrin
Whole-body tremors Phenothrin
Prostration
Type II (CS Pawing and burrowing Deltamethrin
Syndrome) Profuse salivation Fenvalerate
Coarse tremor Cypermethrin
Choreoatetosis Cyhalothrin
Clonic seizures
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
Organochlorine (Chlorinated Hydrocarbons)
Low Toxicity Moderate Toxicity High Toxicity

(LD50 >1g/kg) (LD50 >50 mg/kg) (LD50 <50 mg/kg)
Ethylan (Perthane) Chlordane Aldrin
Hexachlorobenzene DDT Dieldrin
Methoxychlor Heptachlor Endrin
Kepone Endosulfan
Lindane
Mirex
Toxaphene
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)
Recurrent or delayed-onset seizures
Arrythmias
Metabolic acidosis
Signs of hepatitis or renal injury
Hematopoietic dyscrasias
*Muellers 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
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 Parkinsons
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
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
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-chloro-
toluidine & N-formyl-4-chloro-toluidine (causes
hemangioendothelioma)
Amitraz
Widely used for ectoparasites
Acute toxicity similar to clonidine (not associated with deaths)
Other Insecticides
Avermectins
Isolated from Streptomyces avermitilis
Compounds:
Avermectin B1a highest antiparasitic activity
Abamectin 80% Avermectin B1a and 20% Avermectin
B1b
Emamectin, Ivermectin seminsynthetic derivatives of
Avermectin B1a
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
Other Insecticides
Diamides
Fubendiamide, Chlorantraniliprole
Activates ryanodine receptors release of stored
calcium muscle contraction
*Ryanodine alkaloid from Ryania speciosa

which blocks calcium channels
Other Insecticides
Bacillus thuringiensis
A microbial pesticide
Other biopesticides: plant-incorporated protectants,
biochemical pesticides (eg. pheromones)
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-3-
methylbenzamide
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),1-
methyl-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
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)

By Chemical Classes Chlorophenoxy Compounds
Cell membrane damage
Interference with metabolic pathways involving acetyl
coenzyme A
Uncoupling of oxidative phosphorylation
Acute Poisoning Symptoms:

Vomiting, burning of the mouth, abdominal pain, hypotension,
myotonia, coma
Management:
Urine alkalinization with sodium bicarbonate
By Chemical Classes Bipyridyl Compounds
Paraquat
1,1-dimethyl-4-4-bipyridilium dichloride
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
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
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
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
Diquat
Similarto paraquat, but not selectively taken by
pulmonary alveolar cells
Similar to paraquat, but do not cause pulmonary fibrosis
Can cause cerebral and brainstem hemorrhagic
infarctions
Diquat
Diagnosis
Similarto paraquat
Plasma levels obtained through Sygenta
No specific antidote.
By Chemical Classes Chloroacetanilides
Alachlor, Butachlor, Propachlor
MOA: inhibits synthesis of lipids, alcohols, fatty

acids and terpenoids
Alachlor Progressive Uveal Degeneration
Syndrome in rats but not an eye irritant in
humans; skin sensitizer
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 gonadotropin-
releasing hormone
By Chemical Classes Phosphonomethyl AA
Glyphosate
N-phophonomethyl glycine
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
Glyphosate
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)
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)
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)
Chlorothalonil
Highly toxic at IP and inhalational route
Severe irreversible eye irritations
Skin irritation at repeated exposures
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
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
Fluoroacetic Acid and Its Derivatives
Fluoroacetate (Compound 1080)
Sodium monofluoroacetate (SMFA), sodium fluoroacetate
Metabolized to the toxic compound fluorocitrate inhibits
aconitase enzyme within the Krebs cycle blockade of cellular
metabolism
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
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
Thioureas ANTU
-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 2-
napthylamine (bladder carcinogen)
Anticoagulants
Coumarins
Dicoumarol
Warfarin
Superwarfarins (Brodifacoum, Diphacinone,
Bromadiolone, Chlorophacinone, Difenacoum, Pindone,
Valone)
Inhibition of the hepatic synthesis of vitamin K-dependent
coagulation factors
Duration of action: Warfarin 2 to 7 days; Superwarfarins
up to several months
Anticoagulants
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
Anticoagulants
Treatment
Vitamin K1 (Phytonadione) but not Vitamin K3
(Menadione)
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

