SAAM-6636-001: Industrial Toxicology – Winter 2019

Class 3: Mechanisms of Toxicology

1. Classification of Toxic Agents

 Toxic agents are classified in a variety of ways, depending on the interests and needs of the
classifier.
 In this course, toxic agents are discussed in terms of their target organs (liver, kidney, etc.), use
(pesticide, solvent, food additive, etc.), source (animal and plant toxins), effects (cancer, mutation,
liver injury, etc.), and source (industry, agriculture, construction, etc.).
 The term toxin generally refers to toxic substances that are produced by biological systems such
as plants, animals, fungi, or bacteria.
 The term toxicant is used in speaking of toxic substances that are produced by or are a by-product
of anthropogenic (human-made) activities.
 Some toxicants can be produced by both natural and anthropogenic activities.
For example, Arsenic, a toxic metalloid, may occur as a natural contaminant of groundwater or
may contaminate groundwater secondary to industrial activities.
 Toxic agents may also be classified in terms of their:
 Physical state (gas, dust, liquid)
  General chemical structure (aromatic amine, halogenated hydrocarbon, etc.)
 Poisoning potential (extremely toxic, very toxic, slightly toxic, etc.).
 Biochemical mechanisms of action (e.g., alkylating agent, cholinesterase inhibitor,
methemoglobin producer)
 More general classifications such as air pollutants, occupation-related agents, and acute and
chronic poisons which can provide a useful focus on a specific problem.

2. Spectrum of Undesired Effects

2.1. Allergic Reactions
 Chemical allergy is an immunologically mediated adverse reaction to a chemical resulting from
previous sensitization to that chemical or to a structurally similar one.
 Allergic reactions are dose-related.
 The manifestations of allergy are numerous.
 They may involve various organ systems and range in severity from minor skin disturbance to
fatal anaphylactic shock.
2.2. Idiosyncratic Reactions
 Chemical idiosyncrasy refers to a genetically determined abnormal reactivity to a chemical.
 The response observed is usually qualitatively like that observed in all individuals but may take
the form of extreme sensitivity to low doses or extreme insensitivity to high doses of the
chemical.
2.3. Immediate versus Delayed Toxicity
 Immediate toxic effects can be defined as those that occur or develop rapidly after a single
administration of a substance, whereas delayed toxic effects are those that occur after the lapse
of some time.
 While the effect of ethanol on subjects is immediate, carcinogenic effects of chemicals (including
ethanol) usually have a long latency period, often 20 to 30 years after the initial exposure, before
tumors are observed in humans.
2.4. Reversible versus Irreversible Toxic Effects
 Some toxic effects of chemicals are reversible, and others are irreversible.
 If a chemical produces pathological injury to a tissue, the ability of that tissue to regenerate
largely determines whether the effect is reversible or irreversible.
 Thus, for a tissue such as liver, which has a high ability to regenerate, most injuries are reversible
(aside from cirrhosis), whereas carcinogenic and teratogenic effects of chemicals, once they
occur, are usually considered irreversible toxic effects.
 2.5. Local versus Systemic Toxicity
 Local effects are those that occur at the site of first contact between the biological system and
the toxicant.
Such effects are produced for example by the ingestion of caustic substances or the inhalation of
irritant materials.
Chlorine gas reacts with lung tissue at the site of contact, causing damage and swelling of the
tissue, with possibly fatal consequences, even though very little of the chemical is absorbed into
the bloodstream.
 Systemic effects require absorption and distribution of a toxicant from its entry point to a
distant site, at which deleterious effects are produced.
Most substances except highly reactive materials produce systemic effects.
For some materials, both effects can be demonstrated. For example, tetraethyl lead produces
effects on skin at the site of absorption and then is transported systemically to produce its typical
effects on the central nervous system (CNS) and other organs.
2.6. Interaction of Chemicals
 Because of the large number of different chemicals an individual may be in contact with at any
given time (workplace, drugs, diet, hobbies, etc.), it is necessary, in assessing the spectrum of
responses, to consider how different chemicals may interact with each other.
 The response of the organism to combinations of toxicants may be increased or decreased because
of toxicological responses at the site of action.
 An additive effect occurs when the combined effect of two chemicals is equal to the sum of the
effects of each agent given alone (example: 2 + 3 = 5), which is the effect most commonly
observed.
 A synergistic effect occurs when the combined effects of two chemicals are much greater than
the sum of the effects of each agent given alone (example: 2 + 2 = 10).
For example, both carbon tetrachloride and ethanol are hepatotoxic compounds, but together they
produce much more liver injury than the mathematical sum of their individual effects on liver at a
given dose would suggest.
 Potentiation occurs when one substance does not have a toxic effect on a certain organ or system
but when added to another chemical makes that chemical much more toxic (example: 0 + 2 = 10).
Isopropanol, for example, is not hepatotoxic, but when it is administered in addition to carbon
tetrachloride, the hepatotoxicity of carbon tetrachloride is much greater than when it is given
alone.
 Antagonism occurs when two chemicals administered together interfere with each other’s actions
or one interferes with the action of the other (example: 4 + 6 = 8; 4 + (−4) = 0; 4 + 0 = 1).
Antagonistic effects of chemicals are often very desirable in toxicology and are the basis of many
antidotes.
There are four major types of antagonism:
 Functional antagonism occurs when two chemicals counterbalance each other by producing
opposite effects on the same physiologic function.
For example, many chemicals, at toxic dose levels, produce convulsions, and the convulsions
often can be controlled by giving anticonvulsants.
 Chemical antagonism or inactivation is simply a chemical reaction between two compounds
that produces a less toxic product.
The use of antitoxins in the treatment of various animal toxins is an example of chemical
antagonism.
 Dispositional antagonism occurs when the disposition (that is, the absorption, distribution,
biotransformation, or excretion of a chemical) is altered so that the concentration and/or
duration of the chemical at the target organ are diminished.
For example, chelating agents.
 Receptor antagonism occurs when two chemicals that bind to the same receptor produce less
of an effect when given together than the addition of their separate effects (example: 4 + 6 = 8)
or when one chemical antagonizes the effect of the second chemical (example: 0 + 4 = 1).
Receptor antagonists are often termed blockers.
 2.7. Tolerance
Tolerance is a state of decreased responsiveness to a toxic effect of a chemical resulting from
prior exposure to that chemical or to a structurally related chemical.
Two major mechanisms are responsible for tolerance:
 The first is due to a decreased amount of toxicant reaching the site where the toxic effect is
produced (dispositional tolerance), and the other is due to a reduced responsiveness of a tissue to
the chemical.

