1 - (edited) pacop toxi - 2015

PRINCIPLES OF

TOXICOLOGY

PRINCIPLES of TOXICOLOGY 1

OBJECTIVES:

To explain the general nature of toxic

action of substances

To describe the nature of toxic action and

the effects brought about by chemicals

To explain the potential stages in the

development of toxicity


Introduction to Toxicology

Toxicology is the study of the adverse

effects of chemicals on living organisms.

Toxicologist- one who is trained to

examine the nature of those effects

( cellular, biochemical, and molecular

mechanisms of action) and assess the

probability of their occurrence


BRANCHES OF TOXICOLOGY


Clinical toxicology

Effects of substances to patients


Experimental

Effects of chemicals in the biological

system

Measures laboratory parameters


Descriptive toxicology

Toxicity testing

Provide information for safety evaluation

and regulatory requirements

SET LIMITS


Mechanistic toxicology

Mechanism of action or MOA of

poisons

Data may be useful in the design and

production of safer chemicals and in

rational therapy for chemical poisoning

and treatment of disease

Data is useful in demonstrating that an

adverse outcome observed in laboratory

animals is directly relevant to humans


Regulatory toxicology

Involved in the establishment of standards

for the amount of chemicals permitted in

foods, drugs, air, industrial atmosphere and

drinking water


Environmental toxicology

Studying the impacts of chemicals on non

human organisms such as fish, birds,

terrestrial animals and plants


Forensic toxicology

Medico-legal cases of poisoning and

intoxication


All substances are poisons; there is none which is not a

poison.

The right dose differentiates

a poison from a remedy.

Paracelsus (1493-1541)

Paracelsus


The sensitivity of the individual differentiates a

poison from a remedy. The fundamental

principle of toxicology is the individuals

response to a dose.

S. G. Gilbert (1997)

An Individual View


Poison

Any agent that may cause harm or serious

injury


every known chemical has the potential

to produce injury or death if it is present in

a sufficient amount


Dose

The amount of chemical entering the body

This is usually given as

mg of chemical/kg of body weight = mg/kg

The dose is dependent upon

* The environmental concentration

* The properties of the toxicant

* The frequency of exposure

* The length of exposure

* The exposure pathway


Dose-Response Relationship:

As the dose of a toxicant increases, so does the response.

2

3

4

0 1 DOSE

RESPONSE

0-1 NOAEL

2-3 Linear Range

4 Maximum Response

DOSE DETERMINES THE BIOLOGICAL RESPONSE PRINCIPLES of TOXICOLOGY 17

Dose response assumptions

response is due to chemical administered

the response is related to the dose

there is a receptor site with which the

chemical interacts

the degree of response is related to the

concentration at the site

the concentration at the site is related

to the dose administered

has a quantifiable method of measuring and a

precise means of expressing the toxicity


Exposure: Pathways

Routes and Sites of Exposure

Ingestion (Gastrointestinal Tract)

Inhalation (Lungs)

Dermal/Topical (Skin)

Injection

intravenous, intramuscular, intraperitoneal


Rapidity of response with respect to route

of exposure

Intravenous

Inhalation

Intraperitoneal

Subcutaneous

Intramuscular

Intradermal

Topical


Exposure: Duration

Acute < 24hr usually 1 exposure

Subacute 1 month repeated doses

Subchronic 1-3mo repeated doses

Chronic > 3mo repeated doses

Over time, the amount of chemical in the

body can build up, it can redistribute, or it

can overwhelm repair and removal

mechanisms PRINCIPLES of TOXICOLOGY 21

Toxins = toxic substances

produced naturally


Toxicants = toxic substances that are

produced or a by-product of

human activities


Adverse effects

any change from an organisms normal state

dependent upon the concentration of active compound at the target site for a sufficient

time.


Tolerance

state of decreased responsiveness to a

toxic effect of a chemical, resulting from

previous exposure

dispositional tolerance; a decreased amount of drug reaching the site

cellular; reduced responsiveness of a tissue


Toxicity

describes the degree to which a

substance is poisonous or can cause

injury.


Major factors that influence

toxicity

route of administration

duration and frequency of exposure

dose or concentration

shape and structure of the chemical itself,

and individual human factors.


