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3. List the routes of entry of toxicants into the body and routes of their
elimination into the environment.
4. What factors determine the toxicokinetic parameters of a substance?
5. Which substances are classified as membrane toxicants? Give exam-
ples.
6. What is the structure of biological membranes? What are the main
mechanisms of transport of toxic substances across biological membranes?
7. What quantitative parameters characterize the processes of toxicoki-
netics? Explain the use of these parameters in toxicology.
8. What is meant by the bioavailability of a substance?
9. Describe the main phases of biotransformation of toxicants.
10. Describe the molecular mechanisms of xenobiotic metabolism in
humans.
11. What is meant by lethal synthesis? Give examples.
12. Which groups of enzymes control the metabolic processes of Phase
I and II biotransformation?
13. What is the role of cytochrome P-450 in the cell?
14. Give the main chemical reactions involved in the biotransformation
of procarcinogens.
15. What is genetic toxicology (toxicogenetics)?
16. What is the preventive focus of toxicogenetic research?
17. What approaches are used for the assessment of individual bio-
chemical phenotypes of metabolism?
18. Which group of compounds undergo biotransformation under
the action of the enzyme N-acetyltransferase?
19. What is the relevance of biochemical phenotypes in ensuring indi-
vidual chemical safety?
20. Which reactions belong to Phase I processes of biotransformation?
21. Which reactions belong to Phase II processes of biotransformation?
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4 . P O I S O N I N G A N D I T S T R E A T M E N T
4 . 1 . S t a g e s o f p o i s o n i n g
Poisoning or intoxication is considered as a chemical injury, resulting
from the entry of a toxic dose of a xenobiotic into the body. Characteristics
of interaction of a toxic substance with an organism depends on many factors,
related to the toxic agent itself and to the affected organism in a particular
condition. The latter is categorized into internal factors, inherent in the affected organism; and external factors, influencing biological response to
a chemical injury. The mechanisms and characteristics of the course of poisoning depend on the chemical structure of toxic substances, their doses, and
the conditions of interaction with the body. Depending on the duration of
interaction of a chemical substance with an organism, intoxication can be
classified as acute or chronic. The process of intoxication can be divided into
four main stages (Fig. 4.1): period of exposure or contact; latent period; peak
of intoxication; and recovery period.
Fig. 4.1. Stages of intoxication
72
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Nevertheless, an additional stage of the development of complications
is sometimes referred to. The severity and duration of each of the stages depend on the type and properties of a given toxicant, its dose and the conditions of its interaction with the body.
Depending on the position of pathological process, intoxication can be
local or systemic. Local intoxication involves the development of pathological process directly at the site of contact of a toxicant. This may be injury to
the eyes, skin, respiratory tract and lungs or various regions of the gastrointestinal tract.
For example, the effect of acids and bases on the skin, eyes, mucous
membranes of the gastrointestinal or respiratory tract can be seen as inflammatory-necrotic damage to tissues. Local intoxication may also result into
the development of functional reactions without morphological changes.
For instance, the effect of exposure to organophosphorus compounds on
the eyes can be a narrowing of the pupil.
Systemic intoxication occurs, when a pathological process develops
with many organs and systems of the body, including those distant from
the site of contact of a toxicant. Systemic intoxication is characterized by
the entry of toxicant into the internal environment of an organism, distribution of decomposed products of integumentary tissues, as well as reflex
mechanisms.
Chemical substances to which the threshold of sensitivity of an organ
or system is much lower than that of other organs are referred to as having
selective toxicity. Such chemical substances may cause injury to specific tissues without harming others. Examples of selective toxic substances include
neurotoxicants, such as psychotomimetics; nephrotoxicants, such as mercury
salts; hepatotoxicants, such as carbon tetrachloride; and hematotoxicants,
such as arsenic hydride.
Intoxication can be categorized into mild, moderate or severe, depending on the intensity of exposure to a toxicant. Mild intoxication ends with
a complete recovery within a few days. Moderate intoxication is characteristic of the development of complications, irreversible damage to organs and
systems, leading to disability or deformity, such as a chemical burn of
the skin.
