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Файл:Fundamentals of Toxicology. Tutorial
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the amount of chemical substances in food, water and other edible products. This ensures safe levels of human exposure to potential harmful substances based on current scientific knowledge.
2 . 3 . D o s e - e f f e c t r e l a t i o n s h i p s
The effect of chemical substances on biological systems based on
the concentration (dose) of the substance can be represented graphically
(Fig. 2.2).
Fig. 2.2. Dose-effect curve for substances а, b, с
Dose-effect relationships of chemical substances are mostly non-linear;
and are graphically exponential, hyperbola, parabola or sigmoid curves.
These curves represent qualitative and quantitative properties of the interaction of a harmful substance with a biological system under specific conditions. Different regions of the dose-effect curve of a chemical substance
represent either a significant increase or decrease in the effect of varying levels of exposure to the substance. In order of increasing effect, the arrangement of substances a, b, c varies in different zones of the “dose-effect” curves
(Zone I: a > b > c; Zone II: b > a > c; Zone III: b > c > a; Zone IV: c > b > a).
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Thus, the result of a comparative analysis of the toxicity of substances based
on lethality levels may vary with the zone of the dose-effect curves within
which the analysis is performed. In this circumstance, it is important to study
all zones of the dose-effect curves.
There has been significant progress in the quantitative characterization
of dose-effect functions for ionizing radiation. However, these functions are
not well-known for toxic chemical substances. Some progress has been made
in establishing dose-effect functions for human exposure to carcinogenic
chemical substances. So far, these functions have been established in
the form of lifetime risk coefficients, normalized per unit concentration of
a substance in a human habitat.
The effects of a chemical substance always depend on its dose in
the body. Dose-effect curves characterize the relationship between the dose
of a chemical substance and the biological response of an organism to
the substance. The threshold effect of exposure to a chemical substance is
the induced biological response by the substance at the lowest effective dose
(i.e., the threshold concentration, below which the substance does not cause
any adverse effect). Graphically, biological response functions of exposure
to chemical substances above the threshold level are typically sigmoid
curves, having a characteristic S-shape (Fig. 2.3). According to the dose-response function, no metabolic changes occur until a critical concentration,
called practical threshold is reached. The practical threshold represents
the dose boundary, which when exceeded, results in the onset of a significant
toxic effect above existing background level of responses.
The possible reactions (responses) of an organism to specific chemical
substances are represented by four main curves in Fig. 2.3. Curves 2, 3, and
4 refer to non-threshold dependencies, that are characteristic of low toxic effects, including low non-chemical effects, which are often undetected, and
are attributed to supersmall doses of chemical substances. These curves also
represent stochastic health effects. The most widely used is “curve 3”, which
is a linear non-threshold dose-effect relationship, since the assessment of
dose-effect relationships in the region of small concentration values is often
done by linear extrapolation from the region of large concentrations.
In the development of exposure limit standards, this linear relation remains
officially recognized and is recommended by international organizations for
estimations in risk assessments.
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Fig. 2.3. Dose-response relationship of chemical substances
The nonlinear (sublinear) dose-effect relationship with a downward
convexity (curve 4) is characteristic of biological responses to multi-factorial
exposures. Although curve 4 does not have a well-defined threshold,
the point on the dose axis at which a response (above background effect) can
be detected signifies the practical threshold. The guidelines for establishing
occupational exposure limits are often based on sets of practical threshold
values with definite safety factors.
The nonlinear (supralinear) dose-effect relationship with an upward
convexity (curve 2) is characteristic of large disproportionate effects caused
by small doses. This kind of dose-effect relation for small doses of radiation
has been observed in the population exposed to the Chernobyl nuclear accident that occurred on April 26, 1986.
Biological responses to toxicant exposure are categorized into thresh-
old and non-threshold effects. Threshold effects are responses of varying severity to large doses of radioactive substances, physical factors, and non-carcinogenic toxicants. Non-threshold effects include carcinogenic and genetic
effects caused by mutagens on the human genome, or by radiation exposure
in small doses. However, assessments of the lethal risk of non-carcinogenic
substances often apply conservative assumptions of non-threshold property,
using linear dose-effect relationships.
Toxic processes at the organismic level of biological organization are
also grouped by threshold and non-threshold principles. According to
the threshold principle, the cause-effect relationship between the toxic effect
of a substance and the progression of a toxic process is definite and
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predictable. That is, the development of a toxic process occurs only at concentrations of a chemical substance above the threshold level; and the significance of the toxic process increases with increasing dose. For processes that
develop according to the non-threshold principle, the cause-effect relationship between the toxic effect of a substance and the development of a toxic
process is probabilistic. The probability of the occurrence of a toxic effect
may be preserved, when an organism is exposed to even one molecule of
a toxicant; however, the toxic process may not develop in another individual
organism that is exposed to a significantly high dose of the toxicant.
