Toxicology
Introduction (Chapter 1)
The effects of poisonous substances on living systems has been of interest
since ancient times. Numerous ancient manuscripts document various
treatments to poisons. The first real study of the effects of poisons
was perhaps done by Catherine de Medici, who administered poisons to the
poor and meticulously recorded their effects. Paracelsus was one
of the first in the field to correlate dose with effect when he stated
that the only difference between a therapeutic effect and a poison is the
dose employed. Orfila is considered the father of forensic toxicology
for his work in developing methods of detecting poisons.
Toxicology embraces a broad range of science including, but not limited
to, mechanisms of action of toxic substances; physiologic sequelae to their
actions; treatment of exposure; risk of exposure to humans, other target
species, or the environment; transport, care, and handling of toxic substances;
and the regulation of potentially toxic substances.
Toxic substances may be classified by many different criteria.
For the purposes of this course, they will be classified by the following:
Drugs -- only specific "classic" toxicities will be covered in this
course.
Food Additives -- preservatives (nitrates, nitrites), dyes, and food
contaminants
Industrial Chemicals -- Solvents, Heavy Metals
Environmental Pollutants -- Pesticides, Smoke, Liquid and Solid Wastes
Natural Toxins -- Toxins (of plant origin) and Venoms (of animal origin)
Household Poisons -- Cleaning Solutions, Antifreeze
(NOTE that many times these areas may overlap, for instance a worker
in a pesticide plant runs the risk of exposure to what may be more often
considered an environemental pollutant in an industrial setting)
Related to the above classifications are the types of exposure. A
broad categorisation of the means of exposure are
Intentional Ingestion -- which may be conscious (as in suicide, tobacco
use, drinking) or unconscious (murder, food contaminants -- the food is
intentionally ingested but the diner has no knowledge of the murderous
intent of their spouse or the negligence of the cook!)
Occupational Exposure -- These exposures are usually chronic, although
they may be acute with spills or fires. Exposures of this type are
also usually inhalational or contact in nature, rather than ingested.
Environmental Exposure -- This occurs when the toxicant is present in
the work or living area. It may be chronic (as in the Love Canal
incident) or acute (spills or fires, as in the Bhopal incident).
Accidental Exposure -- While very few exposures to poisons are intentional
(the patient meant to spill Ambush(R) all over himself -- this excuse is
not often heard in the clinic), this refers primarily to acute ingestion
often seen with children or the elderly (who may also show chronic accidental
exposure) or in occupational accidents. Many of the above categories
may be described as accidental in nature -- for instance accidental occupational
exposure or accidental environemental exposure.
Dose-Response -- Important in the study of toxicology is the concept
of dose-response. The specific result of a chemical's action may
be either/or (all-or-none -- also sometimes referred to as a quantal response)
such as death or it may be graded (it produced a 20%, 50%, or 75% change
in a particular biological parameter).
Three assumptions are made in using dose-response data
1) the response is proportional to the concentration at the target
site of action
2) the concentration at the target site is related to the dose
3) the response is causally related to the compound administered.
Dose-Response curves may be constructed to demonstrate two different types
of data. A specific biological response may be plotted against varying
doses, showing that an increase in dose produces a greater response (i.e.
doubling the dose caused a 20% increase in blood pressure while trebling
the dose caused a 50% increase in blood pressure). However, the specific
biological effect may also be defined (the criteria is set at a 50% increase
in blood pressure -- if that specific change is not acheived then that
subject is not counted) and the range of doses plotted against the relative
percentage of those subjects exhibiting the defined criterion. For
example a standard dose causes 20% of patients' blood pressure to increase
by 50% and doubling the dose will cause 70% of the patients blood pressure
to increase by 50%. The former method is more often used in evaluation
a single drug in pharmacology while the latter is used more often in estimating
the effect of a toxicant on a population of people in toxicology.
Another method of analysing this data is often used in toxicology.
The median effect (i.e. 50% lethality for an LD50 study)
is assigned the number 5. One PROBIT unit below and above this (that
is 4 and 6) represents one standard deviation (consequently 3 and 7 would
represent 2 standard deviations from the mean and so on). This PROBIT
ANALYSIS was first made prominent by Litchfield and Wilcoxon in their paper
on determining LD50s and is illustrated below.
One advantage of using probit analysis, is that it allows statistical
intepretation of different effects of the same drug (showing the different
doses required to produce effective, toxic, and lethal effects of a compound)
or comparisons of the LD50 of different drugs. As may
be seen by the figure below, compounds A and B both have the same LD50,
however compound B is lethal to more animals at a lower dose, is therefore
more potent, and consequently classified as a more toxic compound.
This concept of LD50 is very important in toxicology and
is used as a standard in assessing potential toxicity. NOTE, however,
that when referring to a specific LD50, the dose is specific
for a particular compound by a specific route in a specific species.
The same compound may have a different LD50 in another species
or by a different route (factors that affect absorption, physiological
differences, et c.).
These concepts of dose:response are often used to quantify the relative
levels of safety when either purposely ingesting a drug or when the risk
of exposure exists. Two methods of quantifying relative safety include
Margin of Safety, defined mathematically as LD1 / LD99
(those doses at which 1% and 99% of the population respectively exhibit
lethality). Note that the smaller the number generated by this calculation,
the safer the compound. As the margin of safety approaches one (1),
the greater the toxicity of the compound, as calculated by this definition.
Therapeutic Index, defined as the LD50 / ED50.
Obviously the larger the number (the wider the dose between efficacy and
lethality) the safer the compound.
Often, exposure to toxic compounds will involve more that one specifc compound.
Many times these toxicants will have effects that may be additive or subtractive.
An additive effect is exerted when two compounds will produce an effect
that is roughly equal to the effect of one plus the effect of the other,
or in simpler terms toxicant A has a toxic effect of 2 and toxicant B also
has a toxic effect of 2. When combined they produce a toxic effect
of 4, or 2 + 2 = 4.
A synergistic effect occurs when the overall effect is greater than
that which would be expected by the simple additive effect, or 2 + 2 =
6.
Potentiation occurs when one of the compounds normally exhibits no toxicity
(0). However it may increase the toxicity of a second compound so
that 0 + 2 = 3.
Compounds may also be antagonistic in their effects, such that they
diminish the toxicity of each other or 2 + 2 = 3.
In most cases exposure to a toxicant at a low enough dose will produce
no effect (there are some that would argue that there is no level at which
something doesn't occur in response to a compound). The dose below
which no measurable response or effect is noticeable is termed the THRESHOLD
dose. The range of doses below this threshold is called the NO OBSERVED
ADVERSE EFFECT LEVEL. This concept of NOAEL is important in analysing
the risk-benefits of exposure and is often used in determining the acceptable
level to which one may be exposed to a toxicant. The Acceptable Daily
Intake (ADI) for a specific toxicant by a specific route is used to set
the allowed exposure workers may be subjected to in employment situations.
It is defined mathematically
ADI = NOAEL (mg/Kg/day) / 100
or the ADI is set at 1/100 of the dose that produces no effect. This concept
is carried a step further in the setting of a Threshold Limit Value (TLV)
or Maximum Exposure Limit (MEL) that is allowable in a specific workday.
That is the TLV may represent the ADI for an eight-hour work day or
TLV = NOAEL (mg/Kg/8 hr) / 100.
Go to Next Lecture (Disposition of Toxicants)