Severe intoxication is a life-threatening condition, an extreme form
of which is referred to as lethal intoxication, resulting into death of the victim. The first phase of severe intoxication, the toxicogenic stage, is
a highly specific or selective interaction of biological targets in the body
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with a toxicant at a high concentration. The toxicogenic stage is characterized by severe pathological syndromes of acute poisoning, including exotoxic shock, toxic coma, gastrointestinal disorders, asphyxia, etc. Clinically, these syndromes are treated as complications of acute poisoning,
which may result in encephalopathy, pneumonia, acute renal failure or
acute hepatorenal failure, sepsis, etc. The toxicogenic phase is also characterized with the onset of non-specific protective reactions, which
are most clearly manifested in the second phase, referred to as the somato-
genic stage.
The somatogenic stage occurs after the removal or neutralization of
toxicant in the body. The concentration of a toxic substance in the body
increases up to maximum in the stage of absorption of the substance.
At this stage, an increase in the total and toxic dose of the substance occurs
against the background of entry into the body. Due to homeostatic and
elimination capacity of the body, the concentration of substance may decrease with termination of its entry into the body. Indeed, the excretion
and metabolic processes, leading to detoxification of a biologically active
substance result in the decrease of the substance’s concentration in
the body. The process of chemical injury involves a combination of pathogenic and protective reactions, the role and significance of which may
differ at different stages. For example, protective reactions, such as hypocoagulation and fibrinolysis often turn pathogenic, requiring a corrective
measure. Such a phenomenon plays a much larger role in the development
of chemical injury than the specific effect of the toxicant that induces the
reactions.
Toxicological classification, i.e. the categorization of chemical substances by characteristics of their toxic effect, is of utmost importance for
ensuring chemical safety. This enables primary diagnosis and elucidation of
mechanisms of poisoning, as well as the development of principles for
the prevention and treatment of poisoning (Table 4.1).
However, toxicological classification is characteristically general, and
thus, additional information is usually required to determine specific toxicity
of substances (Table 4.2).
Nevertheless, data on specific toxic effect of substances is not exhaustive of all the effects of an intoxication process, but only indicates the immediate danger posed to a particular organ or system as the main site of toxic
effect.
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Table 4.1
Toxicological classification of substances
General characteristics of toxic effects
Chemical substances
Neuroparalytic (bronchospasm, uffocation,
convulsions and paralysis)
Organophosphorus compounds,
nicotine
Skin resorptive (local inflammation and necrotic
damage in combination with general toxic resorptive phenomena)
Dichloroethane, hexachlorane,
acids, arsenic and its compounds, mercury salts
Generally toxic (hypoxic convulsions, coma,
cerebral edema, paralysis)
Hydrogen cyanide and its derivatives, carbon monoxide, alcohols
Asphyxiating (toxic pulmonary edema)
Nitrogen oxides, chlorine
Lachrymatory and irritative (causing tears, irritation of outer mucous membranes)
Lachrymators, vapors of acids
and alkalis
Psychotropic (impairment of mental activity
and consciousness)
Narcotic drugs, atropine, barbitrates, lysergic acid derivatives
Table 4.2
Classification of substances by specificity of toxic effect
Characteristics of specific
toxicity
Chemical substances
Cardiotoxic effect: impairment
of rhythm and conduction of the
heart, toxic myocardial dystrophy
Cardiac glycosides; antidepressants (imipramine,
amitriptyline); plant poisons (aconite, hellebore,
quinine); animal poisons (tetrodotoxin); salts of
barium and potassium
Neurotoxic effect: impaired
mental activity, toxic coma,
toxic hyperkinesis and paralysis
Psychopharmacological agents (narcotic analgesics, tranquilizers, hypnotics); organophosphorus
compounds; carbon monoxide; hydrazine derivatives, alcohol
Hepatotoxic effect: toxic dystrophy of the liver
Chlorinated hydrocarbons; poisonous mushrooms;
phenols, aldehydes, hydrazines
Nephrotoxic effect: toxic
nephropathy
Heavy metal compounds; ethylene glycol; oxalic
acid
Hematotoxic effect: hemolysis,
methemoglobinemia
Aniline and its derivatives; Nitrites; Arsenic hydride
Gastroenterotoxic effect: gastroenteritis
Acids and bases; heavy metal compounds
Table 4.3
Mechanism of
antagonism
Antidote
Toxicant
Chemical
EDTA, unithiol, Co-EDTA,
sodium nitrite
Heavy metals, cyanides,
sulfides
Biochemical
Oxygen, cholinesterase reactivators,
reversible cholinesterase inhibitors, pyridoxine, methylene blue
Carbon monoxide, organophosphorus compounds,
hydrazine, methemoglobin-forming agents
Physiological
Atropine, aminostigmine,
flumazenil, naloxone
Organophosphorus compounds, carbamates, anticholinergics, benzodiazepines, opiates
Metabolic modification
Sodium thiosulfate,
acetylcysteine, ethanol
Cyanides, paracetamol,
methanol
4 . 2 . A n t i d o t e s
An antidote (from Greek antidotum – given against) is a medicinal sub-
stance, used in the prevention and treatment of poisoning. The action of an
antidote may be to prevent the effect of a poison, neutralize the poison, eliminate its toxic effect, normalize basic physiological functions or inhibit
the development of functional or structural disorders caused by the poison.