What is toxicodynamics ?

It examines the mechanism by which toxicants

produce unique cellular effects within the

organism

Mechanism of toxic action

The alteration to the cells plasma membrane,

organelles, nucleus, cytoplasm, enzyme

systems, biosynthetic pathways, development

or reproduction


1. Toxic action of a drug is not necessarily

an exaggeration of its therapeutic action.

2. One toxicant may exert several mechanisms

of toxic action.

3. The toxic action may be brought about by the

parent compound and/or its metabolites.

4. The mechanisms of toxic action in acute

exposure may differ from those in chronic

exposure.

5. Intensity of a toxic effect depends primarily on

the concentration and persistence of the ultimate

toxicant at its site of action.


1. Allergic Reactions

Chemical allergy : immunologically

mediated adverse reaction to a

chemical or to structurally

similar one


2. Idiosyncratic Reactions:

Chemical idiosyncrasy : refers to a

genetically determined abnormal

reactivity to a chemical; the

response observed may take the

form of extreme sensitivity to low

doses or extreme insensitivity to

high doses of a chemical

E.g. Nitrites :

deficiency in NADH-methemoglobin reductase


3. Immediate vs. Delayed Toxicity:

Immediate : occurs or develops

rapidly after a single administration

of a substance

Delayed: occurs after a lapse of some

Time (months or years)


4. Reversible vs. Irreversible Toxic Effects:

E.g.

Reversible: injury to the liver by

paracetamol

Irreversible: injury to the CNS by

ethanol


5. Local vs. Systemic Toxicity:

Local : site of first contact between

biological system and toxicant

E.g. Caustics skin, gastrointestinal mucosa Chlorine gas lung tissue

Systemic: absorption and distribution of

toxicant from its entry point to a distant

site at which deleterious effects are

produced

E.g. Caustics (phenol) kidney damage


Casarett & Doulls, 7th edition PRINCIPLES of TOXICOLOGY 36

TOXICATION Biotransformation to

harmful products

E.g. Ethylene glycol converted to

oxalic acid which produces

acidosis and hypercalcemia


Non-covalent binding

Covalent binding

Electron transfer

Enzymatic reaction


Third step: Alteration of regulatory

or maintenance function of the cell


CELLULAR REGULATION

1. Dysregulation of gene expression

Dysregulation of transcription PRINCIPLES of TOXICOLOGY 40

2. Dysregulation of on-going cellular activity

Alteration in neurotransmitter levels

Methamphetamine/amphetamine increases release and inhibit reuptake of norepinephrine, dopamine

and serotonin

Organophosphates decrease hydrolysis of acetylcholine



Toxicant-neurotransmitter receptor interaction

INHIBITION

Atropine & atropine-like drugs produce inhibitory

effect on the muscarinic receptors (M2 and M3)

Increased heart rate

Decreased bowel sounds

Decreased salivation

Decreased perspiration

STIMULATION

Benzodiazepine stimulating GABA A receptor

Sedation PRINCIPLES of TOXICOLOGY 42


Toxicant-signal transducer interactions

DDT, pyrethroids act on

Voltage-gated Na+ channels

Neuronal activation

Overexcitation

Convulsion


2. Dysregulation of

on-going cellular activity Enzyme reactions

Enzyme Inhibition Pyridoxine kinase Glutamic acid decarboxylase Monoamine oxidase Nicotinamide adenine dinucleotide (NAD) (co-enzyme)

EFFECTS:

Seizure Acidosis Increased sympathetic activity


1. Impaired Internal Maintenance

CELLULAR MAINTENANCE

Inhibition of hydrogen delivery to ETC (1)

(fluoroacetate inhibits

aconitase enzyme)

IMPAIRED ATP SYNTHESIS

Inhibition of electron transport complexes (2)

(Cyanide, CO inhibits

cytochrome oxidase)

Inhibition of oxygen delivery to electron

transport chain (3)

(CO, hydrogen sulfide,

nitrites)

Inibition of ADP phosporylation (4)

(DDT & chlordecone

inhibit ATP synthase )


