Zhukov V., Telegin
V., Zaytseva O., Alekseienko
R., Risovanaya L., Miroshnichenko N., Grankina S.
Kharkiv National Medical
University, Kharkiv, Ukraine
Potential danger of polyols new group for warm-blooded animals
Now it is clear that
human activity can lead to a profound transformation of the biosphere, which
adversely will affect on the vital functions. This requires intensification and
expansion of knowledge about the biological effects of chemicals and prognosis
ground of their potential danger for flora and fauna. Our knowledge about the
possible consequences of xenobiotics effects are limited and are inadequate for
the compounds to which people in the process of evolution had never met. This
fully applies to the products of organic synthesis, which in volume of output
and range of goods occupy a leading position in the world. These products
include polyols of grades P-373-2-20, P-5003-AC and P-294-2-35, which are
widely used in various sectors of the economy to produce polyurethanes, foamrubbers,
thermoplastics, lacquers, enamels, hydraulic, and brake fluids, epoxy resins,
plastics, artificial leather, etc. [1].
The aim of this work was to study toxicologic
and hygienic characteristics and prognosis of the potential danger to humans of
a new group of chemicals - polyols of grades P-373-2-20, P-5003- AC and
P-294-2-35.
Materials and research methods.
The research program included the study of the polyoxipropylenpolyols effect on
the warm-blooded animals under conditions of acute and subacute exposure [1-3].
Experiments were performed on adult Wistar white rats, white mouses, guinea
pigs, hybrid mouse lines BALB / C, (SBAc57BL) F1, CBA / Lac, and
rabbits of the chinchilla race [4-5]. The objects of the investigation were
polyoxipropylenthriols with molecular masses 5000M (P-5003-AC), and 370M (P-373-2-20),
and polyoxipropylated amine with molecular mass 290M (P-294-2-35). In order to
obtain toxicologic characteristics of the compounds and to substantiate features
of the mechanism of biological, action we used a set of techniques for estimation
of the status of various organs, systems and organism functions. Taking into
account that given substances have a low toxicity, haven’t high-cumulative
properties, in the subacute experiment we selected doses of 1/10; 1/100; 1/1000
DL50. DL50 for the P-373-2-20, P-5003-AC, and P-294-2-35,
respectively, is 32,3 g/kg; 36,2 g/kg and 14,8 g/kg of animal weight.
Results of research and their discussion. Experiments have shown that the test substances are low-toxic compounds
(IV class of danger), haven’t specific sensitivity and skin-irritating
properties it is coordinates with results of [5], all compounds have weak skin-resorptive
properties. Based on the coefficients of cumulation (Cc), they are
low and moderate-cumulative substances (Table 1). The mean effective time (ET50)
of the animals death was in the range of the first day of observation.
Table 1. Parameters of polyoxipropylenpolyols
toxicity
|
Substance |
Species |
DL0, g / kg |
DL50, g
/ kg |
DL100, g / kg |
ET50, h |
Cc |
|
P-373-2-20 |
white rats white mouses Guinea pigs |
70,0 20,0 20,0 |
32,3±1,4 33,5±1,7 35,0 |
45,0 45,0 45,0 |
17,3 15,8 16,7 |
6,12 - - |
|
P-5003-AC |
white rats white mouses Guinea pigs |
20,0 20,0 20,0 |
36,2±2,3 38,3±1,6 35,0 |
50,0 50,0 50,0 |
20,3 19,8 20,6 |
7,35 - - |
|
P-294-2-35 |
white rats white mouses Guinea pigs |
10,0 10,0 10,0 |
14,8±1,2 15,5±1,3 15,0 |
20,0 20,0 20,0 |
14,7 15,2 16,4 |
3,74 - - |
The clinical picture
of acute poisoning symptoms of disorders in breathing, hemodynamics and central
nervous system are dominated. Polyoxypropylenpolyols at a doses of 1/10 and
1/100 DL50 reduced the percentage of increase in body weight, contents
of erythrocytes, leucocytes, hemoglobin. Changes in the leukocyte formula of
blood are not detected. Dose of 1/1000 DL50 had no effect on the indices
of white and red blood. At the end of subacute experiment (on the 45th day of
observation) there were significantly altered activities of the creatin
phosphokinase (CPK), lactate dehydrogenase (LDG), aspartate and alanine
aminotransferases (AsAT and AlAT), alkaline phosphatase (AlP),
α-hydroxybutyrate dehydrogenase (α- GBDG),
γ-glutamattranspeptidaze (γ-GT). All compounds had a unidirectional
effect on the dynamics of the enzyme activity. In serum they increased the
activities of CPK, AsAT, AlAT, AlP, γ-GT, LDG and decreased the activity
of α-GBDG that witnesses about disorders of the redox processes in the
body and the liver, kidneys, heart fuctions, that is, organs that play a
leading role in the detoxication of xenobiotics (Table 2). Dose of 1/1000 DL50
had no effect on the dynamics of enzyme activity, which allowed to consider
this dose inoperative.