An antidote is specific to a particular toxicant or group of toxicants. The classification of antidotes is based on their mechanism of antagonism to toxicants
(Table 4.3). The mechanisms of action of antidotes can be chemical, biochemical, physiological, or based on the modification of biotransformation
processes. Antidotes with chemical antagonism bind directly to toxicants,
neutralizing their toxicity. This is characteristic of antidotes to freely circulating poisons in the bloodstream. Biochemical antagonists act as competitive ligands, displacing toxicants from binding with target biomolecules, and
thus, restoring normal course of biochemical processes in the body. Physio-
logical antidotes normalize the conduction of nerve impulses in synapses,
that are affected by toxicants. Metabolic modifiers either prevent the conver-
sion of xenobiotics into highly toxic metabolites or accelerate the detoxification of xenobiotics.
Mechanisms of antagonism of antidotes
76
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Antidotes are also divided into direct and indirect forms. A direct antidote
is a substance, that interacts chemically or physicochemically with a toxicant,
resulting into chemical neutralization in the case of freely circulating toxicants;
formation of a less or non-toxic complex; dissociation of a biological receptor
from the toxicant; or acceleration of excretion of the toxicant from the body.
These antidotes are in the form of sorbents, or chemical reactants. Examples of
direct antidotes include calcium gluconate against fluoride poisoning; chelating
agents against heavy metal intoxication, as well as Co-EDTA and hydroxycobalamin, which are cyanide antidotes. Monoclonal antibodies that bind cardiac
glycosides, organophosphorus compounds, as well as plant and animal toxins,
also have characteristics of direct antidotes.
The protective effect of therapeutic sorbents is based on nonspecific
fixation by sorption of toxicant molecules onto the sorbent, resulting in
the decrease of concentration of toxicant, interacting with biostructures.
This leads to a reduction of toxic effect. Sorption can be performed on
the skin, mucous membranes, in the digestive tract (enterosorption), or in the
bloodstream (hemosorption or plasma sorption). However, the use of
sorbents is ineffective in the case of toxicants that have already penetrated
into tissues. Examples of sorbents include activated carbon, kaolin (white
clay), zinc oxide, and ion-exchange resins. One gram of activated charcoal,
for instance, is capable of binding up to several hundred milligrams of strychnine, a strong poison that causes muscle spasms, respiratory failure and
death. Chemical antidotes can act at different locations in the body: before
entry of toxicant into the bloodstream, or during circulation of toxicant with
systemic blood, or after fixation of toxicant in tissues.
Examples of applications of chemical antidotes include:
– the use of salts and oxides, such as K2CO3, NaHCO3, MgO, reacting
as alkaline in aqueous solutions, to neutralize acids that have entered
the body;
– the use of NaCl in the case of poisoning with soluble silver salts, such
as AgNO3, resulting in the formation of insoluble AgCl;
– the use of MgO or ferrous sulphate, which can bind with arsenic in
the case of poisoning with arsenic-containing compounds;
– the use of hydrogen peroxide, a reducing agent, in the case of poisoning with potassium permanganate, which is a strong oxidizing agent;
– the use of weak organic acids, such as citric or acetic acid in the case
of alkali poisoning;
– the use of calcium salts in the case of poisoning with hydrofluoric acid
salts (fluorides). Calcium binds with fluorine to form slightly-soluble CaF2;
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– the use of glucose and sodium thiosulfate to bind hydrocyanic acid
(HCN) in the case of poisoning with cyanides.
Intoxication with compounds of heavy metals, such as mercury, arsenic, cadmium, antimony, etc., is one of the very dangerous forms of poisoning. These toxicants are called thiol poisons, based on their mechanism of
action, by which they bind to thiol (-SH) groups of proteins, leading to structural damage of proteins, and consequently, the impairment of metabolic processes. Thiol poisons are neutralized by dithiol antidotes (donors of
SH groups), resulting in the excretion of toxicant-antidote complex without
causing harm to the body (Fig. 4.2).
