Principles of Toxicology:

The Study of Poisons

Elizabeth Casarez
Department of
Pharmacology and Toxicology
University of Arizona
 The study of the adverse effects
of a toxicant on living organisms
• Adverse effects
– any change from an organism’s normal state
– dependent upon the concentration of active compound at
the target site for a sufficient time.
• Toxicant (Poison)
– any agent capable of producing a deleterious response in a
biological system
• Living organism
– a sac of water with target sites, storage depots and enzymes
 What is a Poison?
All substances are poisons;
there is none that is not a poison.
The right dose
differentiates a poison and a remedy.

Paracelsus (1493-1541)
 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
 What is a Response?
The degree and spectra of responses depend
upon the dose and the organism--describe
exposure conditions with description of dose
• Change from normal state
– could be on the molecular, cellular, organ, or
organism level--the symptoms
• Local vs. Systemic
• Reversible vs. Irreversible
• Immediate vs. Delayed
• Graded vs. Quantal
– degrees of the same damage vs. all or none
 Dose-Response Relationship:
As the dose of a toxicant increases,
so does the response.
4

RESPONSE
0-1 NOAEL
2-3 Linear Range 3
4 Maximum Response

0 1 DOSE
DOSE DETERMINES THE BIOLOGICAL RESPONSE
 LD50
• Quantal responses can be treated as gradient when data
from a population is used.
• The cumulative proportion of the population responding
to a certain dose is plotted per dose--10-30 fold variation
w/in a population
• If Mortality is the response, the dose that is lethal to 50%
of the population LD50 can be generated from the curve
• Different toxicants can be compared--lowest dose is most
potent
 LD50 Comparison
Chemical LD50 (mg/kg)
Ethyl Alcohol 10,000
Sodium Chloride 4,000
Ferrous Sulfate 1,500
Morphine Sulfate 900
Strychnine Sulfate 150
Nicotine 1
Black Widow 0.55
Curare 0.50
Rattle Snake 0.24
Dioxin (TCDD) 0.001
Botulinum toxin 0.0001
 Exposure: Pathways
• Routes and Sites of Exposure
– Ingestion (Gastrointestinal Tract)
– Inhalation (Lungs)
– Dermal/Topical (Skin)
– Injection
• intravenous, intramuscular, intraperitoneal

• Typical Effectiveness of Route of Exposure

iv > inhale > ip > im > ingest > 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
 ADME:
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
 Absorption:
ability of a chemical to enter the blood
(blood is in equilibrium with tissues)
• Inhalation--readily absorb gases into the blood stream
via the alveoli. (Large alveolar surface, high blood
flow, and proximity of blood to alveolar air)
• Ingestion--absorption through GI tract stomach
(acids), small intestine (long contact time, large surface
area--villi; bases and transporters for others)
– 1st Pass Effect (liver can modify)
• Dermal--absorption through epidermis (stratum
corneum), then dermis; site and condition of skin
 Distribution:
the process in which a chemical agent
translocates throughout the body
• Blood carries the agent to and from its site of
action, storage depots, organs of
transformation, and organs of elimination
• Rate of distribution (rapid) dependent upon
– blood flow
– characteristics of toxicant (affinity for the tissue,
and the partition coefficient)
• Distribution may change over time
 Distribution:
Storage and Binding
• Storage in Adipose tissue--Very lipophylic
compounds (DDT) will store in fat. Rapid
mobilization of the fat (starvation) can rapidly
increase blood concentration
• Storage in Bone--Chemicals analogous to
Calcium--Fluoride, Lead, Strontium
• Binding to Plasma proteins--can displace
endogenous compounds. Only free is available for
adverse effects or excretion
 Target Organs: adverse effect is
dependent upon the concentration of active
compound at the target site for enough time
• Not all organs are affected equally
– greater susceptibility of the target organ
– higher concentration of active compound
• Liver--high blood flow, oxidative reactions
• Kidney--high blood flow, concentrates chemicals
• Lung--high blood flow, site of exposure
• Neurons--oxygen dependent, irreversible damage
• Myocardium--oxygen dependent
• Bone marrow, intestinal mucosa--rapid divide
 Target Sites:
Mechanisms of Action
• Adverse effects can occur at the level of the molecule, cell,
organ, or organism
• Molecularly, chemical can interact with
Proteins Lipids DNA
• Cellularly, chemical can
– interfere with receptor-ligand binding
– interfere with membrane function
– interfere with cellular energy production
– bind to biomolecules
– perturb homeostasis (Ca)
 Excretion:
Toxicants are eliminated from the body
by several routes
• Urinary excretion
– water soluble products are filtered out of the blood by the
kidney and excreted into the urine
• Exhalation
– Volatile compounds are exhaled by breathing
• Biliary Excretion via Fecal Excretion
– Compounds can be extracted by the liver and excreted into
the bile. The bile drains into the small intestine and is
eliminated in the feces.
• Milk Sweat Saliva
 Metabolism:
adverse effect depends on the concentration of
active compound at the target site over time
• The process by which the administered chemical (parent
compounds) are modified by the organism by enzymatic
reactions.
• 1o objective--make chemical agents more water soluble and
easier to excrete
– decrease lipid solubility --> decrease
amount at target
– increase ionization --> increase
excretion rate --> decrease toxicity
• Bioactivation--Biotransformation can result in the formation of
reactive metabolites
 Biotransformation (Metabolism)
• Can drastically
effect the rate of
clearance of Compound Without With
compounds Metabolism Metabolism
Ethanol 4 weeks 10mL/hr
• Can occur at any Phenobarbital 5 months 8hrs
point during the
compound’s DDT infinity Days to weeks
journey from
absorption to
excretion
 Biotransformation
• Key organs in biotransformation
– LIVER (high)
– Lung, Kidney, Intestine (medium)
– Others (low)
• Biotransformation Pathways
* Phase I--make the toxicant more water soluble
* Phase II--Links with a soluble endogenous agent
(conjugation)
 Individual Susceptibility
--there can be 10-30 fold difference in
response to a toxicant in a population
• Genetics-species, strain variation, interindividual
variations (yet still can extrapolate between
mammals--similar biological mechanisms)
• Gender (gasoline nephrotox in male mice only)
• Age--young (old too)
– underdeveloped excretory mechanisms
– underdeveloped biotransformation enzymes
– underdeveloped blood-brain barrier
 Individual Susceptibility
• Age--old
– changes in excretion and metabolism rates, body
fat
• Nutritional status
• Health conditions
• Previous or Concurrent Exposures
– additive --antagonistic
– synergistic
 Toxicology
• Exposure + Hazard = Risk
• All substances can be a poison
• Dose determines the response
• Pathway, Duration of Frequency of Exposure and Chemical
determine Dose
• Absorption, Distribution, Metabolism & Excretion
• The extent of the effect is dependent upon the concentration
of the active compound at its site of action over time
• Bioactivation: compounds to reactive metabolites
• Individual variation of the organism will affect ADME