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Файл:Fundamentals of Toxicology. Tutorial
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21
The properties of nanomaterials can be explained in relation to the effect of their thin walls. This is observed in nanostructures, such as carbonaceous materials; in particular, nanotubes and fullerenes. In a sense, these
nanostructures are similar to polymers. The surfaces of graphite nanotube
and graphite fullerene are similar to the crystalline surface of pure graphite,
but have different topologies. The crystalline surface of a graphite crystal is
a plane, nanotube has the topology of a cylinder, and fullerene – a sphere
(Fig. 1.4).
The thickness of the walls of these structures is the diameter of their
constituent carbon atoms. This atomic thickness accounts for the unusual
chemical activity of these carbonaceous materials. It is believed that the formation of nanotubes and fullerenes does not occur in nature; and it is quite
difficult to predict the consequences of their unusual properties outside
the laboratory conditions under which they are synthesized.
a
b
c
Fig. 1.4. Structure of graphite (a), nanotube (b) and fullerene (c)
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Minor changes in the manufacturing technology of nanotubes significantly alter their characteristics. There are currently over 50,000 varieties of
nanotubes with varying degrees of toxicity. In common practice, laboratory
studies of the toxicity of a substance involves the evaluation of its effect on
a particular experimental animal. However, in the case of nanomaterials, this
approach is ineffective. The chemical and toxic properties of nanoparticles
strongly depend not only on their constituent elements, but also on the size
and structure of these particles. For instance, twisted carbon nanotubes are
reported of higher toxicity compared to dispersed carbon nanoparticles. Likewise, conclusions of some scientific studies suggest that highly crushed
nanotubes, even in small concentrations, exhibit higher toxicity than their
large clusters.
The understanding of interactions of nanostructures with living organisms is crucial within the framework of chemical safety, and ultimately, of
their impact on human health. In general, penetration of nanoparticles into the
human body can be in two ways: natural penetration is mainly associated with
the entry of dust into the organism from the environment; while artificial pen-
etration involves the introduction of nanomaterials, for example, in medicine
to visualize pathological conditions of organs, to implement targeted drug delivery or create conditions for physical or chemical effects on cancer cells.
A significant amount of nanoparticles are introduced into the body artificially
than by natural penetration. Indeed, there is currently no information on
the natural penetration pathways of nanoparticles, their distribution, metabolism, accumulation, and excretion in living organisms. The introduction of nanoparticles into the human body is usually through the skin, respiratory or
gastrointestinal tract. In comparison to the lungs and gastrointestinal tract,
the skin is the most effective barrier to this type of xenobiotic. Nanoparticles
that enter the body through the respiratory tract are absorbed into the bloodstream and get transported through tissues and organ systems. In fact, nanoparticles easily penetrate even into cells and various intracellular organelles.
The toxicity of nanoparticles depends on a number of factors, including
dose or concentration, chemical structure, particle size and shape, specific
surface area, the possibility of agglomeration of the particles, and their surface charge. The toxic effect of nanoparticles in an organism, like any other
chemical substance, is determined by individual genetic characteristics of
the organism. However, there is currently inadequate study of the kinetics,
as well as the mechanisms of intracellular distribution of nanoparticles in
living systems. Nanoparticles interact with cells, having non-specific receptors, through electrostatic attraction, steric interference, van der Waals and
23
surface tension forces, resulting into adhesion to cell surface and subsequently, penetration into the cell by passive absorption. The interactions of
nanoparticles with intracellular structures are similar to the mechanisms of
action of viruses.
Intracellular retention of nanoparticles is influenced by particle size; for
example, particles with a size of 250 to 1000 nm are localized in large cytoplasmic vacuoles, while smaller nanoparticles less than 100 nm penetrate organelles, such as mitochondria, leading to structural destruction of the organelles. Very small nanoparticles, such as fullerene molecules and metal clusters, are able to enter the cell through mechanisms other than endocytosis;
possibly, through ion channels and pores in the cell membrane. The dependence of intracellular localization of nanoparticles on their chemical properties
currently remains unclear.
Some toxicological studies have likened nanotubes to asbestos, with the
potential of causing pulmonary cancers by activating a long-term inflammatory process in the lungs. In a series of experiments, traces of free radicals,
responsible for cell damage, were found in the aorta of mice after carbon
nanotubes were injected into their lungs. The result of a similar study in mice
with genetic predisposition to atherosclerosis was the formation of a large
number of arterial plaques, responsible for the occurrence of heart attacks.