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

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)
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
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 earths 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)
Pharml Uses
Arsenic Trioxide reintroduced in USP 2000 as a chemotherapeutic
agent
Inorganic arsenic folk remedy & tonics in Asian countries
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)
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)
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)
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, retinol-
binding 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)
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)
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)
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)
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
<5 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
Major Toxic Metals
Lead (Pb)
Diagnosis
Whole-blood levels most useful indicator
25 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
Major Toxic Metals
Lead (Pb)
Diagnosis
FEP (Free Erythrocyte Protoporphyrin) or ZPP (Zinc
Protoporphyrin)
> 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
Succimer for blood levels greater than 45 mcg/dL
Asymptomatic Adults
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
Acute inhalation of metallic form severe
chemical pneumonitis, noncardiogenic pulmonary
edema, acute gingivostomatitis
Major Toxic Metals
Mercury (Hg)
Chronic inhalation of metallic form Triad
symptoms (tremor, neuropsychiatric disturbances,
gingivostomatitis)
Early 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
Major Toxic Metals
Mercury (Hg)
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
Urinemercury mass of metal per volume of urine or
mass of metal per gram of creatinine
Metallic & inorganic - whole-blood levels rise

faster than urine levels
Organic 90% undergo enterohepatic
recirculation fecal excretion; whole-blood half-
life 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)
Contact Dermatitis most common adverse
effect; Type IV hypersensitivity reaction
Nickel Carbonyl Poisoning in combination with
carbon monoxide
Headache, N/V, epigastric & chest pain cough,
hyperpnea, cyanosis, GI symptoms, weakness, fever,
leucocytosis pneumonia, respiratory failure
cerebral edema, death
Major Toxic Metals
Nickel (Ni)
Treatment
Sodium diethylcarbodithioate (DDTC)
Drug of choice
MOA: Chelation
Alternative chelators: Disulfiram,

penicillamine, DMPS
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
Cobalt (Co)
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
Cobalt (Co)
Essential Metals
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
Copper (Cu)
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
Copper (Cu)
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
Copper (Cu)
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
Copper (Cu)
Idiopathic Copper Toxicosis or Non-Indian
Childhood Cirrhosis
Similar to ICC but occurs in Western countries
Treatment: Chelators
Essential Metals
Copper (Cu)
Essential Metals
Iron (Fe)
Derived from the Ethruscan word aisar meaning
the gods

Essential metal for erythropoiesis & key
component of hemoglobin, myoglobin, heme
enzymes, metalloflavoprotein & mitochondrial
enzymes
Iron deficiency most common nutritional
deficiency worldwide
Essential Metals
Iron (Fe)
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
Iron (Fe)
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
Iron (Fe)
Essential Metals
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
Magnesium (Mg)
Name originates from the Greek word Magnesia, a district
in Thessaly

Cofactor of many enzymes
Deficiency: irritability, frank tetany, convulsions
Clinical Manifestation: Metal fume fever similar to Zn

Treatment: Calcium infusion
Essential Metals
Manganese (Mn)
Named after the Latin word, magnes meaning magnet
Essential metal for many metabolic & cellular functions
Manganism chronic manganese-induced neurotoxicity
which affects dopaminergic neurons
Psychiatric & movement disorders(cock-walk gait)
Co-accumulation of iron
Essential Metals
Manganese (Mn)
Essential Metals
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
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
Keshan Disease
Deficiency in selenium characterized by cardiomyopathy
Occurs in children 15 years of age & women in childbearing age
Essential Metals
Selenium (Se)
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
Selenium (Se)
Essential Metals
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
Zinc (Zn)
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
Zinc (Zn)
Metal Fume Fever
s/sx:fever, chest pain, chills, cough, dyspnea,
nausea, muscle soreness, fatigue, leukocytosis
Neuronal Toxicity
May later develop to Alzheimers disease
Pancreatic Toxicity
May cause -cell death in the Islets of Langerhans
Metals Related to Medical Therapy
Aluminum (Al)
3rd most abundant element in the Earths 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