Table 2. The enzyme
activity in the subacute experiment
on the 45th day
of observation under the influence of
1/100 DL50 dose (M ± m) mcat / l
|
The enzyme |
P-5003-AC |
P-373-2-20 |
P-294-2-35 |
Control |
|
CPK |
10,46±0,35* |
9,62±0,48* |
12,30±0,43* |
5,20±0,30 |
|
LDG |
11,63±1,20* |
10,34±0,65* |
10,72+0,80* |
7,80±0,40 |
|
AsAT |
1,52±0,08* |
1,43±0,22* |
1,60±0,04* |
0,90±0,04 |
|
AlAT |
0,32±0,04* |
0,35±0,06* |
0,27±0,01* |
0,100±0,001 |
|
AlP |
10,30±0,43* |
11,25±0,56* |
9,80±0,30* |
6,30±0,20 |
|
α-GBDG |
6,54±0,15* |
5,72±0,28* |
5,43±0,20* |
9,30±0,08 |
|
γ-GT |
0,620±0,015* |
0,64+0,04* |
0,56±0,02* |
0,20±0,01 |
Note: * - difference from control is valid, p<0,05.
An important step in
hygienic regulation of harmful chemicals in the environment is to study the
effects of the genetic apparatus and the generative function. Gonadotoxic
effect of xenobiotics is studied in adult albino rats (males). Experiments have
shown that the substances in doses of 1/10 and 1/100 DL50 reduce
sperm motility, their number in the suspension of the epididymis, osmotic
stability and acid resistance of spermatozoons in the background of increasing
number of dead forms of sexual cells.
Morphological evaluation of spermatogenic
epithelium showed a reduction in the
index of spermatogenesis, the
number of tubules with the 12th
stage of meiosis, the number of normal forms of spermatogonia and the increase in the number of tubules with desquamated
epithelium (Table 3).
Table
3. Long-term sequences of polyoxipropylenpolyols effect in dose
of 1/100 DL50 in white rats (M ± m)
|
Parameter |
P-5003-AC |
P-373-2-20 |
P-294-2-35 |
Control |
|
The functional state of sperm: motility time, min |
137,2±4,8* |
141,5±6,2* |
129,8±4,5* |
168,4±7,3 |
|
The
number of spermatozoon’s,
million / ml |
14,60±1,05* |
12,3±1,2* |
11,8±1,3* |
21,4±4,4 |
|
The number of dead forms,% |
9,30±0,67* |
10,20±0,93* |
8,60±0,72* |
4,7±0,5 |
|
Osmotic stability,% NaCL |
1,86±017* |
1,9±2,2* |
2,10±0,18* |
3,70±0,15 |
|
Acid resistance, pH |
4,50±0,35* |
4,20±0,27* |
4,60±0,32* |
2,50±0,18 |
|
Morphological indicators of testicles:
the index of spermatogenesis |
2,30±0,18* |
2,80±0,22* |
2,70±0,25* |
4,20±0,16 |
|
The
number of spermatogonia |
47,20±2,65* |
49,60±1,87* |
53,40±1,54* |
69,80±3,14 |
|
The
number of tubules with the 12th stage of
meiosis |
1,90±0,23* |
2,10±0,18* |
2,20±0,26* |
4,10±0,35 |
|
The
number of tubules with desquamated epitheliumlium |
6,20±0,33* |
5,70±0,24* |
6,8±0,3* |
2,70±0,17 |
|
Embryotoxicity: the number of the living embryos |
7,10±0,36* |
7,60±0,25* |
6,80±0,37* |
10,20±0,45 |
|
The
number of resorption |
1,7±0,2* |
1,40±0,18* |
1,80±0,23* |
0,60±0,12 |
|
The
number of yellow bodies of
pregnancy |
10,5±0,8* |
11,3±0,65* |
10,90±0,60* |
11,3±0,7 |
|
Weight
of fetus, g |
2,90±0,16* |
3,1±0,2* |
3,20±014* |
3,90+0,15 |
|
Weight
of placentas, g |
0,77±0,08* |
0,78±0,06* |
0,74±0,05* |
0,51±0,13 |
|
Fetal death: |
|
|
|
|
|
before implantation |
12,4±0,6* |
13,20±1,05* |
10,4±0,8* |
5,30±0,26 |
|
after
implantation |
8,60±0,73* |
7,20±0,65* |
9,3±0,6* |
3,30±0,35 |
|
total |
21,00±0,65* |
20,40±0,83* |
19,70±0,65* |
8,60±0,29 |
|
Influence on gene
mutation: the number of cells with
chromosomic aberrations,% |
6,30±0,42* |
5,90±0,35* |
6,60±0,28* |
0,75±0,10 |
|
The
mitotic index of cells of bone marrow |
2,20±0,18* |
3,10±0,22* |
2,00±0,16* |
6,8±0,4 |
Note: * - difference from control is valid, p<0,05.