There is also a significant similarity of nanotubes with particles contained in
the exhaust emission of diesel engines, the inhalation of which impacts human health negatively. It is, however, not established if nanotubes possess
the property of the diesel engine exhaust particles to directly damage blood
vessels after absorption into the bloodstream. The establishment of such
property for nanotubes, in addition to structural similarity could be a confirmation, that the diesel engine exhaust particles are actually carbon nanotubes.
Indeed, carbon nanotubes have been found in urban air samples, as well as
in emissions from gas furnaces, indicating that these particles can be formed
in the process of combustion. Nevertheless, it is impossible to say with certainty, that the nanotubes found in the environment are identical to those synthesized in laboratory conditions, based on their impact on humans. Laboratory-synthesized nanotubes may have less impact on humans in comparison
to, for instance, soot particles because the nanotubes that are synthesized in
the laboratory differ by a significant higher degree of purity.
The extent to which the environment around us is polluted with nanoparticles remains unclear. Objects, such as windows and walls of subway
stations are often coated with various nanomaterials for antibacterial purposes, as well as for the improvement of their durability. A particular
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significance is attached to the simulation of the effect of solar radiation and
wind on tiles, coated with nanomaterials of titanium dioxide, establishing the
release of some nanoparticles from the tile coating. We are, generally, extremely cautious about highly toxic substances, the concentration of which is
not high in the environment. However, the lack of awareness of the accumulation of substances of low toxicity in large quantities in the environment
poses great danger. There is currently the talk of widespread applications of
nanotechnology as the near future. It is, however, necessary to identify and
minimize the hazard that lies in the high potential toxicity of nanomaterials
as soon as possible.
Q u e s t i o n s & A s s i g n m e n t s
1. Define toxicity.
2. Describe the mechanisms of toxic process.
3. What is a receptor? What are binding sites of receptors?
4. What do you understand by Clark’s occupancy theory?
5. With examples, explain what silent and active receptors are.
6. At what levels of organization of living systems can the toxic prop-
erties of chemical substances be observed?
7. What are toxic effects at the various levels of organization of living
systems?
8. What are ecotoxicants?
9. How does the toxicity of a substance depend on its molecular
weight?
10. How does isomerism influence the toxic properties of a compound?
11. Explain the receptor theory of toxicity.
12. List the main types of “toxicant-receptor” bonds, that characterize
the toxicity of chemical substances.
13. Explain the dependence of biological activity of toxicants on their
water- and lipid-solubility.
14. What is meant by complementarity of toxicant to receptor?
15. What are nanomaterials? What are their sizes?
16. What data are currently available on the toxicity of nanomaterials?
Give examples.
17. What factors influence the intracellular retention of nanoparticles?
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2 . T O X I C O M E T R Y
2 . 1 . T o x i c o m e t r i c p a r a m e t e r s
Toxicometric parameters (Fig. 2.1) are determined in toxicological
studies through the exposure of living systems to chemical substances.
The establishment of the maximum permissible concentration (MPC) of
harmful substances in various environments or media remains a major objective of toxicometry. MPC is the “ceiling limit” at which no changes are observed in the state of health of an organism beyond adaptive physiological
responses. MPCs of various chemical substances serve as standards that establish concentrations of harmful substances per unit volume (of air or water), mass (of food or soil), or surface area (of skin of workers), which, when
exposed to over a certain period of time, do not affect human health or cause
adverse hereditary effects in offsprings.
Fig. 2.1. Toxicometric parameters
Indeed, MPCs form the scientific foundation for the development of
legal frameworks for sanitation safety and toxico-hygiene control regulations. MPCs are established based on the concept of threshold limits of the effects of hazardous chemical substances.
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Contrary to MPC, the threshold limit value (TLV) of a hazardous substance is the minimum environmental concentration (dose) of the substance,
the exposure to which causes latent (temporarily compensated) pathology or
changes in the biological functions of an organism beyond the limits of adaptive physiological responses. Such changes occur under specific conditions
of exposure to the substance and standard statistical groupings of biological
systems. Based on the level of biological activity, TLV is categorized into
Single (acute) threshold dose (Limac), chronic threshold dose (Limch), and
(specific (selective) exposure dose (Limsp).
The degree of toxicity of a substance is usually characterized by its
toxic dose – the amount of substance per unit mass of an exposed organism
that causes a certain toxic effect. The dose per unit time is referred to as dose
level. The lower the toxic dose, the higher the toxicity. Nevertheless, the absolute value of toxic dose of a substance depends on the route of entry of
the substance into the body. Toxic doses are categorized as median lethal
dose (LD50), absolute lethal dose (LD
100
), minimal lethal dose (LD
0-10
), etc.