Fig. 4.2. Mechanism of action of dithiol antidote against thiol poisons
Indirect antidotes do not react with poisons themselves, but eliminate
or prevent toxic effects of poisons in the body. This may be by protection of
receptors from toxic effect. For instance, poisoning by muscarine (fly agaric
poison) and organophosphorus compounds occurs by the mechanism of
blocking cholinesterase enzyme. This enzyme is responsible for the breakdown of acetylcholine, a substance involved in the transmission of nerve impulses from the nerve to muscle tissues. Excess acetylcholine is produced, if
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the enzyme is blocked. The binding of acetylcholine to receptors gives
the signal for muscle contraction. Excess acetylcholine causes an irregular
muscle contraction; i.e. convulsions, which often lead to death. The mechanism of action of atropine, used as an antidote to muscarine, involves
the binding of atropine to acetylcholine receptors; and thus, preventing
the receptors from binding with acetylcholine, leading to muscle relaxation
and termination of convulsion.
Another form of action of indirect antidotes is the restoration or re-
placement of a biostructure damaged by poison. For example, poisoning by
fluorides and oxalic acid causes calcium deficiency by binding calcium ions.
An antidote to this kind of poisoning can be calcium chloride as replacement
for the deficiency caused.
Carbon tetrachloride poisoning, as well as exposure to excessive noise
can lead to the formation of free radicals, the excess of which in the body
causes lipid oxidation, leading to disruption of biomembrane structure.
The remedy to this form of intoxication can be antioxidants, such as tocopherol (vitamin E), that bind free radicals.
Ethanol binds better to the enzyme, alcohol dehydrogenase (ADH),
thereby inhibiting the conversion of methanol to formaldehyde and its subsequent conversion to formic acid. Methanol is, therefore, excreted unchanged from the body. Thus, ethanol acts as an antidote by a competitive
inhibition mechanism in the case of methanol poisoning.
Q u e s t i o n s & A s s i g n m e n t s
1. What factors determine the mechanism and characteristics of chem-
ical poisoning?
2. What are the stages of acute chemical poisoning?
3. Give a classification of chemical poisoning.
4. Outline the provisions of toxicological classification of chemicals.
5. What does the concept of selective toxicity of a substance mean?
6. What is the selectivity of a toxicant that acts on various plants and
animals?
7. Define antidote.
8. Discuss the application of antidotes.
9. Give examples of direct and indirect antidotes.
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5 . E C O T O X I C O L O G Y
Ecotoxicology is the study of adverse effects of pollutants in a wide
variety of species of living organisms (from microorganisms to humans),
usually at the level of populations or ecosystem as a whole. It also explores
the fate of a chemical substance in a biogeocenotic system. In the process of
studying the effects of chemical substances in the environment on humans
and human communities, environmental toxicology operates with established principles and concepts of classical toxicology, applying traditional
experimental, clinical, epidemiological methodology. Ecotoxicology studies
the mechanisms and dynamics of the phenomenon of adverse effects of
the action of toxicants and the products of their transformation in the environment.
5 . 1 . E n v i r o n m e n t a l x e n o b i o t i c p r o f i l e
Ecotoxicology covers chemical substances with bioavailability.
In other words, the focus of ecotoxicology is on substances that are capable
of being absorbed into the systemic circulation of an organism, and thus,
can interact biochemically with living organisms. These are usually chemical compounds in the form of finely dispersed solids (dust particles less
than 50 microns); and aqueous solutions, absorbed into soil or food particles and various surfaces. Some of the bioavailable compounds, in the form
of resources in the habitat of an organism, are utilized by the organism,
participating in processes of energy exchange with the environment.
Xenobiotics, entering plant and animal systems through various
routes, are not used as energy sources; however, in sufficient doses and
concentrations, they can significantly cause modification of the course of
normal physiological processes. A collection of chemical substances, contained in the environment (water, soil, air and living organisms) in a form
(state of aggregation) that enables their entry into chemical and physicochemical interactions with biological systems of the ecosystem constitute
the xenobiotic profile of the biogeocenosis. An important aspect of this
profile is the possibility of xenobiotics to get into food chains through tissues of living organisms. Solid objects, such as rocks, glass, plastics, etc.,
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