Evaluation of embryonic material obtained
at autopsy albino rats (females),
showed that the compounds in doses of
1/10; 1/100 DL50 reduced
fetal weight and increased the amount of resorptions, the weight of placenta, pre-implantatic, postimplantatic, and total fetal death, rate. Xenobiotics
in these doses did not have teratogenic effects. Determination of mutagenic activity of
polyoxipropylenpolyols detected that the test substances increased the number
of bone marrow cells with chromosomic aberrations. Among of them the single and
paired fragments, dicentrics, translocations, breaks, ring chromosomes were
frequently. The increase of chromosomic aberrations under doses of 1/10 and
1/100 DL50 was accompanied by a significant decrease in mitotic
activity of bone marrow cells (Table 3). In all cases, the dose of 1/1000 DL50
had no effect on the generative function and the genetic system of warm-blooded
animals. Toxicologic and hygienic characteristics of xenobiotics require the
study of their influence on the immune system. The results of this research
showed that the polyoxipropylenes in the doses of 1/10 and 1/100 DL50
reduce the hemolysin-producing, antibody forming, antigen-binding abilities of
immune cells and their homotransplantatic activity. In the animals of
experimental groups it was observed inhibition of functional activity of T-and
B-lymphocytes, and their cooperative interaction in the implementation of the
immune response to T-dependent antigen. At these doses the substances violated
the differentiation of immune cells, protein and nucleic acid metabolism in the
limphomyelocytes, inhibited the intensification of these processes during
antigenic stimulation and decreased endocolony formation in tissues of immune
system. The test substances in doses of 1/10 and 1/100 DL50 raised
in the organism the level of circulating immune complexes and disrupted the
morphological, biochemical and cultural properties of the microbiota of the
gastrointestinal tract. In all cases the dose of 1/10000 DL50 was
inoperative.
Analysis of the
results allowed us to obtain toxicological and hygienic characteristics and detect
the potential risk of polyoxipropylenpolyols for warm-blooded animals and
humans.
Findings
1. Polyoxipropylenpolyols
of grades P-5003-AC, P-373-2-20 and P-294-2-35 are low-toxic compounds (IV
class of danger), haven’t the specific and sexual sensitivities, as well as
skin-irritating properties, had the weak skin-resorptive properties. Based on
the cumulative coefficients they are low and moderate-cumulative substances.
The clinical picture of acute poisoning the symptoms of the disorders in breathing,
hemodynamics, and central nervous system, are dominated.
2. Substances in the
subacute experiment under the influence of 1/10, 1/100 DL50 doses
violate the redox processes, lead to the development of hypochromic anemia and
leukopenia, cause structural and metabolic desorders in liver, kidney, heart -
organs that play a leading role in the detoxication of xenobiotics.
3.
Polyoxipropylenpolyols P-5003-AC, P-373-2-20 and P-294-2-35 in doses of 1/10
and 1/100 DL50 have a toxic effect on the generatic function and the
genetic apparatus, and in doses 1/10, 1 / 100 and 1/1000 DL50
inhibit and disrupt the cooperative interaction of cellular and humoral
immunity. In all cases, the dose of 1/10000 DL50 was inoperative, it
is equal to 3.23; 3.62 and 1.48 mg / kg of animal weight, respectively, for
P-373-2-20, P-5003-AC and P-294-2- 35.
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