The index numbers represent the percentage probability of toxic effect (in
this case, death) over a two-week period observation in a group of experimental animals with a particular method of administration (oral, dermal, etc.,
except for inhalation). For inhalation, the concentration (dose) of LC50 and
LC
100
of the chemical substance causes the death of 50 % and 100 %, respectively, of experimental animals. Toxicity, as a measure of incompatibility of
a chemical substance with life, is expressed as the inverse of the absolute
value of the median lethal dose (1/LD50) or concentration (1/LC50) of the substance. The dependence of the degree of biological activity of a toxicant on
its dose (concentration) is shown in Fig. 2.1.
Toxicological parameters characterize the real hazard of acute and
chronic intoxication. The safety factor (Ks) of a chemical substance is the ratio of its threshold limit value under the condition of chronic exposure to its
maximum permissible dose. Numerically, the value of safety factor ranges
from 3 to 20. It is a measure of the margin between actual and estimated toxic
doses; and is used to reduce the value of estimated MPC of substances in
the establishment of safe sanitary regulations. Safety factor increases with:
– decreasing zone of acute toxic effect (Zac);
– increasing absolute toxicity (LD
100
);
– increasing coefficient of inhalant intoxication;
– increasing cumulative properties: cumulative coefficient, zone of
chronic toxic effect (Zch), zone of biological effect (Z
bef
);
– the development of irreversible effects.
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The safety factor of a chemical substance varies with significant differences
in sensitivity of different species of experimental animals to the substance.
For gaseous substances, the safety factor is influenced by skin-resorptive effect. The less known about the effect of a given chemical substance,
the higher the safety factor value used in establishing MPC for the substance.
The zone of single (acute) toxic effect (Zac) is inversely proportional to
the threshold dose of a toxic substance in the instance of a single (acute)
exposure:
Lim
.
This quantity corresponds to change in biological parameters of an organism
beyond adaptive physiological responses. The smaller the zone and threshold
value, the greater the risk of acute toxic effect and vice versa. A zone of toxic
effect covers a range of concentration (dose) of a toxicant; and the threshold
dose is the value of the lower boundary of the zone. The zone of chronic toxic
effect (Zch) and zone of biological effect (Z
bef
) are used to characterize
the hazard of chronic toxic effect of a chemical substance:
Lim
Lim
Lim
.
All chemical substances can be divided into four main hazard classes
(Table 2.1), based on their level of toxicity. This classification enables preliminary assessment of hazard of exposure, as well as the development of
specific safety protocols for working with different substances. The quality
of an environment in relation to human health and the state of ecosystems are
determined by sanitation, hygiene and ecological standards. These standards,
however, do not indicate source of exposure to a chemical substance, nor
regulate the impact of such exposure. The coefficient of inhalant intoxication
is the ratio of the concentration of a gaseous chemical substance in the air at
20 °C to the median lethal concentration (LC50) of the substance for mice
(with a two-hour exposure and a two-week observation period).
The estimation of changes in MPC over time is quite difficult, due to
limitations in the knowledge of safety or hazard of one chemical substance
or the other. For instance, organochlorine pesticides were considered safe
insecticides and were widely promoted for use as household chemicals in
the 1950s but were later found to be highly toxic, characterized with slow
degradation, and thus, persistent bioaccumulation.
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Table 2.1
Hazard classes of chemical substances based
on their characteristics of toxicity
Parameters
Hazard classes
I
Extremely
hazardous
II
Highly
hazardous
III
Moderately
hazardous
IV
Slightly
hazardous
MPC, mg/m3
< 0.1
0.1–1.0
1–10
> 10
LD50 by gastrointestinal tract
exposure, mg/kg body mass
< 15
15–150
150–5000
> 5000
Coefficient of inhalant
intoxication
> 300
30–300
29.9–3.0
< 3
Zone of single (acute) toxic
effect (Zac)
< 6
6–18
18.1–54.0
> 54
Zone of chronic toxic effect
(Zch)
> 10
5–10
2.5–4.9
< 2.5
Zone of biological effect (Z
bef
)
> 1000
101–1000
10.0–100.9
< 10
For chemical substances with inadequate information on their toxic effects, temporary permissible exposure limits are recommended for use for
a period of two to three years. These limits are subject to review and may
change upon the emergence of new evidence, regarding the toxicity or health
effects of a substance.
