Mechanisms of toxicity

• Temporal aspects

• Cellular toxicity

• Organ & tissue toxicity

Pathology of Toxicity (3)

• Delivery (from the site of exposure to the target )

• Reaction of the Ultimate Toxicant with the Target Molecule

• Cellular Dysfunction and Resultant Toxicities

• Repair or Dysrepair

Steps/Mechanisms of Toxicity [4]

• On-target adverse effects

• Off-target adverse effects

• Production of toxic metabolites

• Production of harmful immune responses

• Idiosyncratic responses

MECHANISMS OF TOXICITY [5]

1. Toxicant

2. Delivery

3. Interaction with the Target

4. Aletration of biological environment

5. Cellular dysfunction injury

6. Inappropriate repair and adaptation

Potential Stages in the Development of Toxicity after Chemical Exposure [6]

Nerve Agents

These are potent organophosphorus agents that cause inhibition of acetyl cholinesterase and subsequent excessive muscarinic and nicotinic stimulation

Tabun

GA

Sarin

GB

Soman

GD

Cyclosarin

GF

Methylphosphonothioic Acid

VX

• Organophosphorus

• Carbamate Insecticides

• Tabun

• Sarin

• Soman

• Cyclosarin

• Methylphosphonothioic acid

Example of Neve Agent [7]

Nerve agents

[ Identify it Toxicity Class : ]

Organophosphorus

Nerve agents

[ Identify it Toxicity Class : ]

Carbamate Insecticides

Blister Agents

Vesicants are also known as ____________

Nitrogen and sulfur mustards

_____________ and ______________mustards are hypothesized to act by alkylating cellular DNA and depleting glutathione, leading to lipid peroxidation by oxygen free radicals

• Nitrogen mustrad

• Sulfur mustard

• Phosgene

• Lewisite

Example of Vesicants (5)

Sulfur mustard

HD

Nitrogen Mustard

HN

Lewisite

L

Phosgene

CX

Thiol moieties

Lewisite combines with _________ moieties in many enzymes and also contains trivalent arsenic.

trivalent arsenic

Lewisite combines with thiol moieties in many enzymes and also contains _____

• Phosgene

• diphosgene

• chlorin

• chloropicrin
  

Example of Choking Agents [4]

Choking agents

[ Identify it Toxicity Class : ]

Phosgene

Choking agents

[ Identify it Toxicity Class : ]

diphosgene

Choking agents

[ Identify it Toxicity Class : ]

chlorine

Choking agents

[ Identify it Toxicity Class : ]

chloropicrin

Choking Agents

These agents include chlorine and lacrimator agents

Choking agents

These gases and mists are highly irritating to mucous membranes. In addition, some may combine with the moisture in the respiratory tract to form free radicals that lead to lipid peroxidation of cell walls

pulmonary injury

Phosgene causes less acute irritation but may lead to delayed ____________

Blood agents

Cyanides is aka ____

• Cyanide

• Hydrogen Cyanide

• Cyanogen Chloride

Cyanides include ___ (3)

Cyanides (blood agents)

These compounds have high affinity for metalloenzymes such as cytochrome, thus derailing cellular respiration and leading to the development of a metabolic acidosis.

• metalloenzymes

• cytochrome

Cyanides (blood agents) compounds have high affinity for ____ such as ___, thus derailing cellular respiration and leading to the development of a metabolic acidosis

metabolic acidosis.

Cyanides (blood agents) compounds have high affinity for metalloenzymes such as cytochrome, thus derailing cellular respiration and leading to the development of a____

Incapacitating agents

These are a variety of agents have been considered, including strong anticholinergic agents such as scopolamine, stimulants such as amphetamines and cocaine, hallucinogens such as LSD (Lysergic Acid Diethylamide and Other Hallucinogens), and CNS depressants such as opioids (Opiates and Opioids).