CELLULAR MAINTENANCE

1. Impaired Internal Maintenance

Impaired membrane function

Ethanol and organic solvents increase membrane fluidity Lipid solvents destroy plasma membrane Hydrocarbons destroy lysosomal membranes

2. Impaired External Maintenance

Toxicities interfering with cells specialized to provide support to other cells, tissues or whole organism

Inhibition of hepatic synthesis of coagulation factors by coumarin


REPAIR

Molecular Cellular Tissue

Protein

Lipid

DNA Proliferation Apoptosis

Cells ECM

Repair Mechanisms PRINCIPLES of TOXICOLOGY 47

Tissue necrosis

Fibrosis

Cancer


DYSREPAIR

Failure of DNA repair Failure of apoptosis Failure to terminate cell proliferation


SIGNIFICANCE OF TOXICODYNAMICS:

Choice of antidotal therapy

Determine magnitude and extent of toxicity

More effective and adequate treatment plan


Study of how a substance gets into the body and what happens to it in the body

Modeling and mathematical description of the time course of disposition of

toxicants in the whole organism


Toxicokinetics Only the absorbed dose that makes it to the target organ is capable

of producing an effect

Xenobiotic

Excretion

The effect which a chemical produces is not only dependent on the dose administered but more on

the concentration of the chemical in the target

organ.

The concentration in turn depends on the disposition of the chemical.

The kinetics of a chemical/drug may differ from therapeutic dose to its toxic dose.

The study of toxicokinetics is important in predicting plasma concentration of a chemical.


A result of a number of opposing

actions

Some promotes delivery of the

Toxicant towards the target

Others promote toxicant delivery

Away from the target

The net effect determines how

much of the toxicant

makes it to its site of action


Concentration at site of action

Duration of the Ultimate Toxicant

At Its Site of Action

Intensity of toxic action

The Ultimate Toxicant is the species that interacts with the target or critically modifies the biological microenvironment


The ultimate toxicant can be:

The parent compound

A metabolite of the parent

A reactive Oxygen or Nitrogen species

An endogenous compound


FOUR PROCESSES IN TOXICOKINETICS

ABSORPTION is the process by which a chemical enters the body

DISTRIBUTION is the stage when a substance moves from the site of entry to other organs/areas of the body

METABOLISM is when the body transforms the chemical into metabolites

EXCRETION is the process wherein the parent chemical and its metabolites leave the body


Absorption, Distribution,

Metabolism, and Excretion

Once a living organism has been exposed

to a toxicant, the compound must get into

the body and to its target site in an active

form in order to cause an adverse effect.

The body has defenses:

Membrane barriers

passive and facilitated diffusion, active transport

Biotransformation enzymes, antioxidants

Elimination mechanisms

FACTORS AFFECTING KINETIC PROCESSES

Duration and concentration at the portal of entry

the higher the concentration, the greater will the damage be

Rate and amount of chemical absorbed rate of absorption is slow and the amount absorbed is small,

the toxicity will be low

Distribution of the toxicant within the body most of the toxicants are distributed in highly perfused organs which have vital functions such as the brain

and the kidneys.

the organ in which a chemical is most highly concentrated is not necessarily the organ where most tissue

damage occurs.


FACTORS AFFECTING KINETIC PROCESSES

Efficiency of biotransformation and nature of metabolites

a chemical maybe converted to a toxic metabolite which is

more toxic than the parent compound

Ability of the chemical or its metabolites to pass through cell membranes and come into contact with specific cell

components

a chemical can pass through the placenta or the blood brain

barrier

Amount and duration of storage of the chemical or its metabolites in body tissues

some chemicals are stored in body tissues for a long period

of time and would produce its effect long after the

initial exposure


PRESYSTEMIC ELIMINATION First pass effect

DISTRIBUTION AWAY FROM THE TARGET SITE Binding to plasma proteins because protein-bound chemicals do not exert toxic action

Specialized barriers such as blood-brain barrier which prevent entry of hydrophilic chemicals into the brain

Storage sites which are not target sites of chemicals and where the chemicals are highly concentrated

Association with intracellular binding proteins which are non-target intracellular sites

Export from cells wherein chemicals are transported back into the extracellular space


DETOXIFICATION

Biotransformation of chemical prevents its formation I

nto ultimate toxic metabolites and enhances

its elimination

EXCRETION The liver and the kidneys can remove efficiently highly

hydrophilic, usually ionized chemicals such as weak

acids and bases. Other processes include the bile,

gastrointestinal tract and the breastmilk.