2 . 2 . R e g u l a t i o n o f t o x i c a n t s i n e n v i r o n m e n t a l
s a m p l e s
Air quality refers to a set of atmospheric properties, that determines
the degree of impact of biological, chemical and physical factors on humans,
flora, fauna, and the environment as a whole. Air quality standards define
the permissible limits for hazardous substances in industrial and residential
areas. The MPC of a harmful substance in the atmosphere of an industrial
area is its daily concentration on working days over a period of 8 hours
(or not more than 41 hours per week), that does not cause illness or changes
in the state of health of a person throughout his entire working experience or
in the long-term, the person’s life and his subsequent generations. A working
area is considered to be a space up to 2 meters high above floor level or an
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area of permanent or temporary stay of workers. Industrial MPC (MPC
ind
) is
the standard of exposure limit of an adult working population to a hazardous
chemical substance within an industrial zone over a period of time, established by labor legislation. As a rule, the levels of pollution of residential
areas are never compared with those of industrial areas. Thus, the atmospheric MPC of a chemical substance is always discussed within the context
of a specific standard. For instance, the random or one-time (MPC
rand
) of
a substance refers to the concentration of the substance in the atmosphere of
a populated area, such that 20 minutes inhalation of the air will not cause
reflex (including subsensory) reactions. Average daily MPC (MPC
avd
) is
the concentration of a hazardous chemical substance in the atmosphere of
a populated area, the inhalation of which does not have a direct or indirect
effect on a person over a long-term period (in years). Table 2.2 shows different types of MPC in the air for some substances.
Table 2.2
Values of different types of atmospheric MPC for some substances
Substance
MPC
avd
, mg/m3
MPC
rand
, mg/m3
MPC
ind
, mg/m3
Nitrogen (II) oxide
0.06
0.60
30.00
Cobalt (II) sulfate
0.0004
0.001
0.005
4-Chloraniline
0.01
0.04
0.30
The most stringent sanitary and hygiene standard that establishes
the concentration of a harmful substance in the air is MPC
avd
, as it applies
to exposure limit over an indefinitely long period for all groups of the population.
Water quality refers to the composition and properties of water, that
determine its suitability for a specific use. For instance, drinking water must
be safe in chemical composition and must have favorable organoleptic properties. A good quality drinking water must be colorless, odorless and tasteless. The sanitary standards for the assessment of water quality include chemical, microbiological and physical indicators. The safety of water in terms of
chemical composition involves the absence of toxic chemical substances and
the content of non-toxic substances within the limits of established standards.
Water quality assessment is further carried out based on microbial count per
unit volume and physical properties, such as temperature, particle count,
transparency or turbidity, etc. The standard MPC for water, MPCw is the concentration of a harmful substance, that does not diminish the sanitary and
hygiene conditions of drinking water, as well as water for domestic and
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recreational use, and has no direct or indirect adverse effect on the health of
a person and his subsequent generations. For fishery, MPCwf is the concentration of a harmful substance in water, which does not adversely affect fish
populations. In Table 2.3, the values of MPCw and MPCwf for different chemical substances are compared.
The normalization or standardization of chemical components in soil is
based on the principle of entry of chemical substances into the body through
trophic (food) chains, occurring mainly through contact with soil environments. The MPC of arable layer of soil (MPCs) is the concentration of
a harmful substance in the upper, arable layer of the soil, which does not have
a direct or indirect adverse effect on the environment in contact with the soil
and on human health, as well as on soil self-cleaning capacity.
Table 2.3
Comparison of two forms of maximum permissible concentration
in water for different chemical substances
Substance
MPCwf, mg/dm3
MPCw, mg/dm3
Inorganic mercury compounds
0.0001
0.0005
Ammonium fluoride
0.05
0.7
Triethanolamine (TEOA)
0.01
1.0
The development of standard MPC of harmful substances in food involves review of toxicological data, sanitary and hygiene standards of these
substances in various environmental samples of air, water and soil, in addition to the real content of various chemical elements in food products.
The permissible residual amount of a harmful chemical substance in food
(MPCf) is the concentration of the substance in food, which for an indefinite
long period of daily exposure does not impair human health.
Through metabolism and energy transfer with the environment,
the human body, as well as any biological system, is an open system into
which substances enter and from which substances are excreted. In this
context, the acceptable daily intake (ADI) of a substance is an estimated
rate of entry of the substance into the body daily under conditions of continued exposure of a lifetime without a significant health risk or disruption
of an organism’s homeostasis. Similarly, the acceptable weekly intake
(AWI) of a substance is the rate of entry of the substance into the body,
estimated over a period of one week (7 days), under conditions of continuous life-long exposure without an appreciable risk to health. Both the ADI
and AWI serve as guidelines for establishing regulatory limits of
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