MEDICAL TOXICOLOGY
Currently there are more than 100,000 chemical entities to which the
general human population could be exposed. A student of toxicology could
not be expected to be knowledgeable about the toxicity of even a small
fraction of these. However, in spite of the multitude of chemicals that
are potentially harmful, only a few have been adequately documented as
causative of serious health problems in humans.
Periodically, catastrophic accidents expose large numbers of people to
specific, known chemical agents. Examples of such accidents are given in
Table 1.1. In these instances the consequences consist of not only deaths
but also sublethal clinical effects. These incidents (and the publicity they
receive) have made the general pubUc justifiably concerned about insidious,
sublethal, delayed, and harmful effects of chemicals to which they are
exposed. In regard to sublethal illness from chemical agents, except for those
catastrophic accidents, adequate documentation regarding causation
is frequently lacking. Also, whereas some of the adverse drug or industrial
chemical reactions have been well documented, others appear in the literature
with inadequate documentation to support the role of the drug or
chemical as the causative agent. Verification of possible chemical-induced
illness presents a difficult problem to the clinical toxicologist (see Chapter
14).
In the disasters cited above, the chemical agents involved and the clinical
consequences are clearly delineated. In the emergency rooms of modern
hospitals as well as in the facilities of medical examiners the chemical
involved in most lethal cases is determined by direct analysis. However,
many deaths may be associated with the presence of specific chemical agents
while the cause of death may not be reported in a form that allows it to
be included in the statistical data on chemical-induced deaths. For example,
an automobile driver intoxicated with alcohol may die in a coUision, yet
such a death would not be recorded as due to alcohol since the presence
of the drug may be only coincidental. Similarly the death of a cigarette
smoker may be due to lung cancer, but to record such a death as being
due to cigarette smoke would be speculative. Conversely, a death that
occurs in a residential fire may show that the death was due to carbon
monoxide, but such a death would not be recorded as a chemical-induced
death. Statistics that specify their data sources and limit their conclusions
to the boundaries of the methodology used are the best sources of information
on chemical-induced illness and death.
Regardless of the problems associated with the accuracy and completeness
of data on chemical-induced morbidity and mortality, only through
the acquisition of statistically evaluated data on these subjects can the
magnitude of chemical-induced clinical problems be demonstrated.
Table 1.2 lists data showing that in 1970 and 1990 in the United States
there were, respectively, 5299 and 5803 chemical-induced accidental deaths,
or 2.6 and 2.3 per 100,000 population, and a similar number of chemicalinduced
suicidal deaths. Drugs and medicines were deemed to be responsible
for about 3 out of 4 accidental deaths.
There are many more incidents in which chemicals cause sublethal poisoning
rather than death. Table 1.3 indicates that in the United States in
1992 there were a total of 1.8 miUion inquiries regarding potential poisonings,
from which 705 or 0.04% resulted in deaths. Approximately 50,000 or
2.7% of the total inquiries resulted in moderate or major consequences.
Intentional exposure (that is, suicidal or abusive use) was involved in almost
11% of the exposures.
Table 1.4 summarizes a more detailed examination of the suspected
causative agents responsible for the 705 deaths. It indicates that a variety of
chemical agents were responsible for the observed lethality. Drugs were
responsible for 541 or 76.7% of the 705 deaths. Also, of all drug deaths,
391 or 72.3% were due to only 17 different drugs. Non-drugs were responsible
for 164 or 23.3% of the 705 deaths, and about half of these deaths were
due to only 10 chemical entities. Hence these data suggest that only a few
chemicals or drugs (27) were responsible for a very high percentage of
chemical-induced deaths.
Medical toxicology involves those disciplines that are concerned principally
with the chemical identification, chnical effects, diagnosis, and treatment
of chemical intoxication in human populations. In addition, medical
toxicology involves the acquisition of information and the estimation of
human risk associated with exposures of individuals as well as populations
to chemical entities. This latter function includes the production of statistics
on chemical-induced morbidity and mortality in humans.
FUNDAMENTAL PRINCIPLES IN TOXICOLOGY
From a fundamental and practical standpoint, the consequences of toxicologic
effects on humans can be divided into two categories. One includes
those consequences that are generally considered "irreversible," such as
mutagenicity, carcinogenicity, teratogenicity, and of course death. The second
category includes consequences that are "reversible," providing the
initial damage is not overwhelming. Among these effects are organ damage.
such as damage to liver, kidney, or skin, and functional damage, such as
respiratory depression, loss of consciousness, or convulsive effects.
Regardless of the category of any specific toxicologic effect, there are
at least four basic principles that are generally applicable to all chemicalinduced
biologic effects of toxicologic interest.
1. The chemical must get to the effector site in a biologic system in order
to produce a biologic effect. Although this may seem obvious, it is frequently
overlooked in discussions of toxicity. For example, alcohol can produce
harmful effects on humans, but a liter of whiskey in a bottle can have no
effect (other than a psychologic effect) if it is not consumed; a liter of
whiskey consumed in a short interval, however, contains enough alcohol
to be lethal to the average adult. This concept can be extended to such
scenarios as the asbestos in a building or the polychlorinated biphenyls in the soil at
a dump site. The physical-chemical properties, translocation,
absorption, biotransformation, distribution, and elimination of chemicals
are vital to an understanding of how an agent gets to a biological effector
site.
2. Not all chemical-induced biologic effects are harmful. All therapeutic
drug effects support this concept. This concept may be controversial in
examples such as the increase in the amount (induction) of certain liver
enzymes produced in experimental animals by many different chemicals
and which may be either harmful or beneficial.
3. The occurrence and intensity of chemical-induced biologic effects are
dose related; there is some dose below which no effect can be demonstrated,
and there is a dose above which the agent is lethal. This principle is stated
here because it is scientifically supportable. There is no conflict regarding
the lethality of all compounds; however, the low dose, no effect clause is
controversial since it is popular (but becoming less so) to describe those
chemicals that induce irreversible effects such as cancer as creating a finite
statistical risk, regardless of how small the dose may be.
4. Effects of chemicals on animals, if properly qualified, are applicable
to humans. In order for this concept to be generally acceptable it should
be recognized that there are quantitative differences in the effects of chemicals
both between and within species. Also, the converse of this principle
may be applicable in certain situations; that is, an effect may eventually be
found to appear in humans which did not occur in animals. Usually such
a finding is attributed either to differences between species in biotransformation
systems or in biologic receptor sites, or to simple failure to examine
for the effect in animal experiments. Consequently animal data must be
"qualified" for it to be appUcable to humans. Generally, whenever two
species have similar biotransformation systems and physiological functions,
those two species will respond similarly to chemicals.
