BASIC PRINCIPLES OF TOXICOLOGY
DEFINITIONS:
Toxicology: The
study of the adverse effects of a toxicant on living organisms.
Toxicology is an applied science that incorporates
biology, chemistry, physiology, pathology, physics, statistics, and sometimes immunology
or ecology to help solve problems in forensic medicine, clinical treatments,
pharmacy and pharmacology, public health, industrial hygiene, veterinary
science, agriculture, and more, as well as giving basic insight into how an
organism functions.
Toxicologist: A
living organism who studies the nature of these adverse effects at the
molecular, celllular, organ, organ system, organism, or even community level by
understanding what the agent does to the system and what the system does to the
agent.
Toxicant (Poison):
Any agent capable of producing a deleterious response in a biological system.
“All substances are
poisons; there is none that is not a poison.
The right dose differentiates a poison and a remedy.” Paracelsus (1493-1541)
The shape, size, and solubility of the toxicant will
determine how easily it enters the body, how it will distribute within the
body, and the rate of its excretion from the body.
Dose: The amount of
chemical entering the body.
This
is usually given as milligrams of chemical per kilogram of body weight (mg/kg)
so that dose can be compared across specimens.
How much, how often (duration and frequency), and how the dose is
administered are all important parameters.
Adverse Effect
(Response): Any change from an organism’s normal state
that is irreversible at least for a period of time. Producing an adverse effect
depends on the concentration of the active compound at the target site.
A
description of the dose and the conditions of exposure must accompany a description
of the adverse effect due to a chemical.
An effect or response can be graded (variations of the degree of damage)
or quantal (all or none; i.e., mortality or tumor development).
Living Organism: The species,
strain, individual genetic variation, gender, age, health conditions,
nutrition, and previous and concurrent exposures can affect how an organism
responds to a chemical exposure.
Risk Assessment: Quantitative estimate on the potential
effects of various types of chemical exposure on human health. RISK= HAZARD + EXPOSURE
AXIOMS OF TOXICOLOGY:
¨
There is essential uniformity in the
biochemistry in similar species--among biological mechanisms in mammals. This allows for extrapolation from animal
data for predictions in humans.
¨
Any substance can provoke a dysfunction or
injury at some degree of exposure—the dose makes the poison.
Attenuation of injury can be
achieved by dilution; i.e., lowering the dose of the agent. Complications can occur when there is
exposure to more than one agent, even at non-toxic doses.
¨
There is a dosage or exposure level that has no
effect on the health of animals—as measured by methods which have a finite
sensitivity to measure dysfunction or injury.
¨
Toxicological data from animal experiments can
be used to assess the degree of exposure or dosage that will not adversely
affect human health. However, potential
or real differences in animals or humans (as well as variations in species)
each mandate that judgmental factors be applied when extrapolating form animal
threshold doses in order to insure an adequate margin of safety for humans.
¨
The single most important factor that determines
the potential harmfulness of a chemical is the relationship between the
concentration of the chemical at its site of action and the effect that is
produced.
The Dose-Response Relationship is of
paramount importance in toxicology.
Dose
determines the biological response.
Dose-Response curve: The relationship between the dose of a
chemical (dependent variable) and the response
produced (independent variable) follows a predictable pattern. As the dose of a toxicant increases, so does
the response, either in terms of the proportion of the population responding or
in terms of the severity of the graded responses. For most toxicants, at very low amounts,
there will be no detectable effect of the chemical (NOAEL: no observed adverse
effect level). In the midrange of doses,
the amount of damage will increase as the dose increases (the linear 16-84% of
the curve). Larger amounts of chemical
will cause increasingly more severe biological responses until a maximum level
of damage is reached. Additional toxic
effects may also appear along with increased doses, depicting both dose
response and dose effect relationships.
 |
0-1= no adverse effect level
2-3 = linear portion of the curve
4 = maximal response or effect
Quantal responses can be treated as a gradient when data
from a population is used. The
cumulative proportion of the population responding to a certain dose is plotted
for each dose. A similar S-shaped curve
is produced since there can be a 10-30 fold variation within a population. If one uses mortality as the response, the
dose that is lethal to 50% of the population (LD50) can be
calculated from the generated curve. Different toxicants can be compared, and
the one with the lowest LD50 is the most potent. There are differences in between exposure
routes and animals.
|
Chemical
|
LD50 (mg/kg)
|
|
Chemical
|
LD50
(with route and animal)
|
|
Ethyl Alcohol
|
10,000
|
Caffeine
|
620mg/kg—oral
mouse
192mg/kg—oral
rat
105mg/kg—iv
rat
68mg/kg—iv mouse
|
|
|
Sodium Chloride
|
4,000
|
|||
|
Ferrous Sulfate
|
1,500
|
Chlorine
(LC 50)
|
293ppm/1hr—rat
137ppm/1hr—mouse
|
|
|
Morphine Sulfate
|
900
|
THC
(from
marijuana)
|
175mg/kg—iv
mouse
155mg/kg—iv
rabbit
100mg/kg—iv
dog
|
|
|
Strychnine Sulfate
|
150
|
|||
|
Nicotine
|
1
|
Mercury
(I) Chloride
|
210
mg/kg—oral rat
8 mg/kg—iv mouse
|
|
|
Black Widow
|
0.55
|
Mercury
(II) Chloride
|
37 mg/kg—oral rat
10 mg/kg—oral mouse
|
|
|
Curare
|
0.50
|
Arsenic
acid (V oxidation state)
|
48 mg/kg—oral rat
|
|
|
Rattle Snake
|
0.24
|
Arsenic
trioxide (III oxidation state)
|
20 mg/kg—oral rat
|
|
|
Dioxin (TCDD)
|
0.001
|
Dimethylarsenic
acid
(methylated
arsenic form used
as
a cotton defoliant)
|
700 mg/kg—oral rat
|
|
|
Botulinum toxin
|
0.0001
|
EXPOSURE:
An
organism must be exposed to an agent before there is a risk. The physical properties of the chemical and
the concentration of the chemical in the environment are important in determining
the extent of the exposure.