Involves the movement of chemcials

across cell membranes

Phospholipid bilayer


Factors affecting gastrointestinal absorption of drugs/

chemicals in their toxic states

Type of cells at the specific site Contact time pH of the stomach and small intestine Concentration of the drug/chemical at absorption site

Presence of food or binding substances Rate of gastric emptying Gastrointestinal motility Large absorbing surface of the small intestines

Blood flow to the site Intestinal microflora and GI enzymes General condition of the patient Product formulation


Solubility of the chemical in

the blood

(blood/gas coefficient)

If low, rate of transfer from alveoli to blood is dependent on perfusion

If high, rate of transfer from alveoli to

blood is dependent on ventilation

Particle size

Water solubility


Condition of the skin

Body region

Lipid solubility


Movement of chemicals throughout the body within the bloodstream


Blood flow/perfusion limitation Permeability limitation Capillary membrane passage

Cell membrane passage

Apparent volume of distribution Protein binding Effect of pH Age Tissue reservoir/depots Plasma proteins

Liver and kidneys

Fat

Bone


Process by which the body alters chemicals, typically for energy

production

Biotransformation process by which both endogenous, and exogenous substances that enter

the body are changed from hydrophobic to

hydrophilic molecules to facilitate elimination.


The highest capacity

for biotransformation

is the liver.


Metabolism =

Toxification /Detoxification

Toxication = increase in toxicity

Detoxification = decrease in toxicity


Toxication

Change in Structure increases

interaction with target molecule

Changes in general reactivity lead to the formation of

electrophiles

free radicals

nucleophiles


Detoxication

To be eliminated from the body more

efficiently must be hydrophilic and

ionized

Compounds with no functional groups

Phase I - oxidation via CYP450

Phase II - addition of endogenous acid (conjugation)

Product: hydrophilic organic acids

Electrophiles conjugation with

glutathione a thiol nucleophile


Phase I reactions Oxidation, reduction,

hydrolysis, hydration

Phase II reactions Glucuronidation,

sulfation

TOXICANT PHASE I

PRIMARY PRODUCT

PHASE II

SECONDARY

PRODUCT

ELIMINATION FROM BODY


When does detoxication fail?

Toxicants overwhelm the detoxication processes

Reactive toxicants deactivate a detoxicating enzyme

Conjugation reactions are reversed

Reactive degradation products are formed by detoxicating enzymes


Age Sex Pharmacogenetic factors Pregnancy Nutritional status/ body size and weight

Disease states Bioactivation Enzyme induction/inhibition Changes in kinetic mechanisms


Process by which the body

separates and discharges wastes

or toxic substances from the

body


Most important organ for excretion is the kidney.

Other routes:

Fecal

Respiratory

Cerebrospinal fluid

Milk

Sweat

Saliva


Age

Disease states Rate of excretion Enterohepatic recirculation Ion trapping


Phenomenon by which drugs emptied

through the bile into the small intestine can

be reabsorbed from the intestinal lumen into

systemic circulation. When reaching the

distal ileum, bacterial flora convert the

parent drug and its active metabolites back

into lipophilic states


Removal of Chemicals from the

body

Primary Structures:

Kidney

Glomerular filtration

Tubular excretion

Liver

Usually water soluble and ionic, weak acids and bases

No effective removal of lipophilic, persistent molecules

Some volatiles and non-reactives may leave via the lung


Retention of Chemicals in the Body

In the renal tubule, toxicants can be

reabsorbed prior to excretion:


In the GI tract, compounds secreted

as ionics can be modified by gut

bacteria then reabsorbed

Enterohepatic Recirculation

Aspirin

Carbamazepine Dapsone Digoxin Methamphetamine Paracetamol Phencyclidine Phenothiazine Phenobarbital Phenytoin Quinine

Rifampicin Salicylates Theophylline Anticoagulants Naphthalene Organochlorine

pesticides


Winston Churchill


1 - (edited) pacop toxi - 2015

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