The dose dependence of the severity of damaging effect of a substance,
as a rule, is determined at the population level. In this instance, the frequency
of toxic effect in individuals of a test group increases with increasing dose of
the substance. Major toxic effects that are often observed in populations include the development of malignant neoplasms of tissues and organs, as well
as genetic disorders in subsequent generations. These toxic effects are stochastic or probabilistic in nature. The evaluation of very low toxic effects of
small doses of a substance, which cannot be measured directly, is done by
extrapolation of a known dose-effect relationship of medium and large doses
of the substance, based on appropriate hypotheses and models. This approach
is considered safe, since the estimation of toxic effects, based on a linear
dose-effect is most likely to be slightly overestimated.
In general, the dose-effect relationship (taking into account the biological response of an organism to the toxic action of medium and large doses
of a substance) for induced malignant neoplasms can be represented by the
following expression:
F(D) = (a0 + a1D + a2D2) (– A1D – A2D2),
where F(D) is the additional incidence of cancers (or their specific forms,
characteristic of a particular organ); a0, a1, A1, A2 are parameters; D is dose
for the whole body (or a specific organ).
In the region of small doses, as a rule, this expression is reduced either
to a linear form: F(D) = a1D, or linear-quadratic form: F(D) = a1D + a2D2.
In addition to the dose-response function, the exposure-effect relationship is also used in risk assessment. Exposure level is expressed as the concentration of a harmful substance in a particular environment, such as air,
soil, and water. It is more convenient to use the concept of exposure than
dose in risk assessment, since the concentration of a harmful substance in
environmental samples can be more easily obtained than dose in an organism.
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Nevertheless, there can be the limitation of non-correlation of exposure level
to dose, which is the main parameter on which, ultimately, damage to human
health depends. At a definite level of exposure, characterized, for example,
by the concentration of a harmful substance in the air, the dose can depend
on different factors, including rate of respiration, as well as the metabolic and
pharmacokinetic processes that the harmful substance undergoes. Furthermore, the dose may not directly be due to the substance that is contained in
the consumed air but to its metabolites. For example, the carcinogenic effects
of exposure to benzo(a)pyrene are caused not by benzo(a)pyrene itself but by
its metabolites.
2 . 4 . C h a r a c t e r i s t i c s o f c o m b i n e d a n d c o m p l e x
t o x i c e f f e c t s
Normalization or standardization to ensure chemical safety considers
various routes of entry of toxicants into the body. This, however, rarely reflects the combined toxic effect of chemical substances; that is, the simultaneous or sequential effect of several substances with the same route of entry.
It also does not take into account the effects of complex toxic effect, occurring
from the intake of harmful substances into the body through different routes
of entry from different sources. There is, however, a limited number of substances that exhibit summation effect with their simultaneous presence in atmospheric air.
The recurrence of exposure of biological systems to toxicants results in
complicated toxic effects, occurring with two simultaneous processes of cu-
mulation and adaptation. Cumulation is the phenomenon of gradual accumu-
lation of a chemical substance in the body, when the intake rate of the substance exceeds its excretion rate from the body. The increase in modifications
of a biological system due to repeated exposure to substances is called func-
tional cumulation. The accumulation of minor modifications without complete restoration of impaired functions of the biological system results in
a pathological process. Cumulation, such as the accumulation of radioactive
strontium in skeletal tissues, iodine in the thyroid gland, heavy metals in
the kidneys, organochlorine pesticides in adipose tissue, etc., can occur from
the complexation of the toxicant and its strong binding to a receptor in
the body. A greater specificity of cumulation is observed in complex
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systems, having the ability to pre-concentrate elemental toxicants. The effect
of pre-concentration can be analyzed along trophic (food) chains. For example, mass mercury poisoning of food of the Minamata Tragedy of the late
1950s in Japan reveals, that during transition in the trophic chain of water –
plankton – fish – poultry – human, the concentration of mercury increased
105 times, i.e. 10 times for each link in the chain. Cumulation of a chemical
substance is determined by its cumulation factor, which is the ratio of the total dose of the substance that causes a toxic (lethal) effect in 50 % of experimental animals with multiple dosing regimen of administration, to the dose
that causes the same effect with a single exposure.
.
The value of a cumulation factor, close to one indicates an acute cumulative
effect; while a value greater than five represents a weak cumulative effect.
The adaptation of an organism to the toxic effect of a chemical substance is the physiological adjustment or modification of the organism to
changing environmental conditions caused by the chemical substance.
This modification occurs without irreversible disruption of the biological
system nor exceeding the homeostatic ability of the organism. The adaptation
of an organism to changing environmental conditions in excess of normal
homeostatic capacity is referred to as compensation (pseudo-adaptation).
This is a temporary hidden pathology, which can be discovered as an overt
pathology (decompensation) over time. Thus, the adaptation of an organism
to the environment by compensation is at a cost of damage to the organism’s
homeostasis. Adaptation can be referred to as a decrease or elimination of
response to the exposure of a chemical substance after a period of its toxic
effect (Fig. 2.4).
After adaptation, toxic effect may occur again due to increase in the
dose (concentration) of an impacting substance. In this regard, repeated adaptation can be seen as a mechanism of resistance to chronic poisoning.