Toxic
effects in a biological system are not produced unless the agent or its
metabolic breakdown (biotransformation) products reach appropriate target sites
in the body at a concentration and for a length of time sufficient to cause
toxicity. We need to define, HOW MUCH, HOW LONG, and HOW OFTEN.
Doses of Chemicals:
Dose = Amount / Animal Mass i.e. mg/kg of animal
body weight
A given dose can be compared across animal
species
Example: Need to administer 100mg/kg dose of the drug
to a mouse, a rat, and a human.
20g mouse would get 2mg of drug
200g rat would get 20mg of drug
70kg human would get 7g of the drug
Duration of
Exposure:
Acute: < 24hr usually
single exposure
Subacute 1 month repeated
doses
Subchronic 1-3 months repeated doses
Chronic >3months repeated
doses
Toxic Effects: Acute vs Chronic
Overtime, the amount of chemical in the
body can build up, it can redistribute, or it can overwhelm repair
mechanisms.
Toxicologists are most interested in what
is the most common scenario, chronic exposure to low doses.
Single Dose Repeated
Dose
Benzene CNS Depression Leukemia
Frequency of
Exposure:
The frequency of the exposure affects the
concentration at the target site—can build up to a steady level--why some
medications are taken three times a day vs. once a day to give the wanted
effect.
Route and Site of
Exposure:
Ingestion (gastrointestinal tract)
Inhalation (lungs)
Dermal / topical (skin)
Parenteral (intravenous--iv,
intramuscular—im, intraperitoneal—ip)
Typical Effectiveness of Route of Exposure
iv > inhalation
> ip > im > ingestion > topical
ABSORPTION,
DISTRIBUTION, METABOLISM, AND EXCRETION OF TOXICANTS (ADME):
The
toxicant may have to pass many barriers to get to its site of action
Absorption:
Absorption--the
ability of a chemical agent to enter the blood.
Similar
blood levels are more likely to give similar effects than similar administered
doses. Blood is in equilibrium with the
other tissues and target sites.
Intravenous No limiting factors in absorption (100%
bioavailable)
Inhalation Must penetrate alveolar sacs of
lungs but then into capillary bed
Ingestion Requires absorption through GI tract and is subject to
1st pass effect
Intraperitoneal Like ingestion (still 1st pass
effect) but does not require absorption through the GI tract
Dermal/Topical Requires absorption through the skin
Distribution:
Distribution—the
process in which a chemical agent translocates throughout the body. The blood carries the agent to and from its
site of action, storage depots, organs of biotransformation, and organs of
elimination. The rate of distribution is
usually rapid, and is determined primarily by blood flow and the chemical
characteristics of the toxicant (its affinity for the tissue and the partition
coefficient). The distribution of a
chemical may change over time.
Storage—DDT in Fatty tissues
Lead and Fluoride in Bone
Metabolism:
Metabolism (biotransformation)—the process by which
administered chemicals (parent compounds) are modified by the organism, usually
via enzymes. The primary objective of
metabolism is to make chemical agents more water soluble and easier to excrete
by
Decreasing lipid solubility Ã
Decreased amount that reaches target
Increasing ionization Ã
Increased rate of excretion à Decrease toxicity
In
some situations, biotransformation results in the formation of reactive
metabolites—Bioactivation.
Whether
it is the parent compound or the metabolite, it is the active compound that
does the damage.
Excretion:
Toxicants
are eliminated from the body by several routes.
Urinary excretion
Water soluble
products are filtered out of the blood and excreted into the urine.
Exhalation
Volatile
compounds are exhaled through breathing
Biliary Excretion via Fecal
Excretion
Compounds can be
extracted by the liver, biotransformed, and excreted into the bile. The bile
drains into the
small intestine where the eliminated compound can be excreted into the feces.
Fecal excretion also
rids the body of non-absorbed compounds which pass through the GI tract.
MORE ON
METABOLISM:
Biotransformation
can occur at any point during the compound’s trek from absorption to excretion.
Biotransformation
can drastically effect the rate of clearance of compounds
Without
Biotransformation With
Biotransformation
Ethanol 4 weeks 10mL/hr
Phenobarbital 5 months 8hr
DDT infinity days
to weeks
Key organs of
Biotransformation:
LIVER (High)
Lung, Kidney, Intestine (Medium)
Others (Low)
Biotransformation
Pathways
Phase I enzymes: Makes the toxicant more soluble
Phase II Enzymes: Links with a soluble agent (conjugation)
Individual
Susceptibility:
Individual
variation of the organism will affect the absorption, distribution, metabolism,
and excretion of the toxicant, and there fore the effect of the toxicant.
There
can be a 10-30 fold difference in response to a toxicant in a population due
to:
Genetics—species,
strain variations, inter-individual variations
Gender
Age
(young and old)
Nutritional
status
Health
conditions
Previous
or concurrent exposure to other substances
No comments