3. Characteristics of Exposure
 Toxic effects in a biological system are not produced by a chemical agent unless that agent or its
metabolic breakdown (biotransformation) products reach appropriate sites in the body at a
concentration and for enough time to produce a toxic manifestation.
 Thus, a toxic response is dependent on the chemical and physical properties of the agent, the
exposure situation, how the agent is metabolized by the system, the concentration of the active
form at the target site(s), and the susceptibility of the biological system or subject.
 Major factors that influence toxicity as it relates to the exposure situation for a specific chemical
are the route, the duration, and the frequency of exposure.
3.1. Routes and Sites of Exposure
  Ingestion
 Inhalation
 Absorption through the skin (or dermal)
 Topical, percutaneous, and other parenteral routes.
 Toxic agents generally produce the greatest effect and the most rapid response when given
directly into the bloodstream (the intravenous route).
 The “vehicle” (the material in which the chemical is dissolved) and other formulation factors can
markedly alter absorption after ingestion, inhalation, or topical exposure.
 Occupational exposure to toxic agents most frequently results from breathing contaminated air
(inhalation) and/or direct and prolonged contact of the skin with the substance (dermal
exposure).
3.2. Duration and Frequency of Exposure
 Toxicologists usually divide the exposure of experimental animals to chemicals into four
categories: acute, subacute, subchronic, and chronic.
 Acute exposure is defined as exposure to a chemical for less than 24 hours.
Whereas acute exposure usually refers to a single administration, repeated exposures may occur
within a 24-hours period.
 Acute exposure by inhalation refers to continuous exposure for less than 24 hours, most
frequently for 4 hours.
 Repeated exposure is divided into three categories: subacute, subchronic, and chronic.
 Subacute exposure refers to repeated exposure to a chemical for 1 month or less.
 Subchronic exposure for 1 to 3 months
 Chronic exposure for more than 3 months.
These three categories of repeated exposure can be by any route.
 For many chemicals, the toxic effects that follow a single exposure are quite different from those
produced by repeated exposure.
 Acute exposure to chemicals that are rapidly absorbed is likely to produce immediate toxic
effects but also can produce delayed toxicity that may or may not be similar to the toxic effects of
chronic exposure.
 Conversely, chronic exposure to a toxic chemical may produce some immediate (acute) effects
after each administration in addition to the long-term, low-level, or chronic effects of the toxic
substance.
 The other time-related factor that is important in the temporal characterization of repeated
exposures is the frequency of exposure.
 The relationship between elimination rate and frequency of exposure is shown in the figure
below.
 A chemical that produces severe effects with a single dose may have no effect if the same total
dose is given in several intervals.
For the chemical depicted by line B, in which the half-life for elimination (time necessary for
50% of the chemical to be removed from the bloodstream) is approximately equal to the dosing
frequency, a theoretical toxic concentration (shown conceptually as two Concentration Units in
the figure) is not reached until the fourth dose, whereas that concentration is reached with only
two doses for chemical A, which has an elimination rate much slower than the dosing interval
(time between each repeated dose).
 Conversely, for chemical C, where the elimination time is much shorter than the dosing interval, a
toxic concentration at the site of toxic effect will never be reached regardless of how many doses
are administered.
 Other considerations will be discussed in future classes.