INTRODUCTION TO TOXICOLOGY AND
TOXICOLOGICAL CHEMISTRY
Ultimately, most pollutants and hazardous substances are of concern because of
their toxic effects. To understand toxicological chemistry, it is essential to have some
understanding of biochemistry, the science that deals with chemical processes and
materials in living systems. Biochemistry is summarized in Chapter 10.
Toxicology
A poison, or toxicant, is a substance that is harmful to living organisms because
of its detrimental effects on tissues, organs, or biological processes. Toxicology is
the science of poisons. Toxicants to which subjects are exposed in the environment
or occupationally may be in several different physical forms, such as vapors or dusts
that are inhaled, liquids that can be absorbed through the skin, or solids ingested
orally. A substance with which the toxicant may be associated (the solvent in which
it is dissolved or the solid medium in which it is dispersed) is called the matrix. The
matrix may have a strong effect upon the toxicity of the toxicant.
There are numerous variables related to the ways in which organisms are
exposed to toxic substances. One of the most crucial of these, dose, is discussed in
Section 23.2. Another important factor is the toxicant concentration, which may
range from the pure substance (100%) down to a very dilute solution of a highly
potent poison. Both the duration of exposure per incident and the frequency of
exposure are important. The rate of exposure and the total time period over which
the organism is exposed are both important situational variables. The exposure site
and route also affect toxicity.
It is possible to classify exposures on the basis of four general categories. Acute
local exposure occurs at a specific location over a time period of a few seconds to a
few hours and may affect the exposure site, particularly the skin, eyes, or mucous
membranes. The same parts of the body can be affected by chronic local exposure, for which the time span may be as long as several years. Acute systemic exposure is
a brief exposure or exposure to a single dose and occurs with toxicants that can enter
the body and affect organs that are remote from the entry site. Chronic systemic
exposure differs in that the exposure occurs over a prolonged time period.
In discussing exposure sites for toxicants it is useful to consider the major routes
and sites of exposure, distribution, and elimination of toxicants in the body, as
shown in Figure 23.1. The major routes of accidental or intentional exposure to
toxicants in humans and other animals are the skin (percutaneous route), the lungs
(inhalation, respiration, pulmonary route), and the mouth (oral route). The
pulmonary system is most likely to take in toxic gases or very fine, respirable solid
or liquid particles. In other than a respirable form, a solid usually enters the body
orally. Absorption through the skin is most likely for liquids, solutes in solution, and
semisolids, such as sludges.
The defensive barriers that a toxicant may encounter vary with the route of
exposure. An interesting historical example of the importance of the route of
exposure to toxicants is provided by cancer caused by contact of coal tar with skin.
The permeability of skin is inversely proportional to the thickness of the skin’s
stratum corneum layer, which varies by location on the body in the following
order: soles and palms > abdomen, back, legs, arms > genital (perineal) area.
Evidence of the susceptibility of the genital area to absorption of toxic substances is
to be found in accounts of the high incidence of cancer of the scrotum among
chimney sweeps in London described by Sir Percival Pott, Surgeon General of
Britain during the reign of King George III. The cancer-causing agent was coal tar condensed in chimneys. This material was more readily absorbed through the skin in
the genital areas than elsewhere, leading to a high incidence of scrotal cancer. (The
chimney sweeps’ conditions were aggravated by their lack of appreciation of basic
hygienic practices, such as bathing and regular changes of underclothing.)
Organisms can serve as indicators of various kinds of pollutants, thus serving as
biomonitors. For example, higher plants, fungi, lichens, and mosses can be
important biomonitors for heavy-metal pollutants in the environment.
Synergism, Potentiation, and Antagonism
The biological effects of two or more toxic substances can be different in kind
and degree from those of one of the substances alone. Chemical interaction between
substances may affect their toxicities. Both substances may act upon the same
physiologic function, or two substances may compete for binding to the same
receptor (molecule or other entity acted upon by a toxicant). When both substances
have the same physiologic function, their effects may be simply additive or they
may be synergistic (the total effect is greater than the sum of the effects of each
separately). Potentiation occurs when an inactive substance enhances the action of
an active one, and antagonism when an active substance decreases the effect of
another active one.
