INTRODUCTION TO TOXICOLOGY AND TOXICOLOGICAL CHEMISTRY

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.