In some cases, for example, with allergic reactions, the sensitivity of an organism increases with exposure to the allergen (a chemical substance); a phenomenon referred to as sensitization. Many drugs, especially antibiotics, agrochemicals, such as pesticides, have sensitizing effects.
The combined effect of chemical substances on an organism may lead
to the phenomenon of summation (additivity), potentiation (synergism), or
antagonism (Fig. 2.5).
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Fig. 2.4. Phases of adaptation to chemical exposure by inhalation:
1 – constant concentrations (doubled threshold acute effect);
2 – intermittent effect (exposures with consistent breaks); 3 – random
fluctuating concentrations
Fig. 2.5. Combined effect of chemical substances: 1 – summation
(additivity); 2 – potentiation (synergism); 3 – antagonism
Summation or additivity refers to the joint toxic effect induced by
a mixture of chemical substances based on the sum of the fractions of effects
of the individual components of the mixture. Potentiation or synergism occurs, when a chemical substance does not elicit a toxic effect on its own but
enhances the toxic effect of another chemical substance. Antagonism refers
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to the phenomenon, whereby the combined effect of two or more chemical
substances is less than the sum of their individual effects. Antagonism is
the opposite of synergism. Combined effect can occur through both acute and
chronic exposure to toxicants. Additive effect is observed for exposure to
narcotic substances and irritating gaseous substances, such as chlorine and
nitrogen oxides, or nitrogen oxides and sulfur dioxide.
Synergism may be caused by the inhibition of the metabolic processes of
a substance by another substance. For instance, the inhibition of detoxification
of acetylcholine, resulting in its accumulation, is caused by the suppression of
cholinesterase by organophosphorus compounds. Physical factors, such as elevated temperature and high humidity also contribute to increasing sensitivity to
toxicants, and thus, to the enhancement of their toxic effects.
Antagonism can occur by the combined effect of harmful substances
with same mechanism of action. For example, high concentrations of ethanol
reduce the toxic effect of methanol due to the competition of metabolism of
these alcohols in the body.
Ensuring chemical safety requires consideration of the possible complex toxic effect of chemical substances from different sources and different
routes of entry into the body; i.e. through the respiratory tract with inhaled
air, the gastrointestinal tract with food and water, and through the skin.
In the instance of combined toxic effects, particularly for additivity, permissible exposure limits of individual chemical substances are established by the
relation below:
,
where n is the number of chemical substances, giving a combined toxic effect; Ci is the concentration of individual chemical substances; and MPCi is
the maximum permissible concentration of individual chemical substances.
Q u e s t i o n s & A s s i g n m e n t s
1. How are toxicometric parameters determined in toxicological studies?
2. Explain the concept of maximum permissible concentration of
a chemical substance in the environment.
3. Which toxicological parameters are the basis for establishing MPCs?
4. Explain the types of toxic doses in toxicological studies.
5. Which toxicometric indicators characterize the risk of developing
acute or chronic poisoning?
6. Give a description of the hazard classes of chemicals, depending on
the toxicometric indicators.
7. Define the zone of chronic effect of a chemical substance.
8. Define the threshold limit for the chronic effect of a chemical sub-
stance.
9. Define the zone of acute effect of a chemical substance.
10. Which MPCs are used for the normalization and standardization of
water quality?
11. Which MPCs are designated for soil and food?
12. What are the values of permissible daily intake of chemical sub-
stances used for?
13. Why is it necessary to study dose-effect relationships for biologi-
cally active substances?
14. What is the difference between threshold and non-threshold effects
of exposure to toxicants?
15. What is meant by the phenomenon of cumulation? What
characterizes functional cumulation?
16. Describe the phenomena of adaptation, compensation, antagonism,
synergism in the exposure to chemical substances.
17. What is meant by the combined effect of toxicants?
18. What is the meaning of LD
values of chemical substances?
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3 . T O X I C O K I N E T I C S
3 . 1 . I n t e r a c t i o n o f t o x i c a n t s
w i t h b i o l o g i c a l s y s t e m s
Toxicokinetics is the study of principles of absorption, distribution, biotransformation and excretion of toxic chemical substances in a biological
system, following exposure (Fig. 3.1). The human body is a complex heterogeneous system, consisting of a large number of compartments: blood, extracellular fluid, intracellular components, muscle tissue, with various properties, separated from one another by biological barriers.
Fig. 3.1. Interaction of living organisms with toxicants
The movement of toxic chemical substances between the various compartments is described in the cross-sectional scheme presented in Fig. 3.2.
Among the barriers are cell and intracellular membranes, as well as integumentary tissues, such as skin and mucous membranes. The absorption, distribution and excretion of toxicants involve processes of mixing, dissolution
in the bioenvironment, diffusion, osmosis, and filtration through biological
barriers. The toxicokinetic parameters of a chemical substance are influenced
by the substance’s:
– coefficient of distribution in an oil-water separation system, which
determines the ability of the substance to accumulate in a fat-soluble medium
(lipid) or aqueous medium (water);
– molecular size, which affects the ability of the substance to diffuse in
a medium and penetrate through the pores of biological membranes or barriers;
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