• Anticholinergics

• stimulants

• hallucinogens

• Depressants

DRUG TYPES that are considered 'incapacitating agents' [4]

Incapacitating agents

[ Identify its Toxicity Class ]

scopolamine

Incapacitating agents

[ Identify its Toxicity Class ]

amphetamines

Incapacitating agents

[ Identify its Toxicity Class ]

cocaine

Incapacitating agents

[ Identify its Toxicity Class ]

LSD (Lysergic Acid Diethylamide)

Incapacitating agents

[ Identify its Toxicity Class ]

opioids (Opiates and Opioids)

D. Reduction of glutathione disulfide (GSSG) by glutathione reductase (GR)

WHICH OF THE FOLLOWING IS NOT AN IMPORTANT STEP IN DETOXICATION OF CHEMICALS?

A. Formation of redox-active reactants

B. Reduction of hydrogen peroxide by

glutathione peroxidase

C. Formation of hydrogen peroxide by

superoxide dismutase

D. Reduction of glutathione disulfide

(GSSG) by glutathione reductase (GR)

E. Conversion of hydrogen peroxide to

water and molecular oxygen by catalase

Endogenous compounds

___compound causes cross-linking

Antigen

This is also known as a xenobiotic that is a stranger

• Superoxide Anion Radical

• Superoxide Dismutase

• Peroxynitrite

• Hydroxyl radical

Radicals That Form with Superoxide Ion [4]

• Regulatory

• Functional

Functions Cell [2]

1. Absorption

2. Distribution Toward the Target

3. Reabsorption

4. Toxication

5. Presystemic Elimination

6. Distribution from Target

7. Excretion

8. Detoxication

The process of Toxicant delivery (8)

MNEMONICS : [ ADR TP DED ]

• Protein

• lipid

• nucleic acid macromolecular complex

Target Molecules [3]

• Parent Xenobiotics

• Xenobiotic metabolites

• Reactive Oxygen or Nitrogen Species

• Endogenous compounds

Types of Ultimate Toxicants[4]

Parent xenobiotics

[Classify What Types of Ultimate Toxicants]

Pbions

Parent xenobiotics

[Classify What Types of Ultimate Toxicants]

Tetrodotoxin

Parent xenobiotics

[Classify What Types of Ultimate Toxicants]

TCDD

Parent xenobiotics

[Classify What Types of Ultimate Toxicants]

Methylisocyanate

Parent xenobiotics

[Classify What Types of Ultimate Toxicants]

HCN

Parent xenobiotics

[Classify What Types of Ultimate Toxicants]

CO

Tetrodotoxin

Toxin from Pufferfish

• Amygdalin ► HCN

• Arsenate ►Arsenite

• Fluoroacetate►Fulurocitrate

• Ethylene Glycol►oxalic acid

• Hexane►2,5-Hexanedione

• Acetaminophen►N-Acetyl-p-benzoquinoneimine (NAPQI)

• CCl4►CCl3OO

• Benzo[a]pyrene ►BP-7,8-diol-9,10-epoxide/BP- Radical cation

Example of Xenobiotic Metabolite [7]

HCN (Hydrocyanic Acid)

Xenobiotic metabolites as ultimate toxicants:

Amygdalin ►___

Arsenite

Xenobiotic metabolites as ultimate toxicants:

Arsenate ►___

Fluorocitrate

Xenobiotic metabolites as ultimate toxicants:

Fluoroacetate ►___

Oxalic acid

Xenobiotic metabolites as ultimate toxicants:

ethylene glycol ►___

2,5-Hexanedione

Xenobiotic metabolites as ultimate toxicants:

Hexane ►___

N-Acetyl-p-benzoquinoneimine ( NAPQI )

Xenobiotic metabolites as ultimate toxicants:

Acetaminophen►___

CCl3OO•

Xenobiotic metabolites as ultimate toxicants:

CCl4 (Carbon Tetrachloride) ►___

BP-7,8-diol-9,10-epoxide or BP-Radical Cation

Xenobiotic metabolites as ultimate toxicants:

Benzo[a]pyrene (BP) ►___

Xenobiotic metabolites

[Classify What Types of Ultimate Toxicants]

Amygdalin

Xenobiotic metabolites

[Classify What Types of Ultimate Toxicants]

Arsenate

Xenobiotic metabolites

[Classify What Types of Ultimate Toxicants]

Fluoroacetate

Xenobiotic metabolites

[Classify What Types of Ultimate Toxicants]

Ethylene glycol

Xenobiotic metabolites

[Classify What Types of Ultimate Toxicants]

Hexane

Xenobiotic metabolites

[Classify What Types of Ultimate Toxicants]

Acetaminophen

Xenobiotic metabolites

[Classify What Types of Ultimate Toxicants]

CCl4

Xenobiotic metabolites

[Classify What Types of Ultimate Toxicants]

Benzo[a]pyrene (BP)

• Hydrogen peroxide (H2O2)

• Diquat

• doxorubicin

• nitrofurantoin

• Cr(V)

• Fe(II)

• Mn(II)

• Ni(II)

Examples of toxins that produces Hydroxyl radical (HO•) [4]

Peroxynitrite (ONOO-)

Paraquat produces what reactive nitrogen species ?

Reactive oxygen or nitrogen species

[Classify What Types of Ultimate Toxicants]

Hydrogen peroxide

Reactive oxygen or nitrogen species

[Classify What Types of Ultimate Toxicants]

Diquat

Reactive oxygen or nitrogen species

[Classify What Types of Ultimate Toxicants]

doxorubicin

Reactive oxygen or nitrogen species

[Classify What Types of Ultimate Toxicants]

nitrofurantoin

Reactive oxygen or nitrogen species

[Classify What Types of Ultimate Toxicants]

Cr(V)

Reactive oxygen or nitrogen species

[Classify What Types of Ultimate Toxicants]

Fe(II)

Reactive oxygen or nitrogen species

[Classify What Types of Ultimate Toxicants]

Mn(II)

Reactive oxygen or nitrogen species

[Classify What Types of Ultimate Toxicants]

Ni(II)

Reactive oxygen or nitrogen species

[Classify What Types of Ultimate Toxicants]

Paraquat

Paraquat

Identify The name of the Structure

Diquat

Identify The name of the Structure

Diquat-monopyridone

Identify The name of the Structure

Diquat-dipyridone

Identify The name of the Structure

• Lipid peroxyl radicals

• Lipid alkoxyl radicals

• 4-Hydroxynon-2-enal

Products that may be produced when Carbon Tetrachloride ( CCl3OO ) reacts with unsaturated fatty acids___ (3)

Sulfonamides

This drug family may displace bilirubin in the bound-state in albumin

Sulfonamides

[Identify the Toxicity Class ]

albumin-bound bilirubin

Protein carbonyls

____ can be formed when Hydroxyl radicals (HO•) react with proteins

D. Opening of ion channels

ALL OF THE FOLLOWING ARE COMMON

EFFECTS OF TOXICANTS ON TARGET

MOLECULES EXCEPT:

A. blockage of neurotransmitter

receptors

B. Interference with DNA replication

due to adduct formation

C. Cross-linking of endogenous

molecules

D. Opening of ion channels

E. Mounting of an immune response

Superoxide dismutase

An enzyme that can convert superoxide anion radical into peroxide

Peroxynitrite and peroxide

Superoxide anion radical can be converted into ______ or _______

Hydroxyl Radical and Hydroxide

Peroxide can be further converted into _________ and ___________

• Noncovalent binding

• Covalent binding

• Hydrogen abstraction

• Electron transfer

• Enzymatic reaction

Reaction Types for the Second Step in the Development of Toxicity (5)

Mitochondria

This is the powerhouse of the cell

Toxication

This refers to the biotransformation that causes harmful response ?