DOSE-RESPONSE RELATIONSHIPS
Toxicants have widely varying effects upon organisms. Quantitatively, these
variations include minimum levels at which the onset of an effect is observed, the
sensitivity of the organism to small increments of toxicant, and levels at which the
ultimate effect (particularly death) occurs in most exposed organisms. Some
essential substances, such as nutrient minerals, have optimum ranges above and
below which detrimental effects are observed (see Section 23.5 and Figure 23.4).
Factors such as those just outlined are taken into account by the dose-response
relationship, which is one of the key concepts of toxicology. Dose is the amount,
usually per unit body mass, of a toxicant to which an organism is exposed. Response
is the effect upon an organism resulting from exposure to a toxicant. To define a
dose-response relationship, it is necessary to specify a particular response, such as
death of the organism, as well as the conditions under which the response is
obtained, such as the length of time from administration of the dose. Consider a
specific response for a population of the same kinds of organisms. At relatively low
doses, none of the organisms exhibits the response (for example, all live), whereas at
higher doses all of the organisms exhibit the response (for example, all die). In
between, there is a range of doses over which some of the organisms respond in the
specified manner and others do not, thereby defining a dose-response curve. Doseresponse
relationships differ among different kinds and strains of organisms, types of
tissues, and populations of cells.
Figure 23.2 shows a generalized dose-response curve. The dose corresponding to
the mid-point (inflection point) of the resulting S-shaped curve is the statistical estimate
of the dose that would kill 50 % of the subjects. It is designated as LD50 and is
commonly used to express toxicities.
RELATIVE TOXICITIES
Table 23.1 illustrates standard toxicity ratings that are used to describe estimated
toxicities of various substances to humans. In terms of fatal doses to an adult
human of average size, a “taste” of a supertoxic substance (just a few drops or less)
is fatal. A teaspoonful of a very toxic substance could have the same effect.
However, as much as a quart of a slightly toxic substance might be required to kill
an adult human.
When there is a substantial difference between LD50 values of two different
substances, the one with the lower value is said to be the more potent. Such a
comparison must assume that the dose-response curves for the two substances being
compared have similar slopes.
Nonlethal Effects
So far, toxicities have been described primarily in terms of the ultimate effect—
death of organisms, or lethality. This is obviously an irreversible consequence of
exposure. In many, and perhaps most, cases, sublethal and reversible effects are of
greater importance. The margin of safety (Figure 23.3) is used in connection with
drugs to express the difference between the dose that gives a desired therapeutic
effect and a harmful, potentially lethal, effect. This term applies to other substances,
such as pesticides, for which it is desirable to have a large difference between the
dose that kills a target species and that which harms a desirable species.
23.4 REVERSIBILITY AND SENSITIVITY
Sublethal doses of most toxic substances are eventually eliminated from an
organism’s system. If there is no lasting effect from the exposure, it is said to be
reversible. In cases where the effect is permanent, it is termed irreversible.
Irreversible effects of exposure remain after the toxic substance is eliminated from the organism. Figure 23.3 illustrates these two kinds of effects. For various chemicals
and different subjects, toxic effects can range from the totally reversible to the
totally irreversible.
Hypersensitivity and Hyposensitivity
Some subjects are very sensitive to a particular poison, whereas others are very
resistant to the same substance. These two kinds of responses illustrate hypersensitivity
and hyposensitivity, respectively; subjects in the mid-range of the doseresponse
curve are termed normals. These variations in response tend to complicate
toxicology in that there is no specific dose guaranteed to yield a particular response,
even in a homogeneous population.
In some cases, hypersensitivity is an induced response to exposure to a
substance. After one or more doses of a chemical, a subject may develop an extreme
reaction to it. This occurs with penicillin, for example, in cases where people
develop such a severe allergic response to the antibiotic that exposure is fatal if
countermeasures are not taken.