Bismuth (Bi)
Bisemutum is from the German Wismuth from the
term weiBe Masse for white mass
Clinical Manifestations: Acute renal injury,

encephalopathy
Treatment
D/C Bismuth therapy
Chelation therapy (BAL, DMSA, DMPS)
Gallium (Ga)
From Gallia meaning Gaul or France
Resemble trivalent iron
Lung toxicity
Gold (Au)
Monovalent salts are used in Rheumatoid Arthritis
Contact dermatitis accompanied by stomatitis
Proteinuria, Nephrotic Syndrome if used for RA
Lithium (Li)
Lightest metal
From the Greek word, Lithos meaning stone
DOC for mania & bipolar disorder
Lithium hydride skin burns
Narrow TI seizures, coma, cardiovascular disturbances,
nephritis
Treatment: Amiloride & other diuretics, hemodialysis
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
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
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
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)
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-propamine-
8,8-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
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
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
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

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Nero (37 68 AD)

Moses ben Maimon (1135 1204

All substances are poisons; there is

Promoted the focus on toxicon,

Introduce mercury as the DOC for

Percival Pott (1714 1788)

Oswald Schmiedeberg (1838 1921)

Louis Lewin (1850 1929)

Discovery of Vitamins aka Vital amines

Prohibition of Alcoholic Beverages in the US

1970s: Love Canal

Cellular and Molecular Mechanisms of Toxicity

Zebrafish (C. elegans, D. melanogaster)

Based on Physical State

Based on Biochemical Mechanisms of Action

Based on General Terms

Allergic Reaction and Sensitization Reaction

Classic Example: Malignant hyperthermia from

May be due to the ability to:

Exhibit differences in immune response to adducted proteins

Delayed Toxic Effects Occur after the lapse of

Irreversible pathological injury to a tissue that

Chemical or Inactivation chemical reaction between 2

Receptor aka blockers occurs when 2 chemicals that bind

Provides better understanding of fundamental

Rate of absorption depends on:

Specialized Transport Across the Plasma Membrane ion

Reversible Intracellular Binding

Association with Intracellular Binding Proteins

Export from Cells intracellular toxicants

Mechanism of Excretion for Volatile Nonreactive

Usuallyproduced by insertion of oxygen atom which

By losing an electron eg. Phenols, hydroquinone, aminophenols,

By homolytic fission of a covalent bond eg. Carbon tetrachloride

Detoxication of Toxicants with no Functional Groups

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

By oxidation to carboxylic acid (alcohol and aldehyde

Detoxication of Free Radicals

Detoxication of Protein Toxins

Properties of Target Molecules

Warfarin to Vit K 2,3-epoxide reductase

Spontaneous degradation of target molecule after

Solvents & detergents that physicochemically alter the lipid

Xenobiotics that cause harm by occupying site or space

Chemicals with Proliferative Effects

Eg.2. Arsenite mimics epidermal growth factor

Chemicals with Antiproliferative Effects

Intracellular signal transduction

Toxicant-Signal Terminator Interactions

Production of energy for operation

Necrosis (Worst Outcome) cell lysis

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

Proliferation (Regeneration of Tissue)

1) Normal Lung and Blood Oxygen Transport

2) Normal Lung with Impaired Blood Oxygen Transport

Impaired Oxygen Carbon dioxide Artificial respiration in

Physiologic Type of Poisoning Treatment

Adolescents and Young Adults